AHN YU MI (US)
VOGETI LAKSHMINARAYANA (US)
LE BOURDONNEC BERTRAND (US)
WO2020230028A1 | 2020-11-19 | |||
WO2014151616A1 | 2014-09-25 | |||
WO2022060996A1 | 2022-03-24 |
WANG PENG-FEI ET AL: "A patent review of BRAF inhibitors: 2013-2018", EXPERT OPINION ON THERAPEUTIC PATENTS, vol. 29, no. 8, 13 July 2019 (2019-07-13), GB, pages 595 - 603, XP093021109, ISSN: 1354-3776, DOI: 10.1080/13543776.2019.1640680
CARREIRAKVAEMO: "Classics in Stereoselective Synthesis", 2009, WILEY-VCH
CLAIMS WHAT IS CLAIMED IS: 1. A compound represented by Formula I: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: each of X1 and X4 is independently selected from CR3 and N; X2 is selected from the group consisting of N, CH, C=O, C-O-L2-E2, C-L2-E2, C-N(R4)-L2-E2, and N-L2-E2; X3 is selected from the group consisting of CH, C-L3-E3, C-O-L3-E3, C-N(R4)- L3-E3, C=O, N, and N-L3-E3; provided that not more than two of X1, X2, X3, and X4 are N; when X2 is N, X3 is selected from the group consisting of CH, C-L3-E3, C-O-L3-E3, C-N(R4)-L3-E3, and N; when X3 is N, X2 is selected from the group consisting of N, CH, C-O- L2-E2, C-L2-E2, and C-N(R4)-L2-E2; when X2 is C=O, X3 is N-L3-E3; when X3 is C=O, X2 is N-L2-E2; X5 is independently selected from the group consisting of CH, CF, and N; X6 is independently selected from the group consisting of CH, and CF; L1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E11)m; L2 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E21)p; L3 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E31)p; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; E1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone,optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E11, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and optionally substituted heterocyclyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E21, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E21 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E3 is selected from the group consisting of hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E31, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E31 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; U is an optionally substituted heteroaryl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH2)mNH-; wherein the optionally substituted heterocyclyl or heterocyclyl(CH2)mNH-, at each occurrence, is independently optionally substituted with one or more occurrences of R9; R1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano, and halogen; R2 is selected from the group consisting of H and F; R3, at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R4, at each occurrence, is independently selected from H and alkyl; R9, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each occurrence of p is independently 0, 1, or 2; and each occurrence of m is independently 0, 1, 2, 3, or 4; with the proviso that when X1 and X2 are N, each of X5 and X6 is independently selected from CH and CF, X4 is CR3, R3 is selected from H and alkyl, X3 is C-L3-E3, and L3 is a direct bond, E3 is not morpholinyl; or when X1 and X4 are N, each of X5 and X6 is independently selected from CH, and CF, X2 is C-L2-E2, L2 is a direct bond, E2 is selected from H and alkyl, X3 is C-L3- E3, and L3 is a direct bond, E3 is not morpholinyl; or when X2 is selected from C-O-L2-E2 and C-N(R4)-L2-E2, R4 is H, and each L2 is a direct bond, each E2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when X3 is selected from C-O-L3-E3 and C-N(R4)-L3-E3, R4 is H, and each L3 is a direct bond, each E3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when L1 is direct bond, then E1 is not N-bound heterocyclyl; when X6 is CH, X5 is CH or CF, X4 is CR3, X3 is N, Q is -C(O)NH-, L1 is direct bond, and E1 is selected from the group consisting of C3-C8 cycloalkyl, C2-C8 heterocyclyl, C6-C14 aryl, and C1-C9 heteroaryl, X2 is not C-N(R4)-L2-E2; or when Q is -C(O)-NH- and L1 is direct bond, E1 is not H; or when Q is -NH-C(O)-, L1-E1 is not unsubstituted methyl; or when X3 is N, X1 is CH or N, X4 is CH, X5 and X6 are CH, X2 is CH or C-NH2, and Q is -C(O)-NH-, then L1-E1 is not alkyl substituted with amine. 2. A compound represented by Formula I-AA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E11)m; E1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L1 is a direct bond and E1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E11, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R9; R1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 is selected from the group consisting of H and F; R3, at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R9, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. 3. A compound represented by Formula I-AB: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X3 is selected from the group consisting of C-L3-E3, C-O-L3-E3, and C-N(R4)- L3-E3; X5 is selected from the group consisting of N, CH, and CF; L3 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E31)p; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E11)m; E1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L1 is a direct bond and E1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E11, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E3 is selected from the group consisting of hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted monocyclic heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, and optionally substituted cycloalkyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E31, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E31 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R9; R1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 is selected from the group consisting of H and F; R3, at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R4, at each occurrence, is independently selected from H and alkyl; R9, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; and each m is independently 0, 1, 2, 3, or 4. 4. A compound represented by Formula I-AC: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E11)m; E1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, sulfone, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L1 is a direct bond and E1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E11, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R9; R1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 is selected from the group consisting of H and F; R3, at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R9, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. 5. A compound represented by Formula I-BA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E11)m; E1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L1 is a direct bond and E1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E11, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R9; R1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 is selected from the group consisting of H and F; R3, at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R9, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. 6. A compound represented by Formula I-CA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E11)m; E1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L1 is a direct bond and E1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E11, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R9; R1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 is selected from the group consisting of H and F; R3, at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R9, at each occurrence, is independently selected from the group consisting of is selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. 7. A compound represented by Formula I-DA: Formula I-DA or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E11)m; E1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L1 is a direct bond and E1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E11, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R9; R1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 is selected from the group consisting of H and F; R3, at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R9, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. 8. A compound represented by Formula I-DB: Formula I-DB or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X3 is selected from the group consisting of C-L3-E3, C-O-L3-E3, and C-N(R4)- L3-E3; X5 is selected from the group consisting of N, CH, and CF; L3 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E31)p; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E11)m; E1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L1 is a direct bond and E1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E11, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E3 is selected from the group consisting of hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted monocyclic heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, and optionally substituted cycloalkyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E31, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E31 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R9; R1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 is selected from the group consisting of H and F; R3, at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R4, at each occurrence, is independently selected from H and alkyl; R9, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and each m is independently 0, 1, 2, 3, or 4. 9. A compound represented by Formula I-EA: Formula I-EA or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E11)m; E1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L1 is a direct bond and E1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E11, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R9; R1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 is selected from the group consisting of H and F; R3, at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R9, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. 10. A compound represented by Formula I-EB: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X3 is N-L3-E3; X5 is selected from the group consisting of N, CH, and CF; L3 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E31)p; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E11)m; E1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L1 is a direct bond and E1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E11, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E3 is selected from the group consisting of hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, and optionally substituted cycloalkyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E31, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E31 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R9; R1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 is selected from the group consisting of H and F; R3, at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R9, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; and each m is independently 0, 1, 2, 3, or 4. 11. A compound represented by Formula I-FA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E11)m; E1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L1 is a direct bond and E1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E11, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R9; R1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 is selected from the group consisting of H and F; R3, at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R9 is selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. 12. A compound represented by Formula I-GA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E11)m; E1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L1 is a direct bond and E1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E11, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R9; R1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 is selected from the group consisting of H and F; R3, at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R9, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. 13. A compound represented by Formula I-HA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E11)m; E1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L1 is a direct bond and E1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E11, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R9; R1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 is selected from the group consisting of H and F; R3, at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R9, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. 14. A compound represented by Formula I-JA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E11)m; E1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L1 is a direct bond and E1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E11, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R9; R1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 is selected from the group consisting of H and F; R9, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. 15. A compound represented by Formula I-KA: Formula I-KA or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E11)m; E1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl,the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L1 is a direct bond and E1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E11, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R9; R1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 is selected from the group consisting of H and F; R3, at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R9, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. 16. A compound represented by Formula I-LA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E11)m; E1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L1 is a direct bond and E1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E11, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R9; R1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 is selected from the group consisting of H and F; R3, at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R9, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. 17. A compound represented by Formula I-NA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E11)m; E1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L1 is a direct bond and E1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E11, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R9; R1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 is selected from the group consisting of H and F; R3, at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R9, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. 18. A compound represented by Formula I-OA: Formula I-OA or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; E1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L1 is a direct bond and E1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E11, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R9; R1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 is selected from the group consisting of H and F; R3, at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R9, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. 19. A compound represented by Formula I-PA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E11)m; E1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L1 is a direct bond and E1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E11, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R9; R1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 is selected from the group consisting of H and F; R3, at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R9, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. 20. A compound represented by Formula I-QA: Formula I-Q or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E11)m; E1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L1 is a direct bond and E1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E11, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R9; R1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 is selected from the group consisting of H and F; R3, at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R9, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. 21. A compound represented by Formula I-RA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: each of X1 and X4 is independently selected from CR3 and N; each of X2 and X3 is independently selected from the group consisting of N and CH; provided that not more than two of X1, X2, X3, and X4 are N; each of X8, X9, and X10 is independently selected from CR3 and N; X5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E11)m; E1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L1 is a direct bond and E1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E11, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; R1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 is selected from the group consisting of H and F; R3, at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; and each m is independently 0, 1, 2, 3, or 4. 22. A compound represented by Formula I-SA-i or Formula I-SA-ii: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: each of X1 and X4 is independently selected from CR3 and N; X2 and X3 are each independently selected from the group consisting of N and CH; provided that not more than two of X1, X2, X3, and X4 are N; X5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E11)m; E1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L1 is a direct bond and E1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E11, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; R1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R2 is selected from the group consisting of H and F; R3, at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; and each m is independently 0, 1, 2, 3, or 4. 23. The compound of any one of claims 2-20, wherein Z is -NHC(O)R6, -NHC(O)OR6, or -C(O)NHR7, wherein R6, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, wherein each of alkyl and cycloalkyl is optionally substituted with one or more independent occurrences of R8, and the heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and R7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, wherein each of alkyl and cycloalkyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl, and the heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and R8 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl, wherein each of alkyl and cycloalkyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl, and the heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. 24. The compound of any one of claims 2-20 and 23, wherein Z is -NHC(O)R6, wherein: R6, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, wherein each of alkyl and cycloalkyl is optionally substituted with one or more independent occurrences of R8, and the heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and R8 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl, wherein each of alkyl and cycloalkyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl, and the heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. 25. The compound of any one of claims 2-20 and 23, wherein Z is -C(O)NHR7, wherein: R7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, wherein each of alkyl and cycloalkyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl, and the heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. 26. The compound of any one of claims 2-20 and 23, wherein Z is -NHC(O)OR6, wherein R6, at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, wherein each of alkyl and cycloalkyl is optionally substituted with one or more independent occurrences of R8, and the heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and R8 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl, wherein each of alkyl and cycloalkyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl, and the heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. 27. The compound of any one of claims 1-26, wherein Q is -NH-C(O)-. 28. The compound of any one of claims 1-26, wherein Q is -C(O)-NH-. 29. The compound of claim 1, wherein X1, X4, X5, and X6 are each CH; X2 is N; and X3 is selected from the group consisting of CH, C-L3-E3, C-O-L3-E3, C-N(R4)-L3-E3 and N. 30. The compound of claim 1, wherein X1, X4, X5, and X6 are each CH; X2 is CH; and X3 is selected from the group consisting of CH, C-L3-E3, C-O-L3-E3, C-N(R4)-L3-E3 and N. 31. The compound of claim 21, wherein X1, X4, and X5 are each CH; X2 is CH; X8 is N; and X3 is selected from the group consisting of CH, C-L3-E3, C-O-L3-E3, C-N(R4)-L3-E3 and N. 32. The compound of claim 1, wherein X1 is CR3; X2 and X4 are each N; X3 is selected from the group consisting of CH, C-L3-E3, C-O-L3-E3, and C-N(R4)-L3-E3; X5 is CH or N; and X6 is CH. 33. The compound of claim 21, wherein X1 and X4 are each CR3; X3 is selected from the group consisting of CH, C-L3-E3, C-O-L3-E3, C-N(R4)-L3-E3, and N; X8 is N; and X2, X5, and X6 are CH. 34. The compound of claim 1, wherein X1 and X4 are each CR3; X3 is selected from the group consisting of CH, C-L3-E3, C-O-L3-E3, C-N(R4)-L3-E3, and N; X5 is N; and X2 and X6 are CH. 35. The compound of claim 21, wherein X1 and X4 are each CR3; X3 is selected from the group consisting of CH, C-L3-E3, C-O-L3-E3, C-N(R4)-L3-E3, and N; X5 and X8 are N; and X2 and X6 are CH. 36. The compound of claim 1, wherein X1 is CR3 and X3 is selected from the group consisting of CH, C-L3-E3, C-O-L3-E3, and C-N(R4)-L3-E3; X2 and X4 are N; and X5 and X6 are CH. 37. The compound of claim 1, wherein X1 is CR3; X4 is CR3 or N; X3 is N-L3-E3; X2 is C=O; and X5 and X6 are CH. 38. The compound of claim 1, wherein X1 and X4 are CR3; X3 is C=O; X2 is N-L2-E2; and X5 and X6 are CH. 39. The compound of claim 1, wherein X1 and X4 are CR3; X2 is N; X3 is selected from the group consisting of CH, C-L3-E3, C-O-L3-E3, C-N(R4)-L3-E3 and N; and X5 and X6 are CH. 40. The compound of claim 1, wherein X1 and X2 are N; X4 is CR3; X3 is selected from the group consisting of CH, C-L3-E3, C-O-L3-E3, and C-N(R4)-L3-E3; and X5 and X6 are CH. 41. The compound of claim 1, wherein X1 and X4 are N; X5, and X6 are each CH; X2 is selected from the group consisting of CH, C-L2-E2, C-O-L2-E2, C-N(R4)-L2-E2; and X3 is selected from the group consisting of CH, C-L3-E3, C-O-L3-E3, and C-N(R4)-L3-E3. 42. The compound of claim 1, wherein X1 and X3 are N; X4 is CR3, X5 and X6 are each CH; and X2 is selected from the group consisting of CH, C-L2-E2, C-O-L2-E2, and C-N(R4)- L2-E2. 43. The compound of claim 1, wherein X1 is N; X4 is CR3; X5 and X6 are each CH; X2 is selected from the group constating of CH, C-L2-E2, C-O-L2-E2, and C-N(R4)-L2-E2; and X3 is selected from the group consisting of CH, C-L3-E3, C-O-L3-E3, and C-N(R4)-L3-E3. 44. The compound of claim 1, wherein X1 is CR3; X2 and X6 are CH; and X3, X4, and X5 are N. 45. The compound of claim 1, wherein X1 is CR3; X2, X5, and X6 are CH; and X3 and X4 are N. 46. The compound of claim 21, wherein X1 is CR3; X2, X5, and X6 are CH; and X3, X4 and X8 are N. 47. The compound of any one of claims 1, 3, 8, 29-37, 39-41, and 43, wherein E3 is selected from the group consisting of H, alkyl, and cycloalkyl, wherein cycloalkyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano. 48. The compound of any one of claims 1, 3, 8, 29-37, 39-41, and 43, wherein E3 is selected from the group consisting of hydroxy, alkoxy, and cyano. 49. The compound of any one of claims 1, 3, 8, 29-37, 39-41, and 43, wherein E3 is heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl. 50. The compound of any one of claims 1, 38, and 41-43, wherein E2 is selected from the group consisting of H, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl, alkyl, amine, haloalkoxy, haloalkyl, and sulfonyl. 51. The compound of any one of claims 1-50, wherein R1 is selected from the group consisting of H, alkyl, haloalkyl, and halogen. 52. The compound of any one of claims 1-51, wherein R1 is selected from the group consisting of methyl and fluorine. 53. The compound of any one of claims 1-52, wherein R2 is selected from H and F. 54. The compound of any one of claims 2-20 and 23-53, wherein the Z-substituted ring is selected from the group consisting of . 55. The compound of any one of claims 2-20 and 23-53, wherein the Z-substituted ring is selected from the group consisting of . 56. The compound of any one of claims 2-20 and 23-53, wherein the Z-substituted ring is selected from the group consisting of . 57. The compound of any one of claims 2-20 and 23-53, wherein the Z-substituted ring is selected from the group consisting of wherein each occurrence of R9 is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl. 58. The compound of any one of claims 2-20 and 23-53, wherein the Z-substituted containing ring is selected from the group consisting of . 59. The compound of any one of claims 2-20 and 23-53, wherein the Z-substituted ring is selected from the group consisting of . 60. The compound of any one of claims 2-20 and 23-53, wherein the Z-substituted ring is selected from the group consisting of wherein each occurrence of R9 is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl. 61. The compound of any one of claims 2-20 and 23-53, wherein the Z-substituted ring is selected from the group consisting of . 62. The compound of any one of claims 2-20 and 23-53, wherein the Z-substituted ring is selected from the group consisting of . 63. The compound of any one of claims 2-20 and 23-53, wherein the Z-substituted ring is selected from the group consisting of wherein each occurrence of R9 is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl. 64. The compound of any one of claims 2-20 and 23-53, wherein the Z-substituted ring is selected from the group consisting of . 65. The compound of any one of claims 2-20 and 23-53, wherein the Z-substituted ring is selected from the group consisting of ; wherein each occurrence of R9 is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl. 66. The compound of any one of claims 1-65, wherein E1 is selected from the group consisting of: . 67. The compound of any one of claims 1-65, wherein E1 is selected from the group consisting of: . 68. The compound of any one of claims 1-65, wherein E1 is selected from the group consisting of . 69. The compound of claim 1, wherein E1 is selected from the group consisting of . The compound of any one of claims 1-69, wherein selected from the group consisting of . 71. The compound of any one of claims 1-65, wherein selected from the group consisting of , . consisting of: 73. The compound of any one of claims 1-65, wherein when L1 is a direct bond, . 74. The compound of any one of claims 1-65, wherein when L1 is a direct bond, selected from the group consisting of . 75. The compound of any one of claims 1-65, wherein when L1 is a direct bond, , . 76. The compound of claim 1, wherein selected from the group consisting of CH, C-L3-E3, C-O-L3-E3, and C-N(R4)-L3-E3. 77. The compound of claim 1, wherein . 78. The compound of claim 1, wherein , wherein X3 is selected from the group consisting of CH, C-L3-E3, C-O-L3-E3, and C-N(R4)-L3-E3. 79. The compound of claim 1, wherein . 80. The compound of claim 1, wherein 81. The compound of claim 1, wherein ,wherein X3 is selected from the group consisting of CH, C-L3-E3, C-O-L3-E3, and C-N(R4)-L3-E3. 82. The compound of claim 1, wherein , wherein X3 is N-L3- E3. 83. The compound of claim 1, wherein , wherein X3 is N- L3-E3. 84. The compound of claim 1, wherein , wherein X2 is N- L2-E2. L3-E3. 87. The compound of claim 1, wherein . 89. A compound selected from the group consisting of: and pharmaceutically acceptable salts, enantiomers, stereoisomers, and tautomers thereof. 90. A pharmaceutical composition comprising the compound according to any one of claims 1-89, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 91. A method of treating a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound of any one of claims 1-89, or of the pharmaceutical composition of claim 90. 92. The method of claim 91, 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 tumors, solid tumors, brain cancers, gliomas, glioblastomas, astrocytomas, blood-borne cancers, hairy cell leukemia, acute myelogenous leukemia (AML), or other cancers caused by activation of the RAS ^RAF ^MEK ^ ERK signaling pathway. 93. The method of claim 91 or 92, wherein the cancer has a BRAF oncogenic mutation. 94. The method of any one of claims 91-93, wherein the cancer has a RAS oncogenic mutation. 95. The method of claim 94, wherein the RAS oncogenic mutation is RAS Q61R or Q61K mutation. 96. The method of any one of claims 91-95, wherein the cancer has a NF1 oncogenic mutation. 97. A method of 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 tumors, solid tumors, brain cancers, gliomas, glioblastomas, astrocytomas, blood-borne cancers, hairy cell leukemia, acute myelogenous leukemia (AML), 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 the compound of any one of claims 1-89 or of the pharmaceutical composition of claim 90. |
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 3 is selected from the group consisting of C-L 3 -E 3 , C-O-L 3 -E 3 , and C-N(R 4 )- L 3 -E 3 ; X 5 is selected from the group consisting of N, CH, and CF; L 3 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 ) m ; E 1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L 1 is a direct bond and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted monocyclic heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, and optionally substituted cycloalkyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 31 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH 2 ) m NH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 4 , at each occurrence, is independently selected from H and alkyl; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; and each m is independently 0, 1, 2, 3, or 4. [00094] In some embodiments, the compound is represented by Formula I-AC: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 ) m ; E 1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, sulfone, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L 1 is a direct bond and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH 2 ) m NH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. [00095] In some embodiments, the compound is represented by Formula I-B: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , C-N(R 4 )- L 3 -E 3 , and N; X 5 is selected from the group consisting of N, CH, and CF; L 3 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 )m; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 31 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 4 , at each occurrence, is independently selected from H and alkyl; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and each m is independently 0, 1, 2, 3, or 4; with the proviso that when X 3 is selected from C-O-L 3 -E 3 and C-N(R 4 )-L 3 -E 3 , R 4 is H, and each L 3 is a direct bond, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when L 1 is direct bond, then E 1 is not N-bound heterocyclyl; or when Q is -C(O)-NH- and L 1 is direct bond, E 1 is not H; or when Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl; or when X 3 is N, R 3 is H, X 5 and X 6 are CH, and Q is -C(O)-NH-, then L 1 -E 1 is not alkyl substituted with amine. [00096] In some embodiments, the compound is represented by Formula I-BA:
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 ) m ; E 1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L 1 is a direct bond and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. [00097] In some embodiments, the compound is represented by Formula I-C: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 2 is selected from the group consisting of N, CH, C=O, C-O-L 2 -E 2 , C-L 2 -E 2 , C-N(R 4 )-L 2 -E 2 , and N-L 2 -E 2 ; X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , C-N(R 4 )- L 3 -E 3 , and N; X 5 is selected from the group consisting of N, CH, and CF; L 2 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 21 ) p ; L 3 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 31 )p; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and optionally substituted heterocyclyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 21 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 31 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 4 , at each occurrence, is independently selected from H and alkyl; R 9 , at each occurrence, is independently selected from the group consisting of is selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; and each m is independently 0, 1, 2, 3, or 4; with the proviso that when X 2 is selected from C-O-L 2 -E 2 and C-N(R 4 )-L 2 -E 2 , R 4 is H, and each L 2 is a direct bond, each E 2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when X 3 is selected from C-O-L 3 -E 3 and C-N(R 4 )-L 3 -E 3 , R 4 is H, and each L 3 is a direct bond, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when L 1 is direct bond, then E 1 is not N-bound heterocyclyl; or when X 6 is CH, X 5 is CH or CF, X 3 is N, Q is -C(O)NH-, L 1 is direct bond, and E 1 is selected from the group consisting of C3-C8 cycloalkyl, C2-C8 heterocyclyl, C6- C 14 aryl, and C 1 -C 9 heteroaryl, X 2 is not C-N(R 4 )-L 2 -E 2 ; or when Q is -C(O)-NH- and L 1 is direct bond, E 1 is not H; or when Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl; or when X 3 is N, R 3 is H, X 5 and X 6 are CH, X 2 is CH or C-NH2, and Q is -C(O)- NH, then L 1 -E 1 is not alkyl substituted with amine. [00098] In some embodiments, the compound is represented by Formula I-CA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 ) m ; E 1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L 1 is a direct bond and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 9 , at each occurrence, is independently selected from the group consisting of is selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. [00099] In some embodiments, the compound is represented by Formula I-D:
Formula I-D or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , and C- N(R 4 )-L 3 -E 3 ; X 5 is selected from the group consisting of N, CH, and CF; L 3 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 31 )p; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 )m; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 31 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 4 , at each occurrence, is independently selected from H and alkyl; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and each m is independently 0, 1, 2, 3, or 4; with the proviso that when X 3 is selected from C-O-L 3 -E 3 and C-N(R 4 )-L 3 -E 3 , R 4 is H, and each L 3 is a direct bond, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when L 1 is direct bond, then E 1 is not N-bound heterocyclyl; or when Q is -C(O)-NH- and L 1 is direct bond, E 1 is not H; or when Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl. [000100] In some embodiments, the compound is represented by Formula I-DA: Formula I-DA or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 ) m ; E 1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L 1 is a direct bond and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. [000101] In some embodiments, the compound is represented by Formula I-DB:
Formula I-DB or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 3 is selected from the group consisting of C-L 3 -E 3 , C-O-L 3 -E 3 , and C-N(R 4 )- L 3 -E 3 ; X 5 is selected from the group consisting of N, CH, and CF; L 3 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 31 )p; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 )m; E 1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L 1 is a direct bond and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted monocyclic heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, and optionally substituted cycloalkyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 31 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH 2 ) m NH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 4 , at each occurrence, is independently selected from H and alkyl; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and each m is independently 0, 1, 2, 3, or 4. [000102] In some embodiments, the compound is represented by Formula I-E: Formula I-E or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 3 is N-L 3 -E 3 ; X 4 is selected from CR 3 and N; X 5 is selected from the group consisting of N, CH, and CF; L 3 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 31 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; and each m is independently 0, 1, 2, 3, or 4; with the proviso that when L 1 is direct bond, then E 1 is not N-bound heterocyclyl. [000103] In some embodiments, the compound is represented by Formula I-EA: Formula I-EA or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 )m; E 1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L 1 is a direct bond and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. [000104] In some embodiments, the compound is represented by Formula I-EB: Formula I-EB or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 3 is N-L 3 -E 3 ; X 5 is selected from the group consisting of N, CH, and CF; L 3 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 31 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 ) m ; E 1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L 1 is a direct bond and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, and optionally substituted cycloalkyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 31 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; and each m is independently 0, 1, 2, 3, or 4. [000105] In some embodiments, the compound is represented by Formula I-F: Formula I-F or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 2 is N-L 2 -E 2 ; X 5 is selected from the group consisting of N, CH, and CF; L 2 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 21 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 21 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 9 is selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and each m is independently 0, 1, 2, 3, or 4; with the proviso that when L 1 is direct bond, then E 1 is not N-bound heterocyclyl. [000106] In some embodiments, the compound is represented by Formula I-FA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 )m; E 1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L 1 is a direct bond and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH 2 ) m NH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 9 is selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. [000107] In some embodiments, the compound is represented by Formula I-G: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 2 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , C-N(R 4 )- L 3 -E 3 , and N; X 3 is selected from the group consisting of CH, C-L 2 -E 2 , C-O-L 2 -E 2 , C-N(R 4 )- L 2 -E 2 , and N; X 5 is selected from the group consisting of N, CH, and CF; L 3 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 31 )p; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and optionally substituted heterocyclyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 21 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 31 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 4 , at each occurrence, is independently selected from H and alkyl; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and each m is independently 0, 1, 2, 3, or 4; with the proviso that X 2 and X 3 are both not N; when X 3 is selected from C-O-L 3 -E 3 and C-N(R 4 )-L 3 -E 3 , R 4 is H, and each L 3 is a direct bond, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when X 2 is selected from C-O-L 2 -E 2 and C-N(R 4 )-L 2 -E 2 , R 4 is H, and each L 2 is a direct bond, each E 2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when X 6 is CH, X 5 is CH or CF, X 3 is N, Q is -C(O)NH-, L 1 is direct bond, and E 1 is selected from the group consisting of C 3 -C 8 cycloalkyl, C 2 -C 8 heterocyclyl, C 6 - C14 aryl, and C1-C9 heteroaryl, X 2 is not C-N(R 4 )-L 2 -E 2 ; or when L 1 is direct bond, then E 1 is not N-bound heterocyclyl; or when s direct bond, E 1 is not H; or when not unsubstituted methyl; or when X 6 are CH, X 2 is CH or C-NH 2 , and Q is -C(O)- NH, then L 1 -E 1 is not alkyl substituted with amine. [000108] In some embodiments, the compound is represented by Formula I-GA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 ) m ; E 1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L 1 is a direct bond and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. [000109] In some embodiments, the compound is represented by Formula I-H: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , and C- N(R 4 )-L 3 -E 3 ; X 5 is selected from the group consisting of N, CH, and CF; L 3 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 31 )p; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 )m; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 31 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 4 , at each occurrence, is independently selected from H and alkyl; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and each m is independently 0, 1, 2, 3, or 4; with the proviso that when R 3 is selected from H and alkyl, X 3 is C-L 3 -E 3 , and L 3 is a direct bond, E 3 is not morpholinyl; or when X 3 is selected from C-O-L 3 -E 3 and C-N(R 4 )-L 3 -E 3 , R 4 is H, and each L 3 is a direct bond, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when L 1 is direct bond, then E 1 is not N-bound heterocyclyl; or when Q is -C(O)-NH- and L 1 is direct bond, E 1 is not H; or when Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl. [000110] In some embodiments, the compound is represented by Formula I-HA:
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 )m; E 1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L 1 is a direct bond and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. [000111] In some embodiments, the compound is represented by Formula I-J: Formula I-J or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 2 is selected from the group consisting of CH, C-O-L 2 -E 2 , C-L 2 -E 2 , and C- N(R 4 )-L 2 -E 2 ; X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , and C- N(R 4 )-L 3 -E 3 ; X 5 is selected from the group consisting of N, CH, and CF; L 2 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 21 ) p ; L 3 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 31 )p; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 )m; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 21 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 31 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 4 , at each occurrence, is independently selected from H and alkyl; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and each m is independently 0, 1, 2, 3, or 4; with the proviso that when X 2 is C-L 2 -E 2 , L 2 is a direct bond, E 2 is selected from H and alkyl, X 3 is C-L 3 -E 3 , and L 3 is a direct bond, E 3 is not morpholinyl; or when X 2 is selected from C-O-L 2 -E 2 and C-N(R 4 )-L 2 -E 2 , R 4 is H, and each L 2 is a direct bond, each E 2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when X 3 is selected from C-O-L 3 -E 3 and C-N(R 4 )-L 3 -E 3 , R 4 is H, and each L 3 is a direct bond, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when L 1 is direct bond, then E 1 is not N-bound heterocyclyl; or when Q is -C(O)-NH- and L 1 is direct bond, E 1 is not H; or when Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl. [000112] In some embodiments, the compound is represented by Formula I-JA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 ) m ; E 1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L 1 is a direct bond and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. [000113] In some embodiments, the compound is represented by Formula I-K: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 2 is selected from the group consisting of CH, C-O-L 2 -E 2 , C-L 2 -E 2 , and C- N(R 4 )-L 2 -E 2 ; X 5 is selected from the group consisting of N, CH, and CF; L 2 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 21 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 21 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 4 , at each occurrence, is independently selected from H and alkyl; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; and each m is independently 0, 1, 2, 3, or 4; with the proviso that when X 2 is selected from C-O-L 2 -E 2 and C-N(R 4 )-L 2 -E 2 , R 4 is H, and each L 2 is a direct bond, each E 2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when L 1 is direct bond, then E 1 is not N-bound heterocyclyl; or when X 6 is CH, X 5 is CH or CF, Q is -C(O)NH-, L 1 is direct bond, and E 1 is selected from the group consisting of C3-C8 cycloalkyl, C2-C8 heterocyclyl, C6-C14 aryl, and C 1 -C 9 heteroaryl, X 2 is not C-N(R 4 )-L 2 -E 2 ; or when Q is -C(O)-NH- and L 1 is direct bond, E 1 is not H; or when Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl; or when R 3 is H, X 5 and X 6 are CH, X 2 is CH or C-NH2, and Q is -C(O)-NH-, then L 1 -E 1 is not alkyl substituted with amine. [000114] In some embodiments, the compound is represented by Formula I-KA:
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 )m; E 1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl,the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L 1 is a direct bond and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. [000115] In some embodiments, the compound is represented by Formula I-L: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 2 is selected from the group consisting of CH, C-O-L 2 -E 2 , C-L 2 -E 2 , C-N(R 4 )- L 2 -E 2 , and N; X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , and C- N(R 4 )-L 3 -E 3 ; X 5 is selected from the group consisting of N, CH, and CF; L 2 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 21 ) p ; L 3 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 31 )p; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 21 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 31 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 4 , at each occurrence, is independently selected from H and alkyl; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and each m is independently 0, 1, 2, 3, or 4; with the proviso that when X 2 is N, R 3 is selected from H and alkyl, X 3 is C-L 3 -E 3 , and L 3 is a direct bond, E 3 is not morpholinyl; or when X 2 is selected from C-O-L 2 -E 2 and C-N(R 4 )-L 2 -E 2 , R 4 is H, and each L 2 is a direct bond, each E 2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when X 3 is selected from C-O-L 3 -E 3 and C-N(R 4 )-L 3 -E 3 , R 4 is H, and each L 3 is a direct bond, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when L 1 is direct bond, then E 1 is not N-bound heterocyclyl; or when Q is -C(O)-NH- and L 1 is direct bond, E 1 is not H; or when Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl. [000116] In some embodiments, the compound is represented by Formula I-LA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 )m; E 1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L 1 is a direct bond and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. [000117] In some embodiments, the compound is represented by Formula I-M: Formula I-M or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 2 is selected from the group consisting of CH, C-O-L 2 -E 2 , C-L 2 -E 2 , C-N(R 4 )- L 2 -E 2 , and N; X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , and C- N(R 4 )-L 3 -E 3 ; X 5 is selected from the group consisting of N, CH, and CF; X 8 is selected from the group consisting of N and CH; L 2 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 21 ) p ; L 3 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 31 )p; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 21 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 31 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 4 , at each occurrence, is independently selected from H and alkyl; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and each m is independently 0, 1, 2, 3, or 4; with the proviso that when X 2 is N, R 3 is selected from H and alkyl, X 3 is C-L 3 -E 3 , and L 3 is a direct bond, E 3 is not morpholinyl; or when X 2 is selected from C-O-L 2 -E 2 and C-N(R 4 )-L 2 -E 2 , R 4 is H, and each L 2 is a direct bond, each E 2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when X 3 is selected from C-O-L 3 -E 3 and C-N(R 4 )-L 3 -E 3 , R 4 is H, and each L 3 is a direct bond, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when L 1 is direct bond, then E 1 is not N-bound heterocyclyl; when Q is -C(O)-NH- and L 1 is direct bond, E 1 is not H; or when Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl. [000118] In some embodiments, the compound is represented by Formula I-N: Formula I-N or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 2 is selected from the group consisting of CH, C-O-L 2 -E 2 , C-L 2 -E 2 , and C- N(R 4 )-L 2 -E 2 ; X 5 is selected from the group consisting of N, CH, and CF; L 2 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 21 ) p ; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 21 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 4 , at each occurrence, is independently selected from H and alkyl; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1, or 2; and each m is independently 0, 1, 2, 3, or 4; with the proviso that when X 2 is selected from C-O-L 2 -E 2 and C-N(R 4 )-L 2 -E 2 , R 4 is H, and each L 2 is a direct bond, each E 2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when L 1 is direct bond, then E 1 is not N-bound heterocyclyl; or when Q is -C(O)-NH- and L 1 is direct bond, E 1 is not H; or when Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl. [000119] In some embodiments, the compound is represented by Formula I-NA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 )m; E 1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L 1 is a direct bond and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH 2 ) m NH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. [000120] In some embodiments, the compound is represented by Formula I-O: Formula I-O or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 2 is selected from the group consisting of CH, C-O-L 2 -E 2 , C-L 2 -E 2 , C-N(R 4 )- L 2 -E 2 , and N; X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , and C- N(R 4 )-L 3 -E 3 ; X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 2 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 21 )p; L 3 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 31 ) p ; L 1 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 )m; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 21 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 31 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 4 , at each occurrence, is independently selected from H and alkyl; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each p is independently 0, 1 or 2; and each m is independently 0, 1, 2, 3, or 4; with the proviso that when X 2 is N, R 3 is selected from H and alkyl, X 3 is C-L 3 -E 3 , and L 3 is a direct bond, E 3 is not morpholinyl; or when X 2 is selected from C-O-L 2 -E 2 and C-N(R 4 )-L 2 -E 2 , R 4 is H, and each L 2 is a direct bond, each E 2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when X 3 is selected from C-O-L 3 -E 3 and C-N(R 4 )-L 3 -E 3 , R 4 is H, and each L 3 is a direct bond, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when L 1 is direct bond, then E 1 is not N-bound heterocyclyl; or when Q is -C(O)-NH- and L 1 is direct bond, E 1 is not H; or when Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl. [000121] In some embodiments, the compound is represented by Formula I-OA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; E 1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L 1 is a direct bond and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. [000122] In some embodiments, the compound is represented by Formula I-P: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 )m; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each m is independently 0, 1, 2, 3, or 4, with the proviso that when L 1 is direct bond, then E 1 is not N-bound heterocyclyl,; or when Q is -C(O)-NH- and L 1 is direct bond, E 1 is not H; or when Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl; or when R 3 is H, X 5 and X 6 are CH, and Q is -C(O)-NH-, then L 1 -E 1 is not alkyl substituted with amine. [000123] In some embodiments, the compound is represented by Formula I-PA:
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 ) m ; E 1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L 1 is a direct bond and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. [000124] In some embodiments, the compound is represented by Formula I-Q: Formula I-Q or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 )m; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; each m is independently 0, 1, 2, 3, or 4, with the proviso that when L 1 is direct bond, then E 1 is not N-bound heterocyclyl; or when Q is -C(O)-NH- and L 1 is direct bond, E 1 is not H; or when Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl; or when R 3 is H, X 5 and X 6 are CH, and Q is -C(O)-NH-, then L 1 -E 1 is not alkyl substituted with amine. [000125] In some embodiments, the compound is represented by Formula I-QA
Formula I-Q or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 ) m ; E 1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L 1 is a direct bond and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from the group consisting of acyl, carbamoyl, formyl, amide, alkoxy, alkoxyalkyl, urea, amine, amidine, alkyl, cycloalkyl, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 9 , at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl; and each m is independently 0, 1, 2, 3, or 4. [000126] In some embodiments, the compound is represented by Formula I-R: Formula I-R or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: each of X 1 and X 4 is independently selected from CR 3 and N; X 2 is selected from the group consisting of N, CH, C=O, C-O-L 2 -E 2 , C-L 2 -E 2 , C-N(R 4 )-L 2 -E 2 , and N-L 2 -E 2 ; X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , C-N(R 4 )- L 3 -E 3 , C=O, N, and N-L 3 -E 3 ; provided that not more than two of X 1 , X 2 , X 3 , and X 4 are N; when X 2 is N, X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O- L 3 -E 3 , C-N(R 4 )-L 3 -E 3 , and N; when X 3 is N, X 2 is selected from the group consisting of N, CH, C-O-L 2 -E 2 , C-L 2 -E 2 , and C-N(R 4 )-L 2 -E 2 ; when X 2 is C=O, X 3 is N-L 3 -E 3 ; when X 3 is C=O, X 2 is N-L 2 -E 2 ; X 5 is selected from the group consisting of N, CH, and CF; each of X 8 , X 9 , and X 10 is independently selected from CR 3 and N; L 2 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 21 )p; L 3 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 31 ) p Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 ) m ; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 21 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 31 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 4 , at each occurrence, is independently selected from H and alkyl; each p is independently 0, 1 or 2; and each m is independently 0, 1, 2, 3, or 4; with the proviso that when X 1 and X 2 are N, each of X 5 and X 6 is independently selected from CH and CF, X 4 is CR 3 , R 3 is selected from H and alkyl, X 3 is C-L 3 -E 3 , and L 3 is a direct bond, E 3 is not morpholinyl; or when X 1 and X 4 are N, each of X 5 and X 6 is independently selected from CH and CF, X 2 is C-L 2 -E 2 , L 2 is a direct bond, E 2 is selected from H and alkyl, X 3 is C-L 3 -E 3 , and L 3 is a direct bond, E 3 is not morpholinyl; or when X 2 is selected from C-O-L 2 -E 2 and C-N(R 4 )-L 2 -E 2 , R 4 is H, each L 2 is a direct bond, each E 2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when X 3 is selected from C-O-L 3 -E 3 and C-N(R 4 )-L 3 -E 3 , R 4 is H, each L 3 is a direct bond, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when L 1 is direct bond, then E 1 is not N-bound heterocyclyl; or when X 6 is CH, X 5 is CH or CF, X 4 is CR 3 , X 3 is N, Q is -C(O)NH-, L 1 is direct bond, and E 1 is selected from the group consisting of C3-C8 cycloalkyl, C2-C8 heterocyclyl, C 6 -C 14 aryl, and C 1 -C 9 heteroaryl, X 2 is not C-N(R 4 )-L 2 -E 2 ; or when Q is -C(O)-NH- and L 1 is direct bond, E 1 is not H; or when Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl; or when X 3 is N, X 1 is CH or N, X 4 is CH, X 5 and X 6 are CH, X 2 is CH or C-NH2, and Q is -C(O)-NH-, then L 1 -E 1 is not alkyl substituted with amine. [000127] In some embodiments, the compound is represented by Formula I-RA: or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: each of X 1 and X 4 is independently selected from CR 3 and N; each of X 2 and X 3 is independently selected from the group consisting of N and CH; provided that not more than two of X 1 , X 2 , X 3 , and X 4 are N; each of X 8 , X 9 , and X 10 is independently selected from CR 3 and N; X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 ) m ; E 1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L 1 is a direct bond and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; and each m is independently 0, 1, 2, 3, or 4. [000128] In some embodiments, the compound is represented by Formula I-S:
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: each of X 1 and X 4 is independently selected from CR 3 and N; X 2 is selected from the group consisting of N, CH, C=O, C-O-L 2 -E 2 , C-L 2 -E 2 , C-N(R 4 )-L 2 -E 2 , and N-L 2 -E 2 ; X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , C-N(R 4 )- L 3 -E 3 , C=O, N, and N-L 3 -E 3 ; provided that not more than two of X 1 , X 2 , X 3 , and X 4 are N; when X 2 is N, X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O- L 3 -E 3 , C-N(R 4 )-L 3 -E 3 , and N; when X 3 is N, X 2 is selected from the group consisting of N, CH, C-O-L 2 -E 2 , C-L 2 -E 2 , and C-N(R 4 )-L 2 -E 2 ; when X 2 is C=O, X 3 is N-L 3 -E 3 ; when X 3 is C=O, X 2 is N-L 2 -E 2 ; X 5 is selected from the group consisting of N, CH, and CF; X 8 is selected from CR 3 and N; X 11 is selected from the group consisting of O, C(R 10 )2, and NR 11 ; L 2 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 21 ) p ; L 3 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 31 )p Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 )m; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, H, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 21 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 31 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 4 , at each occurrence, is independently selected from H and alkyl; R 10 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, and F; R 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, and cycloalkyl; each p is independently 0, 1 or 2; and each m is independently 0, 1, 2, 3, or 4; with the proviso that when X 1 and X 2 are N, each of X 5 and X 6 is independently selected from CH and CF, X 4 is CR 3 , R 3 is selected from H and alkyl, X 3 is C-L 3 -E 3 , and L 3 is a direct bond, E 3 is not morpholinyl; or when X 1 and X 4 are N, each of X 5 and X 6 is independently selected from CH, and CF, X 2 is C-L 2 -E 2 , L 2 is a direct bond, E 2 is selected from H and alkyl, X 3 is C-L 3 - E 3 , and L 3 is a direct bond, E 3 is not morpholinyl; or when X 2 is selected from C-O-L 2 -E 2 and C-N(R 4 )-L 2 -E 2 , R 4 is H, and each L 2 is a direct bond, each E 2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when X 3 is selected from C-O-L 3 -E 3 and C-N(R 4 )-L 3 -E 3 , R 4 is H, and each L 3 is a direct bond, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when L 1 is direct bond, then E 1 is not N-bound heterocyclyl; or when X 6 is CH, X 5 is CH or CF, X 4 is CR 3 , X 3 is N, Q is -C(O)NH-, L 1 is direct bond, and E 1 is selected from the group consisting of C3-C8 cycloalkyl, C2-C8 heterocyclyl, C 6 -C 14 aryl, and C 1 -C 9 heteroaryl, X 2 is not C-N(R 4 )-L 2 -E 2 ; or when Q is -C(O)-NH- and L 1 is direct bond, E 1 is not H; or when Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl; or when X 3 is N, X 1 is CH or N, X 4 is CH, X 5 and X 6 are CH, X 2 is CH or C-NH2, and Q is -C(O)-NH-, then L 1 -E 1 is not alkyl substituted with amine. [000129] In some embodiments, the compound is represented by Formula I-SA-i or Formula I-SA-ii: Formula I-SA-i
or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: each of X 1 and X 4 is independently selected from CR 3 and N; X 2 and X 3 are each independently selected from the group consisting of N and CH; provided that not more than two of X 1 , X 2 , X 3 , and X 4 are N; X 5 is selected from the group consisting of N, CH, and CF; Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 )m; E 1 is selected from the group consisting of optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, wherein when L 1 is a direct bond and E 1 is an optionally substituted heterocyclyl or optionally substituted heteroaryl, the heterocyclyl or heteroaryl is C-bound; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; and each m is independently 0, 1, 2, 3, or 4. [000130] In some embodiments, the compound is represented by Formula I-T: Formula I-T or a pharmaceutically acceptable salt, enantiomer, stereoisomer, or tautomer thereof, wherein: each of X 1 and X 4 is independently selected from CR 3 and N; X 2 is selected from the group consisting of N, CH, C=O, C-O-L 2 -E 2 , C-L 2 -E 2 , C-N(R 4 )-L 2 -E 2 , and N-L 2 -E 2 ; X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , C-N(R 4 )- L 3 -E 3 , C=O, N, and N-L 3 -E 3 ; provided that not more than two of X 1 , X 2 , X 3 , and X 4 are N; when X 2 is N, X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O- L 3 -E 3 , C-N(R 4 )-L 3 -E 3 , and N; when X 3 is N, X 2 is selected from the group consisting of N, CH, C-O-L 2 -E 2 , C-L 2 -E 2 , and C-N(R 4 )-L 2 -E 2 ; when X 2 is C=O, X 3 is N-L 3 -E 3 ; when X 3 is C=O, X 2 is N-L 2 -E 2 ; X 5 is independently selected from the group consisting of CH, CF, and N; X 6 is independently selected from the group consisting of CH, and CF; X 7 , X 8 , and X 9 are independently selected from CR 3 and N; provided that not more than one of X 7 , X 8 and X 9 is N; L 2 is selected from the group consisting of a direct bond and optionally substituted C1-C6alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 21 ) p ; L 3 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 31 )p Q is selected from the group consisting of -NH-C(O)- and -C(O)-NH-; L 1 is selected from the group consisting of a direct bond and optionally substituted C 1 -C 6 alkyl, wherein the optionally substituted substituent, at each occurrence, is (E 11 )m; E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl, and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; E 11 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 11 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 2 is selected from the group consisting of H, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, alkyl, amine, amide, acyl, haloalkoxy, haloalkyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl; E 21 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 21 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; E 3 is selected from the group consisting of hydroxy, alkoxy, alkoxylalkyl, cyano, sulfonyl, haloalkoxy, H, alkyl, acyl, amine, aminoalkyl, amide, haloalkyl, cyano, sulfone, optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, or sulfone, optionally substituted heteroaryl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, cyano, cyanoalkyl, and heterocyclyl, and optionally substituted cycloalkyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano; E 31 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, hydroxy, hydroxyalkyl, and halogen; or wherein two occurrences of E 31 taken together with the carbon atom to which they are attached form a cycloalkyl or a heterocyclyl ring having from 3 to 6 atoms in the ring structure; Z is selected from -C(O)NHR 6 ,-NHC(O)R 7 , and -NHC(O)OR 6 ; R 1 is selected from the group consisting of H, alkyl, alkoxy, haloalkyl, cyano, and halogen; R 2 is selected from the group consisting of H and F; R 3 , at each occurrence, is independently selected from the group consisting of H, alkyl, and halogen; R 4 , at each occurrence, is independently selected from H and alkyl; R 6 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, wherein each of alkyl and cycloalkyl is optionally substituted with one or more independent occurrences of R 8 ; and the heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, wherein each of alkyl and cycloalkyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; R 8 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl, wherein each of alkyl and cycloalkyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl, and the heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and each p is independently 0, 1 or 2; each m is independently 0, 1, 2, 3, or 4; with the proviso that when X 1 and X 2 are N, each of X 5 and X 6 is independently selected from CH and CF, X 4 is CR 3 , R 3 is selected from H and alkyl, X 3 is C-L 3 -E 3 , and L 3 is a direct bond, E 3 is not morpholinyl; or when X 1 and X 4 are N, each of X 5 and X 6 is independently selected from CH and CF, X 2 is C-L 2 -E 2 , L 2 is a direct bond, E 2 is selected from H and alkyl, X 3 is C-L 3 -E 3 , and L 3 is a direct bond, E 3 is not morpholinyl; or when X 2 is selected from C-O-L 2 -E 2 and C-N(R 4 )-L 2 -E 2 , R 4 is H, each L 2 is a direct bond, each E 2 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when X 3 is selected from C-O-L 3 -E 3 and C-N(R 4 )-L 3 -E 3 , R 4 is H, each L 3 is a direct bond, each E 3 is not a 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O, and S; or when L 1 is direct bond, then E 1 is not N-bound heterocyclyl; when X 6 is CH, X 5 is CH or CF, X 4 is CR 3 , X 3 is N, Q is -C(O)NH-, L 1 is direct bond, and E 1 is selected from the group consisting of C3-C8 cycloalkyl, C2-C8 heterocyclyl, C 6 -C 14 aryl, and C 1 -C 9 heteroaryl, X 2 is not C-N(R 4 )-L 2 -E 2 ; or when Q is -C(O)-NH- and L 1 is direct bond, E 1 is not H; or when Q is -NH-C(O)-, L 1 -E 1 is not unsubstituted methyl; or when X 3 is N, X 1 is CH or N, X 4 is CH, X 5 and X 6 are CH, X 2 is CH or C-NH2, and Q is -C(O)-NH-, then L 1 -E 1 is not alkyl substituted with amine. [000131] In some embodiments, Z is -NHC(O)R 6 , -NHC(O)OR 6 , or -C(O)NHR 7 , wherein R 6 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, wherein each of alkyl and cycloalkyl is optionally substituted with one or more independent occurrences of R 8 ; and the heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, wherein each of alkyl and cycloalkyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl, and the heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and R 8 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl, wherein each of alkyl and cycloalkyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl, and the heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. [000132] In some embodiments, Z is -NHC(O)R 6 , wherein R 6 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, wherein each of alkyl and cycloalkyl is optionally substituted with one or more independent occurrences of R 8 ; and the heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and R 8 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl, wherein each of alkyl and cycloalkyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl, and the heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. [000133] In some embodiments, Z is -NHC(O)R 6 , wherein R 6 is methyl, ethyl, or iso- propyl. In some embodiments, Z is -NHC(O)R 6 , wherein R 6 is methyl. In some embodiments, Z is -NHC(O)R 6 , wherein R 6 is cyclopropyl or cyclobutyl. In some embodiments, Z is - NHC(O)R 6 , wherein R 6 is cyclopropyl. In some embodiments, Z is -NHC(O)R 6 , wherein R 6 is H. In some embodiments, Z is -NHC(O)R 6 , wherein R 6 is CH2N(R 4 )2. In some embodiments, Z is -NHC(O)R 6 , wherein R 6 is CH2-CN. In some embodiments, Z is -NHC(O)R 6 , wherein R 6 is CH2-OH. In some embodiments, Z is -NHC(O)R 6 , wherein R 6 is CH2-OMe. [000134] In some embodiments, Z is -C(O)NHR 7 , wherein R 7 is selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, wherein each of alkyl and cycloalkyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl, and the heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. [000135] In some embodiments, Z is selected from the group consisting of acyl, amide, alkoxy, alkoxyalkyl, urea, amine, alkyl, cycloalkyl, H, cyano, cyanoalkyl, sulfonamide, hydroxy, hydroxyalkyl, halogen, sulfone, optionally substituted heterocyclyl, and optionally substituted heterocyclyl(CH2)mNH-, wherein the optionally substituted substituent on the heterocyclyl ring, at each occurrence, is independently R 9 . [000136] In some embodiments, Z is -C(O)NHR 7 . In some embodiments, Z is - C(O)NHR 7 wherein R 7 is H. In some embodiments, Z is -C(O)NHR 7 wherein R 7 is alkyl. In some embodiments, Z is -C(O)NHR 7 wherein R 7 is methyl. In some embodiments, Z is - C(O)NHR 7 wherein R 7 is ethyl. In some embodiments, Z is -C(O)NHR 7 wherein R 7 is iso- propyl. In some embodiments, Z is -NH2. In some embodiments, Z is carbamoyl. In some embodiments, Z is formyl. In some embodiments, Z is methylamino. In some embodiments, Z is ethylamino. In some embodiments, Z is beta-hydroxyethylamino. In some embodiments, Z is beta-methoxyethylamino. In some embodiments, Z is heterocyclyl. In some embodiments, Z is oxetanyl, tetrahydrofuranyl, or tetrahydropyranyl. In some embodiments, Z is morpholinyl. In some embodiments, Z is heterocyclylalkylamino. In some embodiments, Z is oxetanylalkylamino. In some embodiments, Z is azetidinylalkylamino. In some embodiments, Z is tetrahydropyranylalkylamino. In some embodiments, Z is heteroaryl. In some embodiments, Z is pyrazolyl. In some embodiments, Z is oxazolyl. In some embodiments, Z is oxadiazolyl. In some embodiments, Z is thiazolyl. In some embodiments, Z is selected from the group consisting of H, alkyl, and cycloalkyl. In some embodiments, Z is H. In some embodiments, Z is methyl. In some embodiments, Z is ethyl. In some embodiments, Z is iso-propyl. In some embodiments, Z is cyclopropyl. [000137] In some embodiments, Z is -NHC(O)OR 6 , wherein R 6 , at each occurrence, is independently selected from the group consisting of H, alkyl, cycloalkyl, and heterocyclyl, wherein each of alkyl and cycloalkyl is optionally substituted with one or more independent occurrences of R 8 ; and the heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone; and R 8 is selected from the group consisting of alkyl, cycloalkyl, and heterocyclyl, wherein each of alkyl and cycloalkyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, cyano, amino, hydroxy, alkoxy, and heterocyclyl, and the heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. [000138] In some embodiments, Q is -NH-C(O)-. [000139] In some embodiments, Q is -C(O)-NH-. [000140] In some embodiments, X 1 , X 4 , X 5 , X 6 , X 7 , X 8 , and X 9 are each CH; X 2 is N; and X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , and C-N(R 4 )-L 3 -E 3 . [000141] In some embodiments, X 1 , X 4 , X 5 , X 6 , X 7 , and X 9 are each CH; X 2 and X 8 are N; and X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , and C-N(R 4 )-L 3 - E 3 . [000142] In some embodiments, X 1 and X 4 are each CR 3 ; X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , C-N(R 4 )-L 3 -E 3 , and N; and X 2 , X 5 , X 6 , X 7 , X 8 , and X 9 are CH. [000143] In some embodiments, X 1 and X 4 are each CR 3 ; X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , C-N(R 4 )-L 3 -E 3 , and N; X 8 is N; and X 2 , X 5 , X 6 , X 7 , and X 9 are CH. [000144] In some embodiments, X 1 and X 4 are each CR 3 ; X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , C-N(R 4 )-L 3 -E 3 , and N; X 5 is N; and X 2 , X 6 , X 7 , X 8 , and X 9 are CH. [000145] In some embodiments, X 1 and X 4 are each CR 3 ; X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , C-N(R 4 )-L 3 -E 3 , and N; X 5 and X 8 are N; and X 2 , X 6 , X 7 , and X 9 are CH. [000146] In some embodiments, X 1 is CR 3 and X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , and C-N(R 4 )-L 3 -E 3 , X 2 and X 4 are N; X 5 , X 6 , X 7 , X 8 , and X 9 are CH; and X 1 is CR 3 . [000147] In some embodiments, X 1 is CR 3 ; X 4 is selected from the group consisting of CR 3 and N; X 3 is N-L 3 -E 3 ; X 2 is C=O; and X 5 , X 6 , X 7 , X 8 , and X 9 are CH. [000148] In some embodiments, X 1 and X 4 are CR 3 ; X 3 is C=O; X 2 is N-L 2 -E 2 ; and X 5 , X 6 , X 7 , X 8 , and X 9 are CH. [000149] In some embodiments, X 1 and X 4 are CR 3 ; X 2 is N; X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , C-N(R 4 )-L 3 -E 3 , and N; X 7 is N; and X 5 , X 6 , X 8 , and X 9 are CH. [000150] In some embodiments, X 1 and X 2 are N; X 4 is CR 3 ; X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , and C-N(R 4 )-L 3 -E 3 ; and X 5 , X 6 , X 7 , X 8 , and X 9 are CH. [000151] In some embodiments, X 1 and X 4 are N; X 5 , X 6 , X 7 , X 8 , and X 9 are each CH; X 2 is selected from the group consisting of CH, C-L 2 -E 2 , C-O-L 2 -E 2 , C-N(R 4 )-L 2 -E 2 and N; and X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , and C-N(R 4 )-L 3 -E 3 . [000152] In some embodiments, X 1 and X 3 are N; X 4 is CR 3 , X 5 , X 6 , X 7 , X 8 , and X 9 are each CH; and X 2 is selected from the group consisting of CH, C-L 2 -E 2 , C-O-L 2 -E 2 , and C- N(R 4 )-L 2 -E 2 . [000153] In some embodiments, X 1 is N; X 4 is CR 3 , X 5 , X 6 , X 7 , X 8 , and X 9 are each CH; X 2 is selected from the group constating of CH, C-L 2 -E 2 , C-O-L 2 -E 2 , and C-N(R 4 )-L 2 -E 2 ; and X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , and C-N(R 4 )-L 3 -E 3 . [000154] In some embodiments, X 1 is CR 3 ; X 2 , and X 6 are CH; and X 3 , X 4 , and X 5 are N. [000155] In some embodiments, X 1 is CR 3 ; X 2 , X 5 , and X 6 are CH; and X 3 and X 4 are N. [000156] In some embodiments, X 1 is CR 3 ; X 2 , X 5 , and X 6 are CH; and X 3 , X 4 , and X 8 are N. [000157] In some embodiments, E 3 is selected from the group consisting of H, alkyl, and cycloalkyl, wherein cycloalkyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano. [000158] In some embodiments, E 3 is selected from the group consisting of hydroxy, alkoxy, and cyano. [000159] In some embodiments, E 3 is heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. [000160] In some embodiments, E 3 is cycloalkyl, wherein cycloalkyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano. In some embodiments, E 3 is H. In some embodiments, E 3 is alkyl. In some embodiments, E 3 is methyl. In some embodiments, E 3 is ethyl. In some embodiments, E 3 is iso-propyl. In some embodiments, E 3 is cyclopropyl. [000161] In some embodiments, E 3 is selected from the group consisting of hydroxyalkyl, cyanoalkyl, hydroxy, alkoxy, alkoxyalkyl, cyano, and sulfonyl. In some embodiments, E 3 is hydroxy. In some embodiments, E 3 is alkoxy. In some embodiments, E 3 is methoxy. [000162] In some embodiments, E 3 is heterocyclyl, wherein the heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. In some embodiments, E 3 is oxatanyl. In some embodiments, E 3 is tetrahydrofuranyl. In some embodiments, E 3 is tetrahydropyranyl. In some embodiments, E 3 is azetidinyl. In some embodiments, E 3 is pyrrolidinyl. In some embodiments, E 3 is morpholino. In some embodiments, E 3 is piperazinyl. In some embodiments, E 3 is piperidinyl. [000163] In some embodiments, E 2 is selected from the group consisting of H, hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, and heterocyclyl wherein heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl, alkyl, amine, haloalkoxy, haloalkyl, and sulfone. In some embodiments, E 2 is heterocyclyl wherein heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl. In some embodiments, E 2 is H. In some embodiments, E 2 is hydroxy or alkoxy. In some embodiments, E 2 is alkoxyalkyl. In some embodiments, E 2 is cyano. In some embodiments, E 2 is alkyl. In some embodiments, E 2 is oxetanyl. In some embodiments, E 2 is azetinyl. In some embodiments, E 2 is pyrrolidinyl. In some embodiments, E 2 is tetrahydropyranyl. In some embodiments, E 2 is morpholino. In some embodiments, E 2 is piperazinyl. In some embodiments, E 2 is piperidinyl. In some embodiments, E 2 is selected from the group consisting of hydroxy, alkoxy, alkoxyalkyl, cyano, sulfonyl, and heterocyclyl, wherein heterocyclyl is optionally substituted with one or more occurrences of a substituent independently selected from the group consisting of alkyl, alkoxy, amide, amine, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, and cyanoalkyl, H, alkyl, amine, haloalkoxy, haloalkyl, and sulfone. [000164] In some embodiments, R 1 is selected from the group consisting of H, alkyl, haloalkyl, cyano, and halogen. In some embodiments, R 1 is methyl or fluorine. In some embodiments, R 1 is H. In some embodiments, R 1 is alkyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is ethyl. In some embodiments, R 1 is cyano. In some embodiments, R 1 is F. In some embodiments, R 1 is Cl. In some embodiments, R 1 is CF3. [000165] In some embodiments, R 2 is selected from H and F. In some embodiments, R 2 is H. In some embodiments, R 2 is F. [000166] In some embodiments, R 1 is methyl and R 2 is H. In some embodiments, R 1 is methyl and R 2 is F. [000167] In some embodiments, the Z-substituted ring is selected from the group consisting of
. [000168] In some embodiments, the Z-substituted ring is selected from the group consisting of . [000169] In some embodiments, the Z-substituted ring is selected from the group consisting of . [000170] In some embodiments, the Z-substituted ring is selected from the group consisting of . [000171] In some embodiments, the Z-substituted ring is selected from the group consisting of
wherein each occurrence of R 9 is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl. [000172] In some embodiments, the Z-substituted ring is selected from the group consisting of ; wherein each occurrence of R 9 is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl. [000173] In some embodiments, the Z-substituted ring is selected from the group consisting of . [000174] In some embodiments, the Z-substituted ring is selected from the group consisting of
. [000175] In some embodiments, the Z-substituted ring is selected from the group consisting of wherein each occurrence of R 9 is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl. [000176] In some embodiments, the Z-substituted ring is selected from the group consisting of ; wherein each occurrence of R 9 is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl. [000177] In some embodiments, the Z-substituted ring is selected from the group consisting of . [000178] In some embodiments, the Z-substituted ring is selected from the group consisting of . [000179] In some embodiments, the Z-substituted ring is selected from the group consisting of ; wherein each occurrence of R 9 is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl. [000180] In some embodiments, the Z-substituted ring is selected from the group consisting of ; wherein each occurrence of R 9 is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl. [000181] In some embodiments, the Z-substituted ring is selected from the group consisting of
[000182] In some embodiments, the Z-substituted ring is selected from the group consisting of . [000183] In some embodiments, the Z-substituted ring is selected from the group consisting of . [000184] In some embodiments, the Z-substituted ring is selected from the group consisting of; wherein each occurrence of R 9 is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl. [000185] In some embodiments, the Z-substituted ring is selected from the group consisting of occurrence of R 9 is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfonyl. [000186] In some embodiments, E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and the optionally substituted heteroaryl is not wherein s1 is the site covalently linked to L 1 ; and s2 is the site covalently linked to H or the optionally substituted substituent, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. [000187] In some embodiments, E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, optionally substituted alkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano, optionally substituted heteroaryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, sulfone, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and the optionally substituted heteroaryl is not wherein s1 is the site covalently linked to L 1 ; and s2 is the site covalently linked to H or the optionally substituted substituent, optionally substituted aryl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone, and optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. [000188] In some embodiments, E 1 is optionally substituted 5-6 membered heteroaryl or optionally substituted phenyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, amide, acyl, alkoxyalkyl, haloalkyl, haloalkoxy, halogen, hydroxy, cyano, hydroxyalkyl, cyanoalkyl, aminoalkyl, cycloalkyl and heterocyclyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the heterocyclyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. [000189] In some embodiments, E 1 is optionally substituted 5-6 membered heteroaryl or optionally substituted phenyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, haloalkyl, haloalkoxy halogen, cyano, cyanoalkyl, and cyclopropyl, wherein the alkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl, and the cycloalkyl substituent is independently optionally substituted, at each occurrence, with a substituent selected from the group consisting of cycloalkyl, cyano, alkoxy, and aminoalkyl. [000190] In some embodiments, E 1 is selected from the group consisting of H, alkoxy, cyano, haloalkoxy, halogen, and optionally substituted alkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano. [000191] In some embodiments, E 1 is selected from the group consisting of alkoxy, cyano, haloalkoxy, and optionally substituted alkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano. [000192] In some embodiments, E 1 is optionally substituted cycloalkyl wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, amine, haloalkyl, haloalkoxy, halogen, hydroxy, and cyano. [000193] In some embodiments, E 1 is optionally substituted heterocyclyl, wherein the optionally substituted substituent, at each occurrence, is independently selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, amide, amine, aminoalkyl, acyl, haloalkyl, haloalkoxy, halogen, hydroxy, hydroxyalkyl, oxo, cyano, cyanoalkyl, and sulfone. [000194] In some embodiments, E 1 is selected from the group consisting of
. [000195] In some embodiments, E 1 is selected from the group consisting of [000196] In some embodiments, E 1 is selected from the group consisting of . [000197] In some embodiments, E 1 is selected from the group consisting of .
[000198] In some embodiments, E 1 is selected from the group consisting of . [000199] In some embodiments, E 1 is selected from the group consisting of . [000200] In some embodiments, L 3 is a direct bond. In some embodiments, L 3 is C1- C6alkyl optionally substituted with (E 31 )p. In some embodiments, L 3 is ethylene. In some embodiments, L 3 is propylene. [000201] In some embodiments, X 3 is selected from the group consisting of CH, C-L 3 - E 3 , C-O-L 3 -E 3 , C-N(R 4 )-L 3 -E 3 , C=O, N, and N-L 3 -E 3 . In some embodiments, X 3 is CH. In some embodiments, X 3 is C-L 3 -E 3 . In some embodiments, X 3 is C-O-L 3 -E 3 . In some embodiments, X 3 is C-N(R 4 )-L 3 -E 3 . In some embodiments, X 3 is C=O. In some embodiments, X 3 is N. In some embodiments, X 3 is N-L 3 -E 3 . [000202] In some embodiments, X 2 is selected from the group consisting of N, CH, C=O, C-O-L 2 -E 2 , C-L 2 -E 2 , C-N(R 4 )-L 2 -E 2 , and N-L 2 -E 2 . In some embodiments, X 2 is N. In some embodiments, X 2 is CH. In some embodiments, X 2 is C(O). In some embodiments, X 2 is C-O-L 2 -E 2 . In some embodiments, X 2 is C-L 2 -E 2 . In some embodiments, X 2 is C-N(R 4 )-L 2 - E 2 . In some embodiments, X 2 is N-L 2 -E 2 . [000203] In some embodiments, L 1 is selected from the group consisting of direct bond, . [000204] In some embodiments, L 1 is a direct bond. In some embodiments, L 1 is a C1- C 6 alkyl optionally substituted with (E 11 ) m . In some embodiments, L 1 is taken together with R 3 and the N atom to which L 1 and R 3 are attached to form a heterocycle having from 4 to 6 atoms in the ring structure. [000205] In some embodiments, selected from the group consisting of .
[000206] In some embodiments, is selected from the group consisting of . [000207] In some embodiments, is selected from the group consisting of
[000208] In some embodiments, when L 1 is a direct bond, selected from the group consisting of .
[000209] In some embodiments, when L 1 is a direct bond, selected from the group consisting of . [000210] In some embodiments, L 1 is a direct bond, selected from the group consisting of
. [000211] In some embodiments, , wherein X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , and C-N(R 4 )-L 3 -E 3 . [000212] In some embodiments, [000213] In some embodiments, , wherein X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , and C-N(R 4 )-L 3 -E 3 . [000214] In some embodiments, [000215] In some embodiments, [000216] In some embodiments, wherein X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , and C-N(R 4 )-L 3 -E 3 . [000217] In some embodiments, , wherein X 3 is N-L 3 -E 3 . [000218] In some embodiments, , wherein X 3 is N-L 3 -E 3 . [000219] In some embodiments, , wherein X 2 is N-L 2 - E 2 . [000220] In some embodiments, , wherein X 2 is selected from the group consisting of CH, C-O-L 2 -E 2 , C-L 2 -E 2 , and C-N(R 4 )-L 2 -E 2 ; and wherein X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , and C-N(R 4 )-L 3 -E 3 . [000221] In some embodiments, , wherein X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , and C-N(R 4 )-L 3 -E 3 . [000222] In some embodiments, [000223] In some embodiments, . [000224] In some embodiments, , wherein X 3 is selected from the group consisting of CH, C-L 3 -E 3 , C-O-L 3 -E 3 , and C-N(R 4 )-L 3 -E 3 . [000225] In some embodiments, the compound is selected from the group consisting of:
and pharmaceutically acceptable salts, enantiomers, stereoisomers, and tautomers thereof. Methods of Treatment [000226] Compounds described herein can act as RAF inhibitors, e.g., BRAF inhibitors or CRAF inhibitors, and are therefore useful in the treatment of diseases and disorders in patients in need thereof, such as cancer. 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 tumors, solid tumors, blood-borne cancers, acute myelogenous leukemia (AML), or other cancers caused by activation of the RAS ^RAF ^MEK ^ERK signaling pathway. In some embodiments, a 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 RAS Q61R or Q61K mutation. In some embodiments, the cancer has a NF1 oncogenic mutation. In some embodiments, the lung cancer is non-small lung cancer (NSCL). In some embodiments, the colorectal cancer is colon cancer. In some embodiments, the colorectal cancer is rectal cancer. [000227] The compounds provided herein may be administered to patients (animals and humans) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. It will be appreciated that the dose required for use in any particular application will vary from patient to patient, not only with the particular compound or composition selected, but also with the route of administration, the nature of the condition being treated, the age and condition of the patient, concurrent medication or special diets then being followed by the patient, and other factors which those skilled in the art will recognize, with the appropriate dosage ultimately being at the discretion of the attendant physician. For treating clinical conditions and diseases noted above, a compound provided herein may 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 may include subcutaneous injections, intravenous or intramuscular injections or infusion techniques. [000228] Treatment can be continued for as long or as short a period as desired. The compositions may be administered on a regimen of, for example, one to four or more times per day. 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 1 year, or indefinitely. A treatment period can terminate when a desired result is achieved. Combination Therapy [000229] Compounds described herein, e.g., a compound of Formula I as defined herein (or a compound of Formula I-A, I-AA, I-AB, I-AC, I-B, I-B, I-C, I-CA, I-D, I-DA, I-DB, I-E, I-EA, I-EB, I-F, I-FA, I-G, I-GA, I-H, I-HA, I-J, I-JA, I-K, I-KA, I-L, I-LA, I-M, I-N, I-NA, I-O, I-O, I-P, I-PA, I-Q, I-QA, I-R, I-RA, I-S, I-SA-i, I-SA-ii, or I-T), can be administered in combination with one or more additional therapeutic agents to treat a disorder described herein, such as a cancer described herein. For example, provided in the present disclosure is a pharmaceutical composition comprising a compound described herein, e.g., a compound of Formula I as defined herein (or a compound of Formula I-A, I-AA, I-AB, I-AC, I-B, I-B, I-C, I-CA, I-D, I-DA, I-DB, I-E, I-EA, I-EB, I-F, I-FA, I-G, I-GA, I-H, I-HA, I-J, I-JA, I-K, I-KA, I-L, I-LA, I-M, I-N, I-NA, I-O, I-O, I-P, I-PA, I-Q, I-QA, I-R, I-RA, I-S, I-SA-i, I-SA-ii, or I- T), one or more additional therapeutic agents, and a pharmaceutically acceptable excipient. In some embodiments, a compound of Formula I as defined herein (or a compound of Formula I- A, I-AA, I-AB, I-AC, I-B, I-B, I-C, I-CA, I-D, I-DA, I-DB, I-E, I-EA, I-EB, I-F, I-FA, I-G, I- GA, I-H, I-HA, I-J, I-JA, I-K, I-KA, I-L, I-LA, I-M, I-N, I-NA, I-O, I-O, I-P, I-PA, I-Q, I-QA, I-R, I-RA, I-S, I-SA-i, I-SA-ii, or I-T) and one additional therapeutic agent is administered. In some embodiments, a compound of Formula I as defined herein (or a compound of Formula I- A, I-AA, I-AB, I-AC, I-B, I-B, I-C, I-CA, I-D, I-DA, I-DB, I-E, I-EA, I-EB, I-F, I-FA, I-G, I- GA, I-H, I-HA, I-J, I-JA, I-K, I-KA, I-L, I-LA, I-M, I-N, I-NA, I-O, I-O, I-P, I-PA, I-Q, I-QA, I-R, I-RA, I-S, I-SA-i, I-SA-ii, or I-T) and two additional therapeutic agents are administered. In some embodiments, a compound of Formula I as defined herein (or a compound of Formula I-A, I-AA, I-AB, I-AC, I-B, I-B, I-C, I-CA, I-D, I-DA, I-DB, I-E, I-EA, I-EB, I-F, I-FA, I-G, I-GA, I-H, I-HA, I-J, I-JA, I-K, I-KA, I-L, I-LA, I-M, I-N, I-NA, I-O, I-O, I-P, I-PA, I-Q, I- QA, I-R, I-RA, I-S, I-SA-i, I-SA-ii, or I-T) 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 Formula I as defined herein (or a compound of Formula I-A, I-AA, I-AB, I-AC, I-B, I-B, I-C, I-CA, I-D, I-DA, I-DB, I-E, I-EA, I-EB, I-F, I-FA, I-G, I-GA, I-H, I-HA, I-J, I-JA, I-K, I-KA, I-L, I-LA, I-M, I-N, I-NA, I-O, I-O, I-P, I-PA, I-Q, I-QA, I-R, I-RA, I-S, I-SA-i, I-SA-ii, or I- T) 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, for example a pharmaceutical composition comprising a compound of Formula I (or a compound of Formula I-A, I-AA, I-AB, I-AC, I-B, I-B, I-C, I-CA, I-D, I-DA, I-DB, I-E, I-EA, I-EB, I-F, I-FA, I-G, I-GA, I-H, I-HA, I-J, I-JA, I-K, I-KA, I-L, I-LA, I-M, I- N, I-NA, I-O, I-O, I-P, I-PA, I-Q, I-QA, I-R, I-RA, I-S, I-SA-i, I-SA-ii, or I-T) as one therapeutic agent and one or more additional therapeutic agents such as a MAPK pathway inhibitor or chemotherapeutic agent. For example, a compound of Formula I as defined herein (or a compound of Formula I-A, I-AA, I-AB, I-AC, I-B, I-B, I-C, I-CA, I-D, I-DA, I-DB, I-E, I-EA, I-EB, I-F, I-FA, I-G, I-GA, I-H, I-HA, I-J, I-JA, I-K, I-KA, I-L, I-LA, I-M, I-N, I-NA, I-O, I-O, I-P, I-PA, I-Q, I-QA, I-R, I-RA, I-S, I-SA-i, I-SA-ii, or I-T) and an additional therapeutic agent can be administered in a single formulation. Other combinations are also encompassed by combination therapy. While the two or more agents in the combination therapy can be administered simultaneously, they need not be. For example, administration of a first agent (or combination of agents) can precede administration of a second agent (or combination of agents) by minutes, hours, days, or weeks. Thus, the 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, 14 days of each other or within 2, 3, 4, 5, 6, 7, 8, 9, or weeks of each other. In some cases, even longer intervals are possible. While in many cases it is desirable that the two or more agents used in a combination therapy be present in within the patient's body at the same time, this need not be so. [000230] Combination therapy can also include two or more administrations of one or more of the agents used in the combination using different sequencing of the component agents. For example, if agent X and agent Y are used in a combination, one could administer them sequentially in any combination one or more times, e.g., in the order X-Y-X, X-X-Y, Y-X-Y, Y-Y-X, X-X-Y-Y, etc. [000231] In some embodiments, compounds described herein are combined with other agents including MAPK pathway inhibitors. In some embodiments, the other agent is an inhibitor of RAS. In some embodiments, the other agent is an inhibitor of RAS. In some embodiments, the other agent is an inhibitor of oncogenic KRAS. In some embodiments, the other agent is an inhibitor of KRAS G12C. In some embodiments, the other agent is an inhibitor of RAS. In some embodiments, the other agent is an inhibitor of KRAS G12D. In some embodiments, the other agent is a MEK inhibitor. In some embodiments the other agent is an ERK inhibitor. [000232] In some embodiments, compounds described herein are combined with an immunomodulatory agent. In some embodiments, the immunomodulatory enhances the adaptive immune response. In some embodiments, the immunomodulatory 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 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. [000233] In some embodiments, the one or more additional therapeutic agents that may be administered in combination with a compound provided herein can be a MAPK pathway inhibitor. Such MAPK pathway inhibitors include, for example, MEK inhibitors, ERK inhibitors, and Ras inhibitors. [000234] Exemplary MEK inhibitors include, but are not limited to, trametinib, selumetinib, cobimetinib, binimetinib, and pharmaceutically acceptable salts thereof. Exemplary ERK inhibitors include, but are not limited to, 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. [000235] In some embodiments, the additional therapeutic agents can be immunomodulatory agents including but not limited to anti-PD-1 or anti-PDL-1 therapeutics including pembrolizumab, nivolumab, pidilizumab, cemiplimab, atezolizumab, durvalumab, BMS-936559, or avelumab. In some embodiments, the additional therapeutic agents can be anti-TIM3 (anti-HAVcr2) therapeutics including but not limited to TSR-022 or MBG453, anti- LAG3 therapeutics including but not limited to relatlimab, LAG525, or TSR-033, anti-4-1BB (anti-CD37, anti-TNFRSF9), CD40 agonist therapeutics including but not limited to SGN-40, CP-870,893 or RO7009789, anti-CD47 therapeutics including but not limited to Hu5F9-G4, anti-CD20 therapeutics, anti-CD38 therapeutics, STING agonists including but not limited to ADU-S100, MK-1454, ASA404, or amidobenzimidazoles. In some embodiments, the additional therapeutic agents can be anti-CTLA4 agents including ipilimumab, tremelimumab. In some embodiments, the additional therapeutic agents can be hypomethylating agents including but not limited to azacytidine or decitabine, other immunomodulatory therapeutics including but not limited to epidermal growth factor inhibitors, statins, metformin, angiotensin receptor blockers, thalidomide, lenalidomide, pomalidomide, prednisone, or dexamethasone. In some embodiments, the additional therapeutic agents can be immunotherapeutic agents including targeted therapeutic agents, cancer vaccines, and CAR-T cell therapy. [000236] The compounds described herein may be administered in combination with other therapeutic agents known to treat cancers. Such other therapeutic agents include radiation therapy, anti-tubulin agents, DNA alkylating agents, DNA synthesis-inhibiting agents, DNA intercalating agents, anti-estrogen agents, anti-androgens, steroids, anti-EGFR agents, 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, anti-angiogenic agents, proteasome inhibitors, PARP (poly ADP ribose polymerase) inhibitors, cell cycle regulating kinase inhibitors, thalidomide, lenalidomide, antibody-drug-conjugates (ADCs). [000237] In an embodiment, the additional therapeutic agents can be chemotherapeutic agents including but not limited to an anti-tubulin agents (for example, paclitaxel, paclitaxel protein-bound particles for injectable suspension including but not limited to nab-paclitaxel, eribulin, docetaxel, ixabepilone, vincristine, auristatins, or maytansinoids), vinorelbine, DNA- alkylating agents (including but not limited to cisplatin, carboplatin, oxaliplatin, cyclophosphamide, ifosfamide, temozolomide), DNA intercalating agents or DNA topoisomerase inhibitors (including but not limited to anthracyclines such as doxorubicin, pegylated liposomal doxorubicin, daunorubicin, idarubicin, mitoxantrone, or epirubicin, camptothecins such as topotecan, irinotecan, or exatecan), 5-fluorouracil, capecitabine, cytarabine, decitabine, 5-aza cytadine, gemcitabine and methotrexate. [000238] In some embodiments, the additional therapeutic agents can be kinase inhibitors 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, dasatinib, imatinib, nilotinib, idelalisib, ibrutinib, BLU-667, Loxo 292, larotrectinib, and quizartinib, [000239] In some embodiments, the additional therapeutic agents can be anti-estrogen agents including but not limited to tamoxifen, fulvestrant, anastrozole, letrozole, and exemestane, anti-androgen agents including but not limited to abiraterone acetate, enzalutamide, nilutamide, bicalutamide, flutamide, cyproterone acetate, steroid agents including but not limited to prednisone and dexamethasone, PARP inhibitors including but not limited to neraparib, olaparib, talazoparib, and rucaparib, topoisomerase I inhibitors including but not limited to irinotecan, camptothecin, exatecan, and topotecan, topoisomerase II inhibitors including but not limited to anthracyclines, etoposide, etoposide phosphate, and mitoxantrone, Histone Deacetylase (HDAC) inhibitors including but not limited to vorinostat, romidepsin, panobinostat, valproic acid, and belinostat, DNA methylation inhibitors including but not limited to DZNep and 5-aza-2′-deoxycytidine, proteasome inhibitors including but not limited to bortezomib and carfilzomib, biological agents including but not limited to trastuzumab, ado-trastuzumab, pertuzumab, cetuximab, and panitumumab. [000240] In some embodiments, the additional therapeutic agents can be anti-angiogenic agents including but not limited to bevacizumab, rebastinib, aflibercept, and AMG386. [000241] In some embodiments, the additional therapeutic agents can be antibody-drug- conjugates (ADCs) including but not limited to ADCs containing DM1, DM4, MMAE, MMAF, or camptothecin payloads, brentuximab vedotin and trastuzumab emtansine, radiotherapy, therapeutic vaccines including but not limited to sipuleucel-T. [000242] In some embodiments, the additional therapeutic agent can be autophagy inhibitors, inhibitors of vesicular trafficking, including but not limited to ULK inhibitors such as ULK1 inhibitors, ULK2 inhibitors, ULK1/ULK2 inhibitors, VPS34 inhibitors, PPT1 inhibitors, or lysosomal blocking agents. In some embodiments, the additional therapeutic agent can be DCC-3116, SAR405, SB02024, hydroxychloroquine, chloroquine, and LYS05. [000243] In some embodiments, the additional therapeutic agent can be EGFR inhibitors including, but not limited to, cetuximab, osimertinib, and afatinib, and pharmaceutically acceptable salts thereof. [000244] In some embodiments, the additional therapeutic agent is selected from a luteinizing hormone-releasing hormone (LHRH) analog, including goserelin and leuprolide. [000245] In some embodiments, the additional therapeutic agent is selected from the group consisting of selected from the group consisting of everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurin, vandetanib, ARQ-197, MK-0457, MLN8054, PHA-739358, R-763, AT-9263, pemetrexed, erlotinib, dasatanib, nilotinib, decatanib, panitumumab, amrubicin, oregovomab, Lep-etu, nolatrexed, AZD 2171, batabulin, of atumtunab, zanolimumab, edotecarin, tetrandrine, rubitecan, tesmilifene, oblimersen, ticilimumab, ipilimumab, gossypol, Bio 111, 131-I-TM-601, ALT- 110, BIO 140, CC 8490, cilengitide, gimatecan, IL13-PE38QQR, INO 1001, IPdR1 KRX- 0402, lucanthone, LY 317615, neuradiab, vitespan, Rta 744, alanosine (Sdx 102), talampanel, atrasentan, XR 311, romidepsin, ADS-100380, sunitinib, 5-fluorouracil, vorinostat, etoposide, gemcitabine, doxorubicin, irinotecan, liposomal doxorubicin, 5'-deoxy-5-fluorouridine, vincristine, temozolomide, ZK-304709, seliciclib; PD0325901, AZD-6244, capecitabine, L- Glutamic acid, N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidi n-5-yl)- ethyl]benzoyl]-, disodium salt, heptahydrate, camptothecin, PEG-labeled irinotecan, tamoxifen, toremifene citrate, anastrazole, exemestane, letrozole, DES(diethylstilbestrol), estradiol, estrogen, conjugated estrogen, bevacizumab, IMC-1C11, CHIR-258, 3-[5- (methylsulfonylpiperadinemethyl)-indolylj-quinolone, vatalanib, AG-013736, AVE-0005, the acetate salt of [D-Ser(tBu) 6, Azgly 10] (pyro-Glu-His-Trp-Ser-Tyr-D-Ser(tBu)-Leu-Arg-Pro- Azgly-NH 2 acetate [C 59 H 84 N 18 O 14 -(C 2 H 4 O 2 ) x where x=1 to 2.4], goserelin acetate, leuprolide acetate, triptorelin pamoate, medroxyprogesterone acetate, hydroxyprogesterone caproate, megestrol acetate, raloxifene, bicalutamide, flutanide, nilutamide, megestrol acetate, CP- 724714; TAK-165, HKI-272, erlotinib, lapatanib, canertinib, ABX-EGF antibody, erbitux, EKB-569, PKI-166, GW-572016, ionafarnib, BMS-214662, tipifarnib; amifostine, NVP- LAQ824, suberoyl analide hydroxamic acid, valproic acid, trichostatin A, FK-228, SU11248, sorafenib, KRN951, aminoglutethimide, arnsacrine, anagrelide, L-asparaginase, Bacillus Calmette-Guerin (BCG) vaccine, bleomycin, buserelin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, clodronate, cyproterone, cytarabine, dacarbazine, dactinomycin, daunorubicin, diethylstilbestrol, epirubicin, fludarabine, fludrocortisone, fluoxymesterone, flutamide, gemcitabine, gleevac, hydroxyurea, idarubicin, ifosfamide, imatinib, leuprolide, levamisole, lomustine, mechlorethamine, melphalan, 6-mercaptopurine, mesna, methotrexate, mitomycin, mitotane, mitoxantrone, nilutamide, octreotide, oxaliplatin, pamidronate, pentostatin, plicamycin, porfimer, procarbazine, raltitrexed, rituximab, streptozocin, teniposide, testosterone, thalidomide, thioguanine, thiotepa, tretinoin, vindesine, 13-cis-retinoic acid, phenylalanine mustard, uracil mustard, estramustine, altretamine, floxuridine, 5-deooxyuridine, cytosine arabinoside, 6-mecaptopurine, deoxycoformycin, calcitriol, valrubicin, mithramycin, vinblastine, vinorelbine, topotecan, razoxin, marimastat, COL-3, neovastat, BMS-275291, squalamine, endostatin, SU5416, SU6668, EMD121974, interleukin-12, IM862, angiostatin, vitaxin, droloxifene, idoxyfene, spironolactone, finasteride, cimitidine, trastuzumab, denileukin diftitox, gefitinib, bortezimib, irinotecan, topotecan, doxorubicin, docetaxel, vinorelbine, bevacizumab (monoclonal antibody) and erbitux, cremophor-free paclitaxel, epithilone B, BMS-247550, BMS-310705, droloxifene, 4- hydroxytamoxifen, pipendoxifene, ERA-923, arzoxifene, fulvestrant, acolbifene, lasofoxifene, idoxifene, TSE-424, HMR-3339, ZK186619, PTK787/ZK 222584, VX-745, PD 184352, rapamycin, 40-O-(2-hydroxyethyl)-rapamycin, temsirolimus, AP-23573, RAD001, ABT-578, BC-210, LY294002, LY292223, LY292696, LY293684, LY293646, wortmannin, ZM336372, L-779450, PEG-filgrastim, darbepoetin, erythropoietin, granulocyte colony-stimulating factor, zolendronate, prednisone, cetuximab, granulocyte macrophage colony-stimulating factor, histrelin, pegylated interferon alfa-2a, interferon alfa-2a, pegylated interferon alfa-2b, interferon alfa-2b, azacitidine, PEG-L-asparaginase, lenalidomide, gemtuzumab, hydrocortisone, interleukin-11, dexrazoxane, alemtuzumab, all-transretinoic acid, ketoconazole, interleukin-2, megestrol, immune globulin, nitrogen mustard, methylprednisolone, ibritgumomab tiuxetan, androgens, decitabine, hexamethylmelamine, bexarotene, tositumomab, arsenic trioxide, cortisone, editronate, mitotane, cyclosporine, liposomal daunorubicin, Edwina-asparaginase, strontium 89, casopitant, netupitant, an NK-1 receptor antagonist, palonosetron, aprepitant, diphenhydramine, hydroxyzine, metoclopramide, lorazepam, alprazolam, haloperidol, droperidol, dronabinol, dexamethasone, methylprednisolone, prochlorperazine, granisetron, ondansetron, dolasetron, tropisetron, pegfilgrastim, erythropoietin, epoetin alfa and darbepoetin alfa, ipilumumab, and mixtures thereof. Pharmaceutical Compositions and Kits [000246] Another aspect of this disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with a pharmaceutically acceptable carrier. In particular, the present disclosure provides pharmaceutical compositions comprising compounds as disclosed herein formulated together with one or more pharmaceutically acceptable carriers. These formulations include those suitable for oral, rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal, or intravenous) rectal, vaginal, or aerosol administration, although the most suitable form of administration in any given case will depend on the degree and severity of the condition being treated and on the nature of the particular compound being used. For example, disclosed compositions may be formulated as a unit dose, and/or may be formulated for oral or subcutaneous administration. [000247] Exemplary pharmaceutical compositions may be used in the form of a pharmaceutical preparation, for example, in solid, semisolid or liquid form, which contains one or more of the compounds described herein, as an active ingredient, in admixture with an organic or inorganic carrier or excipient suitable for external, enteral or parenteral applications. The active ingredient may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The active object compound is included in the pharmaceutical composition in an amount sufficient to produce the desired effect upon the process or condition of the disease. [000248] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical carrier, e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g., water, to form a solid preformulation composition containing a homogeneous mixture of a compound provided herein, or a non-toxic pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. [000249] In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules and the like), the subject composition is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glycerol monostearate; (8) absorbents, such as kaolin and bentonite clay; (9) lubricants, such a talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like. [000250] A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the subject composition moistened with an inert liquid diluent. Tablets, and other solid dosage forms, such as dragees, capsules, pills and granules, may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. [000251] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous, or organic solvents, or mixtures thereof, and powders. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the subject composition, the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, cyclodextrins and mixtures thereof. [000252] Suspensions, in addition to the subject composition, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. [000253] Formulations for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing a subject composition with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the body cavity and release the active agent. [000254] Dosage forms for transdermal administration of a subject composition include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active component may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required. [000255] The ointments, pastes, creams and gels may contain, in addition to a subject composition, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof. [000256] Powders and sprays may contain, in addition to a subject composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances. Sprays may additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. [000257] Compositions and compounds of the present disclosure may alternatively be administered by aerosol. This is accomplished by preparing an aqueous aerosol, liposomal preparation or solid particles containing the compound. A non-aqueous (e.g., fluorocarbon propellant) suspension could be used. Sonic nebulizers may be used because they minimize exposing the agent to shear, which may result in degradation of the compounds contained in the subject compositions. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of a subject composition together with conventional pharmaceutically acceptable carriers and stabilizers. The carriers and stabilizers vary with the requirements of the particular subject composition, but typically include non-ionic surfactants (Tweens, Pluronics, or polyethylene glycol), innocuous proteins like serum albumin, sorbitan esters, oleic acid, lecithin, amino acids such as glycine, buffers, salts, sugars or sugar alcohols. Aerosols generally are prepared from isotonic solutions. [000258] Pharmaceutical compositions of the present disclosure suitable for parenteral administration comprise a subject composition in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents. [000259] Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions provided herein include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate and cyclodextrins. Proper fluidity may be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. [000260] In another embodiment, provided are enteral pharmaceutical formulations including a disclosed compound and an enteric material, and a pharmaceutically acceptable carrier or excipient thereof. Enteric materials refer to polymers that are substantially insoluble in the acidic environment of the stomach, and that are predominantly soluble in intestinal fluids at specific pHs. The small intestine is the part of the gastrointestinal tract (gut) between the stomach and the large intestine, and includes the duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5, the pH of the jejunum is about 6.5 and the pH of the distal ileum is about 7.5. [000261] Accordingly, enteric materials are not soluble, for example, until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, of about 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, of about 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, of about 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, of about 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, of about 9.8, or of about 10.0. Exemplary enteric materials include cellulose acetate phthalate (CAP), hydroxypropyl methylcellulose phthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate trimellitate, hydroxypropyl methylcellulose succinate, cellulose acetate succinate, cellulose acetate hexahydrophthalate, cellulose propionate phthalate, cellulose acetate maleate, cellulose acetate butyrate, cellulose acetate propionate, copolymer of methylmethacrylic acid and methyl methacrylate, copolymer of methyl acrylate, methylmethacrylate and methacrylic acid, copolymer of methylvinyl ether and maleic anhydride (Gantrez ES series), ethyl methyacrylate-methylmethacrylate- chlorotrimethylammonium ethyl acrylate copolymer, natural resins such as zein, shellac and copal collophorium, and several commercially available enteric dispersion systems (e.g., Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit S100, Kollicoat EMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of each of the above materials is either known or is readily determinable in vitro. The foregoing is a list of possible materials, but one of skill in the art with the benefit of the disclosure would recognize that it is not comprehensive and that there are other enteric materials that would meet the objectives described herein. [000262] Advantageously, provided herein are kits for use by a e.g., a consumer in need of treatment of cancer. Such kits include a suitable dosage form such as those described above and instructions describing the method of using such dosage form to mediate, reduce or prevent inflammation. The instructions would direct the consumer or medical personnel to administer the dosage form according to administration modes known to those skilled in the art. Such kits could advantageously be packaged and sold in single or multiple kit units. An example of such a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process recesses are formed in the plastic foil. The recesses have the size and shape of the tablets or capsules to be packed. Next, the tablets or capsules are placed in the recesses and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are sealed in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening. [000263] It may be desirable to provide a memory aid on the kit, e.g., in the form of numbers next to the tablets or capsules whereby the numbers correspond with the days of the regimen which the tablets or capsules so specified should be ingested. Another example of such a memory aid is a calendar printed on the card, e.g., as follows "First Week, Monday, Tuesday, ... etc.... Second Week, Monday, Tuesday, ... " etc. Other variations of memory aids will be readily apparent. A "daily dose" can be a single tablet or capsule or several pills or capsules to be taken on a given day. Also, a daily dose of a first compound can consist of one tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa. The memory aid should reflect this. EXAMPLES [000264] The compounds described herein can be prepared in a number of ways based on the teachings contained herein and synthetic procedures known in the art. In the description of the synthetic methods described below it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be chosen to be the conditions standard for that reaction, unless otherwise indicated. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule should be compatible with the reagents and reactions proposed. Substituents not compatible with the reaction conditions will be apparent to one skilled in the art, and alternate methods are therefore indicated. The starting materials for the examples are either commercially available or are readily prepared by standard methods from known materials. [000265] The following abbreviation are used in this disclosure and have the following definitions: “ADP” is adenosine diphosphate, “Ag 2 CO 3 ” is silver acetate, “aq” is aqueous, “ATP” is adenosine triphosphate, “Ar” is argon gas, “Boc” is t-butylcarbonate, “BSA” is bovine serum albumin, “conc” is concentrated, “Cs2CO3” is cesium carbonate, “CuI” is copper (I) iodide, “DCM” is dichloromethane, “DIEA” is N,N-diisopropylethylamine, “DMF” is N,N- dimethylformamide, “dppf” is 1,1′-bis(diphenylphosphino)ferrocene, “DMSO-d6” is dimethylsulfoxide-deuterium, “EDC” is 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, “ESI” is electrospray ionization, “EtOAc” is ethyl acetate, “EtOH” is ethanol, “GST” is glutathione S-transferase, “h” is hour or hours, “HATU” is hexafluorophosphate azabenzotriazole tetramethyl uronium, “H2” is hydrogen gas, “HCl” is hydrochloric acid, “H 2 O” is water, “IC 50 ” is half maximal inhibitory concentration, “K 2 CO 3 ” is potassium carbonate, “KOAc” is potassium acetate, “K3PO4” is potassium phosphate, “LiOH” is lithium hydroxide, “mCPBA” is meta-Chloroperoxybenzoic acid, “MeCN” is acetonitrile, “MeOH” is methanol, “MgSO4” is magnesium sulfate, “MHz” is megahertz, “min” is minute or minutes, “MS” is mass spectrometry, “m/z” is mass/charge number, “NaCN” is sodium cyanide, “NADH” is nicotinamide adenine dinucleotide, “NaH” is sodium hydride, “NaHCO3” is sodium bicarbonate, “NaOEt” is sodium methoxide, “Na 2 SO 4 ” is sodium sulfate, “NH 4 Cl” is ammonium chloride, “NH4OH” is ammonium hydroxide, “NMR” is nuclear magnetic resonance, “OMs” is O-mesylate, “PBS” is phosphate buffered saline, “Pd” is palladium, “Pd/C” is palladium on carbon, “Pd(OAc)2” is palladium (II) acetate, “rt” is room temperature which is also known as “ambient temp,” which will be understood to consist of a range of normal laboratory temperatures ranging from 15-25 °C, “sat’d.” is saturated, “SFC” is supercritical fluid chromatography, “SM” is starting material, “SNAr” is nucleophilic aromatic substitution, “TCFH” is chloro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate, “T3P” is 1-propanephosphonic acid anhydride, “TBAF” is tetrabutyl ammonium fluoride, “TEA” is triethylamine, “TFA” is trifluoroacetic acid, “THF” is tetrahydrofuran, “Xantphos” is 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, “X-Phos” is 2-dicyclohexylphosphino- 2′,4′,6′-triisopropylbiphenyl and “ZnCl 2 ” is zinc chloride. General Chemistry [000266] Exemplary compounds described herein are available by the general synthetic methods illustrated in the Schemes below, intermediate preparations, and the accompanying Examples. Synthetic Schemes Scheme 1 [000267] Scheme 1 illustrates an exemplary preparation of boronates 1-4. Amines 1-1 react with carboxylic acids E 1 -L 1 -COOH (commercially available or synthesized by those skilled in the art) to afford amides 1-2. Compounds 1-2 upon borylation provide boronates 1- 4. Borylation is a well-documented reaction to those skilled in the art (for example, Pd (0) catalyzed reaction with bis(pinacolato)diboron). Alternatively, boronates 1-4 can be prepared by amide coupling reaction of 1-3 (commercially available or synthesized by Pd-catalyzed borylation from 1-1) with acids E 1 -L 1 -COOH in the presence of coupling reagents such as T3P, TCFH, HATU, and EDC. Scheme 2 [000268] Scheme 2 illustrates an exemplary preparation of intermediates 2-4. Treatment of boronates 2-1 (commercially available or synthesized by those skilled in the art) with bromides 1-1 in the presence of a palladium catalyst (Suzuki reaction) affords 2-2. Compounds 2-2 (X 2 = N and Y = F) react with alcohols E 3 -L 3 -OH or amines E 3 -L 3 -N(R 4 )H by SNAr reaction in the presence of base to afford 2-3a and 2-3b, respectively. Alternatively, compounds 2-2 (X 2 = N or CH and Y = Cl) react with boronates or boronic acids E 3 -L 3 -X 31 - B(OR)2 (X 31 = direct bond) under Pd (0) catalyzed coupling conditions using well known established literature conditions to those skilled in the art to afford 2-3c. Amines 2-3a, 2-3b and 2-3c can be reacted with acids E 1 -L 1 -COOH (commercially available or synthesized by those skilled in the art) to form amides 2-4a, 2-4b and 2-4c, respectively under a typical amide coupling condition. In another embodiment, Suzuki reaction of 2-1 (X 2 = N, CH and Y = H, alkyl: commercially available or synthesized by those skilled in the art) with boronates 1-2 affords intermediates, 2-4d and 2-4e, respectively. [000269] Scheme 3 illustrates an exemplary preparation of intermediates 3-4a and 3-4b. 4-bromo-6-chloropyridin-2-ol (3-1) reacts with alkylating reagents E 3 -L 3 -X (X = Cl, Br, I, OMs) in the presence of base such as Ag 2 CO 3 in an aprotic solvent like toluene to produce a mixture of O-alkylated (3-2a) and N-alkylated (3-2b) compounds which can be separated by a suitable method such as SFC purification, crystallization or chromatography. Each of 3-2a and 3-2b reacts with boronates 1-3 under Suzuki reaction conditions to afford 3-3a and 3-3b, respectively. Amide coupling reaction of 3-3a and 3-3b with carboxylic acids E 1 -L 1 -COOH affords 3-4a and 3-4b, respectively. In another embodiment, Suzuki reaction of 3-2a and 3- 2b with boronates 1-4 affords 3-4a and 3-4b, respectively. Scheme 4 [000270] Scheme 4 illustrates an exemplary preparation of intermediates 4-4a and 4-4b. In a similar manner as described in scheme 3, 4-1 reacts with alkylating reagents E 3 -L 3 -X (X = Cl, Br, I, OMs ) to produce a mixture of O-alkylated (4-2a) and N-alkylated (4-2b) compounds which can be separated by a suitable method well known to those skilled in the art. Suzuki reaction of 4-2a and 4-2b with boronates 1-3 affords 4-3a and 4-3b, respectively. Finally, each of 4-3a and 4-3b upon treatment with carboxylic acids E 1 -L 1 -COOH under amide coupling conditions affords 4-4a and 4-4b, respectively. In another embodiment, Suzuki reaction of 4-2a and 4-2b with boronates 1-4 affords 4-4a and 4-4b, respectively. Scheme 5
[000271] Scheme 5 illustrates an exemplary preparation of pyridazine intermediates 5-4, 5-6 and 5-7.5-Bromo-3-chloropyridazine 5-1 reacts with alcohols or amines U-H to afford 5- 2 by S N Ar reaction. U-substituted bromides 5-2 react with boronates 1-3 to afford 5-4 by Pd catalyzed Suzuki reactions. Alternatively, the treatment of 5-bromo-3-chloropyridazine 5-1 with boronates 1-3 under Suzuki reaction conditions affords 5-3. Chlorides 5-3 react with boronates or boronic acids U-B(OR)21-7 to provide 5-4 by Pd (0) catalyzed Suzuki reaction. Chlorides 5-3 react with carboxylic acids E 1 -L 1 -COOH under amide coupling conditions to afford intermediates 5-7. Alternatively intermediates 5-7 can be directly prepared from 5-1 with boronates 1-4 by Suzuki reaction. The treatment of 5-bromo-3-chloropyridazine 5-1 with boronates or boronic acids U-B(OR)21-7 under Suzuki reaction conditions affords 5-5. U-substituted chlorides 5-5 react with boronates 1-3 to provide 5-6 by Pd (0) catalyzed Suzuki reaction. Scheme 6 [000272] Scheme 6 illustrates an exemplary preparation of intermediates 6-4.4,6- Dichloro-2-(methylthio)pyrimidine (6-1) reacts with boronates 1-5 in the presence of a palladium catalyst (Suzuki reaction), followed by nitro reduction of the resulting intermediate under mild reducing conditions (zinc or iron metal with ammonium chloride) to afford 6-2. Compounds 6-2 upon treatment with carboxylic acids E 1 -L 1 -COOH under amide coupling conditions afford 6-3. Alternatively, 6-3 can be directly prepared from 6-1 with boronates 1-4 by Suzuki reaction. Finally, chlorides 6-3 react with boronates or boronic acids U-B(OR)21-7 (commercially available or synthesized by those skilled in the art) by Suzuki reaction to afford 6-4. Scheme 7 [000273] Scheme 7 illustrates an exemplary preparation of compounds of Formula I. 2,6-Dichloropyrazine (7-1) reacts with boronates 1-5 by Suzuki reaction to afford 7-2 which can be subjected to another Suzuki reaction with boronates or boronic acids U-B(OR) 2 1-7 to furnish 7-3. Finally, nitro reduction of 7-3 under mild reducing conditions (zinc or iron metal with ammonium chloride) affords the corresponding amines which can be reacted with carboxylic acids E 1 -L 1 -COOH under amide coupling conditions to afford compounds of Formula I. [000274] Scheme 8 illustrates an exemplary preparation of compounds of Formula I. Compounds either 2,4-dichloropyrimidine or 4-bromo-2-chloropyrimidine (8-1) react with boronates 1-4 by Suzuki reaction to afford 8-2a which can be subjected to another Suzuki reaction with boronates or boronic acids U-B(OR)21-7 to furnish compounds of Formula I. In a similar manner, compounds either 2,4-dichloropyrimidine or 4-bromo-2- chloropyrimidine (8-1) react with boronates or boronic acids U-B(OR)21-7 by Suzuki reaction to afford 8-2a which can be subjected to another Suzuki reaction with boronates 1-4 to furnish compounds of Formula I. Scheme 9 [000275] Scheme 9 illustrates an exemplary preparation of intermediates 9-3. Treatment of bromides 9-1 (commercially available or synthesized by those skilled in the art) with boronates 1-5 (commercially available or synthesized by those skilled in the art) in the presence of a palladium catalyst (Suzuki reaction) affords amines 9-2. Amines 9-2 react with carboxylic acids E 1 -L 1 -COOH under amide coupling conditions to those skilled in the art to afford 9-3. In another embodiment, bromides 9-1 react with boronates 1-4 by Suzuki reaction to afford 9-3. Scheme 10 [000276] Scheme 10 illustrates an exemplary preparation of intermediates 10-4. Treatment of 2,6-dichloropyridin-4-amine (10-1a, R = NH 2 ) with boronates 1-5 (commercially available or synthesized by those skilled in the art) in the presence of a palladium catalyst (Suzuki reaction) affords 10-2. Treatment of 10-2 with aldehydes or ketones to introduce R 4 by reductive alkylation known to those skilled in the art gives the R 4 substituted secondary amines. N-alkylation of the secondary amines with different alkylating reagents (E 3 -L 3 -X: X = Cl, Br, OMs) in the presence of base affords 10-3. Nitro reduction of 10-3 under mild reducing conditions (zinc or iron metal with ammonium chloride) affords amines which are reacted with carboxylic acids E 1 -L 1 -COOH under amide coupling conditions to those skilled in the art to afford 10-4a (R 3 = N(R 4 )-L 3 -E 3 ). In another embodiment, commercially available 10-1b (R = H, alkyl) reacts with boronates 1-4 by Suzuki reaction to afford 10-4b (R 3 = H, alkyl). Scheme 11 [000277] Scheme 11 illustrates an exemplary preparation of compounds of Formula I. Treatment of boronates 2-1 (commercially available or synthesized by those skilled in the art) with chloride or bromides 1-6 (commercially available or synthesized by those skilled in the art) in the presence of a palladium catalyst (Suzuki reaction) affords 11-1. Compound 11-1 (Y = F) reacts with alcohols E 3 -L 3 -OH or amines E 3 -L 3 -N(R 4 )H by S N Ar reaction in the presence of base to afford 11-2a. Alternatively, compound 11-1 (Y = Cl) reacts with boronates or boronic acids E 3 -L 3 -X 31 -B(OR) 2 (X 31 = direct bond) under Pd (0) catalyzed coupling conditions using well known established literature conditions to those skilled in the art to afford 11-2b. Finally, chlorides 11-2 can be reacted with boronates 1-4 by Suzuki reaction to afford compounds of Formula I. Scheme 12 [000278] Scheme 12 illustrates an exemplary preparation of compounds of Formula I. Compounds of Formula I can be prepared by Suzuki reaction of chlorides (2-4, 3-4a, 3-4b, 4- 4a, 4-4b, 5-3, 8-2, 9-4 and 10-4) with boronates or boronic acids U-B(OR) 2 1-7 (commercially available or synthesized by those skilled in the art). Alternatively, chlorides (2-4, 3-4a, 3-4b, 4-4a, 4-4b, 5-3, 8-2, 9-4 and 10-4) can be converted boronates 12-1 by borylation under Pd(0) conditions. Boronates 12-1 react with U-substituted chlorides (or bromides) 1.6 (commercially available or synthesized by those skilled in the art) by Suzuki reaction to afford compounds of Formula I. Dichlorides 12-2 (commercially available or synthesized by those skilled in the art) react with boronates or boronic acids U-B(OR)21-7 (commercially available or synthesized by those skilled in the art) under Suzuki conditions to afford intermediates 12-3. Finally, compounds of Formula I can be prepared by Suzuki reaction of chlorides (12-3) with boronates 1-4. In another embodiment, sulfides 6.4 are converted to compounds of Formula I according to a well-documented reaction sequence: an oxidation reaction using conditions known in the art such as mCPBA in DCM, followed by substitution reaction of the resulting intermediate with commercially available alcohols E 3 - L 3 -OH or amines E 3 -L 3 -N(R 4 )H. Scheme 13 [000279] Scheme 13 illustrates an exemplary preparation of key intermediates 13-4. Carboxylic acids 13-1 (R = H, commercially available or synthesized by those skilled in the art) reacts with amines E 1 -L 1 -NH2 (commercially available or synthesized by those skilled in the art) by standard amide bond formation conditions which is known in the literature to afford 13-2. Bromides 13-2 convert to boronates 13-4 by Pd-catalyzed borylation. In another embodiment, 13-4 can be prepared from 13-3 (prepared by Pd-catalyzed borylation of 13-1 (R = Me)) by hydrolysis, followed by amide coupling reaction of the resulting intermediate with amines E 1- NH 2 . Scheme 14 [000280] Scheme 14 illustrates an exemplary preparation of intermediates 14-3. Treatment of boronates 2-1 (commercially available or synthesized by those skilled in the art) with bromides 13-2 in the presence of a palladium catalyst (Suzuki reaction) affords 14-2. Compounds 14-2 (X 2 = N and Y = F) react with alcohols E 3 -L 3 -OH or amines E 3 -L 3 -N(R 4 )H by SNAr reaction in the presence of base to afford 14-3a and 14-3b, respectively. Alternatively, compounds 14-2 (X 2 = N or CH and Y = Cl) react with boronates or boronic acids E 3 -L 3 -X 31 -B(OR)2 (X 31 = direct bond) under Pd (0) catalyzed coupling conditions using well known established literature conditions to those skilled in the art to afford 14-3c. In another embodiment, Suzuki reaction of 2-1 (X 2 = N or CH and Y = H or alkyl, commercially available) with bromides 13-1 affords 14-1. Hydrolysis of 14-1, followed by amide coupling reaction of the resulting intermediate with amines E 1 -L 1 -NH 2 affords intermediates 14-3d and 14-3e. Scheme 15 [000281] Scheme 15 illustrates an exemplary preparation of intermediates 15-1. Compounds 3-2a, 3-2b, 4-2a, 4-2b, 5-1,7-1, 8-1, and 9-1 react with boronates 13-4 in the presence of a palladium catalyst (Suzuki reaction) to afford 15-1. Scheme 16 [000282] Scheme 16 illustrates an exemplary preparation of intermediates 16-3. Each of 10-1a and 10-1b reacts with boronates 13-3 (commercially available or synthesized by those skilled in the art) in the presence of a palladium catalyst (Suzuki reaction) to afford 16-1a and 16-1b, respectively. Treatment of 16-1a (R = NH2) with aldehydes or ketones to introduce R 4 by reductive alkylation conditions known to those skilled in the art gives the R 4 substituted secondary amines. N-alkylation of the secondary amines with different alkylating reagents (E 3 -L 3 -X: X = Cl, Br, OMs) in the presence of base affords 16-2. Hydrolysis of 16-2 affords the corresponding acids which react with amines E 1 -L 1 -NH2 under amide coupling conditions to afford 16-3a. In a similar manner, hydrolysis of 16-1b (R = H, alkyl), followed by amide coupling reaction of the resulting intermediate with amines E 1 -L 1 -NH2 affords 16-3b. Scheme 17 [000283] Scheme 17 illustrates an exemplary preparation of intermediates 17-3.4,6- Dichloro-2-(methylthio)pyrimidine (6-1) reacts with boronates 13-3 in the presence of a palladium catalyst (Suzuki reaction) to afford 17-1. Hydrolysis of 17-1, followed by amide coupling reaction of the resulting intermediate with amines E 1 -L 1 -NH 2 affords 17-2. Alternatively, 17-2 can be directly prepared from 6-1 with boronates 13-4 by Suzuki reaction. Chlorides 17-2 react with boronates or boronic acids U-B(OR) 2 1-7 (commercially available or synthesized by those skilled in the art) by Suzuki reaction to afford 17-3. Scheme 18 [000284] Scheme 18 illustrates an exemplary preparation of compounds of Formula I. Compounds of Formula I can be prepared by Suzuki reaction of chlorides (14-3, 15-1 and 16- 3) with boronates or boronic acids U-B(OR)21-7 (commercially available or synthesized by those skilled in the art). Compound 8-2b (X 1 , X 4 = N and X 2 , X 3 = CH) reacts with boronates 13-4 in the presence of a palladium catalyst (Suzuki reaction) to afford compounds of Formula I. In another embodiment, sulfides 17-3 are converted to compounds of Formula I according to a well-documented reaction sequence: an oxidation reaction using conditions known in the art such as mCPBA in DCM, followed by substitution reaction of the resulting intermediate with commercially available alcohols E 3 -L 3 -OH or amines E 3 -L 3 -N(R 4 )H. Preparation of Intermediates. [000285] Using the synthetic procedures and methods described herein and methods known to those skilled in the art, the following compounds were made: General Method A: Borylation [000286] Intermediate A1: tert-butyl methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyridin-2-yl)carbamate [000287] A mixture of tert-butyl (4-bromopyridin-2-yl)(methyl)carbamate (0.82 g, 2.9 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.87 g, 3.4 mmol) and KOAc (0.84 g, 8.6 mmol) in DMF (15 mL) was allowed to stir at rt. The reaction mixture was sparged with Ar for 10 min. Pd(dppf)Cl 2 .DCM adduct (0.12 g, 0.14 mmol) was added and the reaction mixture was sealed and heated to 80 ºC overnight. The reaction was cooled to rt and diluted with EtOAc (30 mL). The organic layer was separated and washed with brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford a brown oil. The brown oil was treated with hexanes (20 mL) and the solid was filtered. The filtrate was concentrated to dryness under vacuum to afford tert-butyl methyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridi n-2-yl)carbamate (1.09 g, 100 % yield) as a brown solid. 1 H NMR (400 MHz, DMSO-d 6 ): ^ 8.40 (d, J = 4.8 Hz, 1H), 7.90 (s, 1H), 7.27 (d, J = 4.8 Hz, 1H), 3.29 (s, 3H), 1.48 (s, 9H), 1.30 (s, 12H); MS (ESI) m/z: 335.2 (M+H + ). [000288] Using the General Method A above, the following Intermediates of Table A were prepared. Table A.
General Method B: Suzuki Coupling Reaction [000289] Intermediate B1: 3-(2,6-dichloropyridin-4-yl)-4-methylaniline [000290] A solution of 2,6-dichloro-4-iodopyridine (2.0 g, 7.3 mmol), and 4-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.0 g, 8.8 mmol) in 1,4-dioxane (50 mL) was treated with K2CO3 (2.0 N, 7.3 mL, 15 mmol). The reaction mixture was sparged with Ar for 2 min and then Pd(dppf)Cl 2 (0.3 g, 0.37 mmol) was added. The reaction mixture was heated at 80 ºC for 20 h and then cooled to rt. The solution was filtered through a pad of celite and washed with EtOAc (50 mL). The filtrate was washed with brine and the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude. The crude was purified by silica gel column chromatography (0 to 70 % EtOAc/hexanes) to obtain 3-(2,6-dichloropyridin-4-yl)-4-methylaniline (1.7 g, 92 % yield) as a light brown solid. MS (ESI) m/z: 253.0 (M+H + ). [000291] Using the General Method B above, the `following Intermediates of Table B were prepared. Table B.
General Method C: Nitro Reduction [000292] Intermediate B46: 3-(6-chloro-2-(methylthio)pyrimidin-4-yl)-4-methylaniline [000293] A solution of 4-chloro-6-(2-methyl-5-nitrophenyl)-2-(methylthio)pyrimidine (B10, 0.53 g, 1.8 mmol) in a mixture of THF (6 mL) and MeOH (3 mL) was treated with NH4Cl (0.096 g, 1.8 mmol) and zinc (1.17 g, 1.8 mmol). The reaction mixture was stirred at rt for 1.5 h. The reaction mixture was diluted with THF (15 mL) and filtered through a pad of celite. The filtrate was concentrated under reduced pressure and the residue was dissolved in EtOAc (30 mL). The solution was washed with brine and the organic layer was dried over anhydrous Na 2 SO 4 and concentrated under reduced pressure to give 3-(6-chloro-2- (methylthio)pyrimidin-4-yl)-4-methylaniline (B46, 0.49 g, 102 % yield) as an orange residue. MS (ESI) m/z: 266.0 (M+H + ). General Method D: Hydrolysis [000294] Intermediate B47: 3-(2-chloropyridin-4-yl)-4-methylbenzoic acid [000295] A mixture of methyl 3-(2-chloropyridin-4-yl)-4-methylbenzoate (B13, 0.32 g, 1.2 mmol) and LiOH (3.0 g, 71 mmol) in a mixture of 1,4-dioxane (3.0 mL) and water (3.0 mL) was heated to 60 ºC for 2 h. The reaction mixture was cooled to rt and diluted with water (30 mL). conc-HCl was added until the reaction mixture pH = 2. The solution was treated with DCM (50 mL) and then washed with sat’d NaHCO 3 (aq, 50 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain 3- (2-chloropyridin-4-yl)-4-methylbenzoic acid (B47, 0.31 g, 100 % yield) as a white solid. MS (ESI) m/z: 248.0 (M+H + ). [000296] Using the General Method D above, the following Intermediates of Table C were prepared. Table C. General Method E: Aromatic Substitution Reaction-NaH as a base [000297] Intermediate C1: 3-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6- chloropyridin-4-yl)-4-methylaniline [000298] A solution of 2-((tert-butyldimethylsilyl)oxy)ethan-1-ol (0.42 g, 2.4 mmol) in DMF (5.0 mL) was added with NaH (0.15 g, 3.8 mmol, 60 % in mineral oil) portion wise under an ice-water bath and the reaction mixture was stirred at rt for 30 min. A solution of 3- (2-chloro-6-fluoropyridin-4-yl)-4-methylaniline (B3, 0.45 g, 1.9 mmol) in DMF (1 mL) was added into the reaction mixture and the reaction mixture was heated at 40 ºC for 2 h. The reaction mixture was quenched with sat’d NaHCO 3 (aq, 20 mL) under an ice-water bath. The solution was extracted with DCM (4 x 25 mL) and the combined organics were dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (5 to 40 % EtOAc/hexanes) to obtain 3-(2-(2-((tert- butyldimethylsilyl)oxy)ethoxy)-6-chloropyridin-4-yl)-4-methy laniline (0.47 g, 62 % yield). MS (ESI) m/z: 393.2 (M+H + ). [000299] General Method F: Aromatic Substitution Reaction-Cs 2 CO 3 as a base [000300] Intermediate C2: 3-(2-chloro-6-morpholinopyridin-4-yl)-4-methylaniline [000301] A solution of 3-(2-chloro-6-fluoropyridin-4-yl)-4-methylaniline (B3, 0.9 g, 3.6 mmol) in DMF (10 mL) was treated with Cs 2 CO 3 (1.15 g, 3.6 mmol). Morpholine (0.9 mL, 10.7 mmol) was added and the reaction mixture was stirred at 90 ºC overnight. The mixture was cooled to rt and then quenched with water (80 mL). The solution was extracted with EtOAc (2 x 70 mL) and the combined organics were washed with brine, dried over anhydrous MgSO 4 , filtered, concentrated under reduced pressure. The crude was purified silica gel column chromatography (0 to 60 %, EtOAc/hexanes) to afford 3-(2-chloro-6- morpholinopyridin-4-yl)-4-methylaniline (0.81 g, 75 % yield) as a gummy mass. 1 H NMR (500 MHz, DMSO-d6): δ 6.92 (d, J = 8.1 Hz, 1H), 6.63 (s, 1H), 6.59 (s, 1H), 6.52 (dd, J = 2.4 and 8.1 Hz, 1H), 6.43 (d, J = 2.4 Hz, 1H), 4.97 (s, 2H), 3.67 (t, J = 4.8 Hz, 4H), 3.46 (t, J = 4.8 Hz, 4H), 2.05 (s, 3H); MS (ESI) m/z: 304.2 (M+H + ). General Method G: Suzuki reaction [000302] Intermediate C3: ethyl 2’-acetamido-4-chloro-[2,4’-bipyridine]-6-carboxylate [000303] A solution of ethyl 4,6-dichloropicolinate (3.0 g, 13.6 mmol) and N-(4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)ac etamide (A5, 8.93 g, 34.1 mmol) in a mixture of 1,4-dioxane (45 mL) and water (5 mL) was treated with NaHCO3 (2.3 g, 27.3 mmol). The reaction mixture was purged with nitrogen for 20 min and then PdCl2(dppf)DCM adduct (0.55 g, 0.68 mmol) was added. The reaction mixture was heated at 90 °C for 6 h and then cooled to rt. The reaction mixture was diluted with EtOAc (30 mL) and the solution was filtered through a pad of celite. The filtrate was washed with water (50 mL) and the organic layer was dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (0 to 60 % EtOAc/heptane) to obtain ethyl 2’-acetamido-4-chloro-[2,4’-bipyridine]-6-carboxylate (0.8 g, 18 % yield) as light brown solid. 1 H NMR (400 MHz, DMSO-d 6 ): ^ ^ ^ ^ ^ ^ (brs, 1H), 8.77 (s, 1H), 8.47 (d, J = 6.0 Hz, 1H), 8.39 (s, 1H), 8.14 (brs, 1H), 7.80 (brs, 1H), 4.40 (m, 2H), 2.13 (s, 3H), 1.15 (m, 3H); MS (ESI) m/z: 320.2 (M+H + ). [000304] Using the General Methods E, F, and G above, the following Intermediates of Table D were prepared. Table D.
[000305] Preparation of Example C16: N-(4-chloro-6-(2-hydroxypropan-2-yl)-[2,4’- bipyridin]-2’-yl)acetamide l [000306] A solution of ethyl 2’-acetamido-4-chloro-[2,4’-bipyridine]-6-carboxylate (C3, 1.0 g, 3.1 mmol) in THF (50 mL) was stirred at -78 °C. Methyl lithium (1.6 M in THF, 9.8 mL, 15.7 mmol) was added dropwise at -78 °C and then the reaction mixture was stirred - 78 °C for 3 h. The reaction mixture was allowed to increase gradually to rt and then stirred at rt for 16 h. The reaction mixture was quenched with chilled water (20 mL) and the solution was extracted with EtOAc (3 x 60 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (0 to 80 % EtOAc/heptane) to obtain N-(4-chloro-6-(2- hydroxypropan-2-yl)-[2,4’-bipyridin]-2’-yl)acetamide (C16, 0.3 g, 31 % yield) as white solid. 1 H NMR (400 MHz, DMSO-d 6 ): ^ ^ ^ ^ ^ ^ (brs, 1H), 8.85 (s, 1H), 8.47 (brs, 1H), 7.96 (s, 1H), 7.77 (brs, 2H), 5.4 (s, 1H), 2.13 (s, 3H), 1.50 (s, 6H); MS (ESI) m/z: 306.3 (M+H + ). General Method H: Suzuki Reaction [000307] Intermediate D1: N-(4-(5-amino-2-methylphenyl)-6-(2-hydroxypropan-2-yl)- [2,4’-bipyridin]-2’-yl)acetamide [000308] [000309] A solution of N-(4-chloro-6-(2-hydroxypropan-2-yl)-[2,4’-bipyridin]-2’ - yl)acetamide (C16, 0.28 g, 0.91 mmol) and 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)aniline (0.64 g, 2.75 mmol) in a mixture of 1,4-dioxane (6 mL) and water (1 mL) was treated with K 2 CO 3 (0.38 g, 2.75 mmol). The reaction mixture was purged with nitrogen for 10 min. PdCl2(dppf)DCM adduct (0.037 g, 0.045 mmol) was added and then the mixture was heated at 90 °C for 5 h. The reaction was cooled to rt and then diluted with EtOAc (30 mL). The solution was filtered through a pad of celite and washed with EtOAc (50 mL). The filtrate was washed with water (10 mL) and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (0 to 80 % EtOAc/heptane) to obtain N-(4-(5-amino-2- methylphenyl)-6-(2-hydroxypropan-2-yl)-[2,4’-bipyridin]-2 -yl)acetamide (0.22 g, 64 % yield) as light brown solid. 1 H NMR (400 MHz, DMSO-d6): ^ ^ ^ ^ ^ ^ (brs, 1H), 8.82 (s, 1H), 8.39 (brs, 1H), 7.78 (m, 1H), 7.70 (s, 1H), 7.65 (s, 1H), 6.99 (d, J = 8.0 Hz, 1H), 6.56 (m, 2H), 5.3 (s, 1H), 5.0 (brs, 2H), 2.11 (s, 6H), 1.55 (s, 6H); MS (ESI) m/z: 377.2 (M+H + ). [000310] Using the General Method H above, the following Intermediates of Table E were prepared. Table E.
General Method I: Amide Coupling Reaction with acyl chloride [000311] Intermediate E1: N-(5-bromo-2-fluoro-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide [000312] [000313] A solution of 2-(trifluoromethyl)isonicotinic acid (1.40 g, 7.4 mmol) in anhydrous THF (25 mL) under Ar was cooled to 0 ºC. DMF (0.076 mL, 0.98 mmol) was added and then oxalyl dichloride (0.84 mL, 9.8 mmol) was added dropwise. The reaction mixture was stirred at 0 ºC for 1 h while slowly warming to rt. The mixture was concentrated to almost complete dryness (approximately 1mL left) and then the residue was dissolved in anhydrous THF (15 mL). The solution was stirred at 0 ºC under Ar. A solution of 5-bromo- 2-fluoro-4-methylaniline (1.0 g, 4.9 mmol) and DIEA (1.88 mL, 10.8 mmol) in anhydrous THF (10 mL) was added dropwise at 0 ºC into a solution of 2-(trifluoromethyl)isonicotinoyl chloride in THF. The reaction mixture was stirred at 0 ºC for 10 min and then warmed to rt slowly for 1 h. The mixture was quenched with sat’d NaHCO3 (aq, 50 mL) and then the solution was extracted with EtOAc (3 x 30 mL). The combined organics were washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified silica gel column chromatography (0 to 5 %, DCM/MeOH) to give N-(5-bromo-2-fluoro-4-methylphenyl)-2-(trifluoromethyl)isoni cotinamide (1.29 g, 70 % yield) as a white solid. MS (ESI) m/z: 377.0 (M+H + ) and 379.0. [000314] Using the General Method I above, the following Intermediates of Table F were prepared. Table F. General Method J: Amide coupling Reaction with HATU [000315] Intermediate F1: N-(3-(2-chloropyridin-4-yl)-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide [000316] A solution of 2-(trifluoromethyl)isonicotinic acid (2.63 g, 14 mmol) in DMF (34 mL) was treated with HATU (5.23 g, 14 mmol) and DIEA (3.61 mL, 21 mmol). The reaction mixture was stirred for 10 min and then 3-(2-chloropyridin-4-yl)-4-methylaniline (B2, 1.50 g, 6.9 mmol) was added. The reaction was then stirred at rt for 4 h. and then cooled to rt. The reaction mixture was quenched with ice water (100 mL) and allowed to stir for 90 min. The yellow solid was filtered and dissolved in MeOH. The solution was concentrated under reduced pressure to afford a yellow oil. The yellow oil was purified by silica gel column chromatography (0 to 50 % EtOAc/hexanes) to afford N-(3-(2-chloropyridin-4-yl)-4- methylphenyl)-2-(trifluoromethyl)isonicotinamide (1.49 g, 55 % yield) as a yellow solid. 1 H NMR (500 MHz, DMSO-d6): ^ 10.7 (s, 1H), 8.99 (d, J = 5.0 Hz, 1H), 8.49 (d, J = 5.1 Hz, 1H), 8.36 (s, 1H), 8.18 (d, J = 5.0 Hz, 1H), 7.78 (dd, J = 2.2 and 8.3 Hz, 1H), 7.70 (d, J = 2.2 Hz, 1H), 7.55 (s, 1H), 7.46 (d, J = 5.1 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 2.24 (s, 3H); MS (ESI) m/z: 392.0 (M+H + ). General Method K: Amide coupling Reaction with T3P [000317] Intermediate F2: N-(3-(6-chloro-1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-4- methylphenyl)-2-(trifluoromethyl)isonicotinamide [000318] A solution of 4-(5-amino-2-methylphenyl)-6-chloro-1-methylpyridin-2(1H)- one (B6, 0.6 g, 2.4 mmol) and 2-(trifluoromethyl)isonicotinic acid (0.55 g, 7.2 mmol) in THF (12 mL), was treated with DIEA (1.2 g, 9.6 mmol). T3P (50 % in EtOAc, 4.6 mL, 7.2 mmol) was added and the reaction mixture was stirred at rt for 6 h. The reaction mixture was quenched with water (12 mL) and the solution was extracted with EtOAc (3 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous Na 2 SO 4 , filtered, and concentrated under reduced pressure to afford N-(3-(6-chloro-1-methyl-2-oxo- 1,2-dihydropyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl) isonicotinamide (0.95 g, 93 % yield) as brown solid. 1 H NMR (500 MHz, DMSO-d6): δ 10.7 (s, 1H), 8.99 (d, J = 4.8 Hz, 1H), 8.35 (s, 1H), 8.19 (d, J = 4.0 Hz, 1H)), 7.74 (d, J = 8.0 Hz, 1H), 7.68 (d, J = 2.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.55 (s, 1H), 6.35 (s, 1H), 3.61 (s, 3H), 2.27 (s, 3H); MS (ESI) m/z: 422.0 (M+H + ). General Method L: Amide coupling Reaction with acyl chloride [000319] Intermediate F3: N-(3-(2-chloropyridin-4-yl)-4-methylphenyl)-3- methylbenzamide [000320] A mixture of DMF (0.071 mL, 0.91 mmol) and 3-methylbenzoic acid (0.75 g, 5.5 mmol) in THF (15 mL) was cooled to 0 ºC. Oxalyl chloride (0.80 mL, 9.1 mmol) was added dropwise and the reaction mixture was stirred for 30 min under the same conditions. The mixture was concentrated to dryness and then THF (20 mL) was added and concentrated (repeat twice). A mixture of 3-(2-chloropyridin-4-yl)-4-methylaniline (B2, 1.0 g, 4.6 mmol) and DIEA (1.8 mL, 10.1 mmol) in THF (30 mL) was cooled to 0 ºC and the solution of the acid chloride in THF (20 mL) was added into the amine solution. The reaction mixture was stirred under the same condition for 30 min. The reaction mixture was concentrated under reduced pressure and the residue was treated with sat’d NaHCO3 (aq, 50 mL) and DCM (30 mL). The aq. layer was extracted with DCM (2 x 30 mL). The combined organic extracts were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to obtain N-(3-(2-chloropyridin-4-yl)-4-methylphenyl)-3-methylbenzamid e (1.54 g, crude). 1 H NMR (500 MHz, DMSO-d6): δ 10.3 (s, 1H), 8.48 (d, J = 5.1Hz, 1H), 7.75 (m, 4H), 7.54 (s, 1H), 7.45 (dd, J = 1.5 and 5.1 Hz, 1H), 7.39 (m, 2H), 7.32 (d, J = 8.3 Hz, 1H), 2.39 (s, 3H), 2.23 (s, 3H); MS (ESI) m/z: 337.0 (M+H + ). General Method M: Suzuki Reaction [000321] Intermediate F4: N-(3-(2,6-dichloropyridin-4-yl)-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide [000322] A mixture of 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyridine (1.53 g, 5.6 mmol), N-(3-bromo-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide (E2, 2.0 g, 5.6 mmol) and K2CO3 (1.54 g, 11 mmol) in a mixture of 1,4-dioxane (25 mL) and water (3 mL) was sparged with Ar for 2 min. Pd(dppf)Cl2 (0.10 g, 0.14 mmol) was added and then sparged with Ar again for 2 min. The reaction mixture was heated to 85 ºC for 2 h and then cooled to rt. The reaction mixture was diluted with DCM (100 mL) and the solution was filtered through a pad of celite. The filtrate was treated with sat’d NaHCO 3 (aq, 125 mL) and then the organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to yield a brown solid. The crude was purified by silica gel column chromatography (0 to 50 % EtOAc/hexanes) to obtain N-(3-(2,6-dichloropyridin-4-yl)-4-methylphenyl)-2-(trifluoro methyl)isonicotinamide (2.22 g, 93 % yield) as a tan solid. MS (ESI) m/z: 426.0 (M+H + ). [000323] Using the General Methods J, K, L and M above, the following Intermediates of Table G were prepared. Table G.
General Method N: Substitution Reaction [000324] Example G1: N-(3-(2-chloro-6-ethoxypyridin-4-yl)-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide [000325] A solution of N-(5-(2-chloro-6-fluoropyridin-4-yl)-2-fluoro-4-methylphenyl )- 2-(trifluoromethyl) isonicotinamide (F13, 0.3 g, 0.70 mmol) in 1,4-dioxane (3.0 mL) was treated with NaOEt (21% in ethanol, 0.45 mL, 1.40 mmol). The reaction mixture was stirred at rt for 2.5 h. The reaction mixture was quenched with water (10 mL) and the solution was extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain N-(5-(2-chloro-6-ethoxypyridin-4-yl)-2-fluoro-4- methylphenyl)-2-(trifluoromethyl)isonicotinamide (0.25 g, 92 % yield) as light brown solid. 1 H NMR (400 MHz, DMSO-d 6 ): ^ 10.6 (s, 1H), 9.00 (d, J = 4.8 Hz, 1H), 8.35 (s, 1H), 8.18 (d, J = 4.4 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 11.6 Hz, 1H), 7.09 (s, 1H), 6.80 (s, 1H), 4.34 (q, J = 7.2 Hz, 2H), 2.25 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H); MS (ESI) m/z: 454.1 (M+H + ). General Method O: Suzuki Reaction [000326] Intermediate G2: N-(3-(2-chloro-6-cyclopropylpyridin-4-yl)-4-methylphenyl)- 2-(trifluoromethyl)isonicotinamide [000327] A mixture of cyclopropylboronic acid (0.22 g, 2.5 mmol), N-(3-(2,6- dichloropyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)iso nicotinamide (F4, 1.0 g, 2.3 mmol) and K3PO4 (1.0 g, 4.7 mmol) in a mixture of toluene (10 mL) and water (1.2 mL) was sparged with Ar for 2 min. Pd(OAc)2 (53 mg, 0.23 mmol) and tricyclohexylphosphane (0.10 g, 0.35 mmol) were added. The reaction mixture was heated to 90 ºC for 3 h. The reaction was cooled to rt and then diluted with DCM (30 mL). The solution was filtered through a pad of celite and the filtrate was treated with sat’d NaHCO3 (aq, 50 mL). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to yield a brown oil. The crude was purified silica gel column chromatography (0 to 50 % EtOAc/hexanes) to afford N-(3-(2-chloro-6- cyclopropylpyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl) isonicotinamide (0.23 g, 23 % yield) as a clear solid. 1 H NMR (500 MHz, DMSO-d6): δ 10.7 (s, 1H), 8.99 (d, J = 5.0 Hz, 1H), 8.36 (s, 1H), 8.18 (d, J = 5.0 Hz, 1H), 7.77 (dd, J = 2.2 and 8.4 Hz, 1H), 7.68 (d, J = 2.2 Hz, 1H), 7.36 (m, 2H), 7.24 (s, 1H), 2.24 (s, 3H), 2.17 (m, 1H), 1.01 (m, 2H), 0.95 (m, 2H); MS (ESI) m/z: 432.0 (M+H + ). [000328] Using the General Methods A, N and O above, the following Intermediates of Table H were prepared. [000329] Table H.
General Method P: Suzuki reaction [000330] Example 1a: N-(3-(2'-acetamido-6-(2-((tert-butyldiphenylsilyl)oxy)ethoxy )- [2,4'-bipyridin]-4-yl)-4-methylphenyl)-2-(trifluoromethyl)is onicotinamide [000331] [000332] A solution of N-(3-(2-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-6- chloropyridin-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isoni cotinamide (F5, 0.17 g, 0.30 mmol) and N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2- yl)acetamide (A5, 0.12 g, 0.45 mmol) in a mixture of EtOH (3.0 mL) and toluene (3.0 mL) was treated with K2CO3 (2.0 N, 0.30 mL, 0.60 mmol). The reaction mixture was sparged with Ar for 2 min and then Xphos Pd G2 (24 mg, 0.03 mol) was added. The mixture was heated at 80 ºC under Ar overnight. The reaction was cooled to rt and quenched with sat’d NaHCO3 (aq, 30 mL). The solution was extracted with DCM (4 x 25 mL). The combined organics were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford a brown oil. The brown oil was purified by silica gel column chromatography (0 to 80 % EtOAc/hexanes) to afford N-(3-(2’-acetamido-6-(2-((tert- butyldimethylsilyl)oxy)ethoxy)-[2,4’-bipyridin]-4-yl)-4-me thylphenyl)-2- (trifluoromethyl)isonicotinamide (0.18g, crude) as a yellow oil. General Method Q: Deprotection [000333] Example 1: N-(3-(2’-acetamido-6-(2-hydroxyethoxy)-[2,4’-bipyridin]- 4-yl)-4- methylphenyl)-2-(trifluoromethyl)isonicotinamide [000334] [000335] A solution of N-(3-(2’-acetamido-6-(2-((tert-butyldimethylsilyl)oxy)etho xy)- [2,4’-bipyridin]-4-yl)-4-methylphenyl)-2-(trifluoromethyl) isonicotinamide (1a, 0.18 g, 0.30 mmol) in THF (10 mL) was treated with TBAF (1.0 M in THF, 0.90 mL, 0.90 mmol). The reaction mixture was stirred at rt for 3 h. The reaction was concentrated under reduced pressure. The crude was purified by silica gel column chromatography (0 to 7 % MeOH/DCM) to obtain N-(3-(2’-acetamido-6-(2-hydroxyethoxy)-[2,4’-bipyridin]- 4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide (0.11 g, 68 % yield) as a white solid. 1 H NMR (500 MHz, DMSO-d 6 ): ^ 10.7 (s, 1H), 10.6 (s, 1H), 8.98 (d, J = 5.0 Hz, 1H), 8.80 (s, 1H), 8.40 (d, J = 5.3 Hz, 1H), 8.37 (s, 1H), 8.19 (d, J = 5.0 Hz, 1H), 7.78 (m, 2H), 7.74 (d, J = 2.2 Hz, 1H), 7.56 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 6.89 (s, 1H), 4.88 (t, J = 5.5 Hz, 1H), 4.46 (t, J = 5.1 Hz, 2H), 3.81 (m, 2H), 2.28 (s, 3H), 2.11 (s, 3H); MS (ESI) m/z: 552.2 (M+H + ). General Method R: Amide coupling reaction [000336] Example 21: N-(3-(2'-acetamido-1-methyl-2-oxo-1,2-dihydro-[3,4'-bipyridi n]- 5-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide [000337] [000338] A solution of 2-(trifluoromethyl)isonicotinic acid (0.13 g, 0.69 mmol) in DMF (5 mL) was treated with DIEA (0.5 mL, 2.87 mmol). HATU (0.44 g, 1.15 mmol) was added and then the reaction mixture was stirred at rt for 15 min. N-(5-(5-amino-2- methylphenyl)-1-methyl-2-oxo-1,2-dihydro-[3,4'-bipyridin]-2' -yl)acetamide (D2, 0.2 g, 0.57 mmol) was added and the reaction mixture was stirred at rt for 5 h. The mixture was quenched with chilled water (10 mL) and the solution was extracted with EtOAc (4 x 30 mL). The combined organic extracts were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (0 to100 % EtOAc/heptane) to obtain N-(3-(2'-acetamido-1-methyl-2- oxo-1,2-dihydro-[3,4'-bipyridin]-5-yl)-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide (0.055 g, 18 % yield) as a pale yellow solid. 1 H NMR (400 MHz, DMSO-d6): ^ ^ 10.7 (s, 1H), 10.4 (s, 1H), 8.99 (d, J = 4.8 Hz, 1H), 8.44 (s, 1H), 8.36 (s, 1H), 8.30 (d, J = 5.2 Hz, 1H), 8.19 (d, J = 4.4 Hz, 1H), 7.96 (brs, 1H), 7.72 (m, 3H), 7.48 (m, 1H), 7.34 (d, J = 8.4 Hz, 1H), 3.60 (s, 3H), 2.31 (s, 3H), 2.08 (s, 3H); MS (ESI) m/z: 522.2 (M+H + ). General Method S: Amide coupling and Substitution [000339] Example 39: N-(3-(2'-(2-cyanoacetamido)-[2,4'-bipyridin]-4-yl)-4- methylphenyl)-2-(trifluoromethyl)isonicotinamide [000340] A solution of N-(3-(2'-amino-[2,4'-bipyridin]-4-yl)-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide (16, 0.10 g, 0.22 mmol) in EtOAc (10 ml) was treated with sat’d NaHCO 3 (aq, 10 mL). 2-Chloroacetyl chloride (0.1 mL, 1.1 mmol) was added dropwise under an ice-water bath and then the reaction mixture was allowed to warm to rt. The reaction mixture was stirred at rt for 4 h. The aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organics were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to obtain N-(3-(2'-(2-chloroacetamido)-[2,4'- bipyridin]-4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicot inamide (0.11 g, crude). [000341] A solution of N-(3-(2'-(2-chloroacetamido)-[2,4'-bipyridin]-4-yl)-4- methylphenyl)-2-(trifluoromethyl)isonicotinamide (0.11 g, 0.22 mmol) in DMSO (5 mL) was treated with NaCN (0.022 g, 0.45 mmol). The reaction mixture was stirred at rt for 1 h. The reaction mixture was quenched with sat’d NaHCO3 (aq, 40 mL) and the solution was extracted with DCM (4 x 20 mL). The combined organics were dried over anhydrous Na 2 SO 4 , filtered and concentrated under reduced pressure to obtain N-(3-(2'- (2-cyanoacetamido)-[2,4'-bipyridin]-4-yl)-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide (0.026 g, 23 % yield) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): ^ ^ 11.0 (s, 1H), 10.8 (s, 1H), 8.98 (d, J = 5.0 Hz, 1H), 8.82 (d, J = 5.0 Hz, 1H), 8.79 (brs, 1H), 8.44 (d, J = 5.0 Hz, 1H), 8.38 (s, 1H), 8.21 (d, J = 5.0 Hz, 1H), 8.02 (s, 1H), 7.88 (dd, J = 1.6 and 5.3 Hz, 1H), 7.82 (dd, J = 2.2 and 8.3 Hz, 1H), 7.76 (d, J = 2.2 Hz, 1H), 7.53 (dd, J = 1.5 and 5.0 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 4.02 (s, 2H), 2.29 (s, 3H); MS (ESI) m/z: 517.2 (M+H + ). General Method T: Oxidation and Substitution [000342] Example 41: N-(3-(6-(2-acetamidopyridin-4-yl)-2-(dimethylamino)pyrimidin - 4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide [000343] A suspended of N-(3-(6-(2-acetamidopyridin-4-yl)-2-(methylthio)pyrimidin-4- yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide (G6, 0.15 g, 0.27 mmol) in DCM (5 mL) was cooled to 0 ºC and m-CPBA (0.070 g, 0.30 mmol) was added. The mixture was warmed to rt and stirred at rt for 30 min. The reaction mixture was treated with sat’d NaHCO3 solution (25 mL) and stirred for 15 min. The aqueous layer was extracted with DCM (2 x 25 mL) and the combined organics were dried over anhydrous Na 2 SO 4, filtered and concentrated under reduced pressure to obtain N-(3-(6-(2-acetamidopyridin-4-yl)-2- (methylsulfinyl)pyrimidin-4-yl)-4-methylphenyl)-2-(trifluoro methyl)isonicotinamide (0.15 g, crude). [000344] A solution of N-(3-(6-(2-acetamidopyridin-4-yl)-2-(methylsulfinyl)pyrimidi n- 4-yl)-4-methylphenyl)-2-(trifluoromethyl)isonicotinamide (0.15 g, 0.27 mmol) in THF (3 mL) was added dimethylamine (2 N in THF, 0.41 mL, 0.82 mmol). The reaction mixture was stirred at rt for 3 h. The solution was quenched with 5 % Na2SO3 (aq, 30 mL) and the extracted with DCM (3 x 25 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (0 to 50 %, EtOAc/hexanes) to obtain N-(3- (6-(2-acetamidopyridin-4-yl)-2-(dimethylamino)pyrimidin-4-yl )-4-methylphenyl)-2- (trifluoromethyl)isonicotinamide (0.034 g, 23 % yield). 1 H NMR (400 MHz, DMSO- d 6 ): ^ ^ 10.8 (s, 1H), 10.6 (s, 1H), 8.99 (d, J = 5.0 Hz, 1H), 8.85 (s, 1H), 8.44 (d, J = 5.2 Hz, 1H), 8.38 (s, 1H), 8.20 (d, J = 5.0 Hz, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.84 (dd, J = 2.3 and 8.3 Hz, 1H), 7.80 (dd, J = 1.6 and 5.2 Hz, 1H), 7.37 (d, J = 8.3 Hz, 1H), 7.25 (s, 1H), 3.25 (s, 6H), 2.42 (s, 3H), 2.12 (s, 3H); MS (ESI) m/z: 536.2 (M+H + ). [000345] Using the General Methods K, P, Q, R, S and T above, the following Intermediates of Table I were prepared. [000346] Table I. Biochemical assay for A-Raf (1) [000347] Activity of A-Raf kinase (SEQ. ID No: 1) was determined spectroscopically using a coupled pyruvate kinase/lactate dehydrogenase assay that continuously monitors the ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al., Science, 2000, 289, 1938-1942). Assays were conducted in 384-well plates (100 µL final volume) using 5.55 nM A-Raf (Sigma), 1.5 units pyruvate kinase, 2.1 units lactate dehydrogenase, 1 mM phosphoenol pyruvate, 0.28 mM NADH, 30.1 nM MEK (SignalChem), and 1 mM ATP in assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl 2 , 0.5 mM DTT, 0.1% octyl-glucoside, 0.002% (w/v) BSA, and 0.002% Triton X-100). Inhibition of A-Raf was measured by adding serial diluted test compound (final assay concentration of 1% DMSO). A decrease in absorption at 340 nm was monitored continuously for 6 h at 30 ºC on a multi-mode microplate reader (BioTek). The reaction rate was calculated using the 4 to 5 h time frame. The reaction rate at each concentration of compound was converted to percent inhibition using controls (i.e., reaction with no test compound and reaction with a known inhibitor) and IC50 values were calculated by fitting a four-parameter sigmoidal curve to the data using Prism (GraphPad software). Biochemical assay for A-Raf (2) Activity of A-Raf kinase (SEQ. ID No: 1) was determined spectroscopically using a coupled pyruvate kinase/lactate dehydrogenase assay that continuously monitors the ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al., Science, 2000, 289, 1938- 1942). Assays were conducted in 384-well plates (25 µL final volume) using 20 nM A-Raf (Eurofins), 1.5 units pyruvate kinase, 2.1 units lactate dehydrogenase, 1 mM phosphoenol pyruvate, 0.7 mM NADH, 100 nM MEK (SignalChem), and 1 mM ATP in assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl2, 0.5 mM DTT, 0.1% octyl-glucoside, 0.002% (w/v) BSA, and 0.002% Triton X-100). Inhibition of A-Raf was measured by adding serial diluted test compound (final assay concentration of 1% DMSO). A decrease in absorption at 340 nm was monitored hourly for 4 h at 30 ºC on a multi-mode microplate reader (BioTek). The reaction rate was calculated using the 3 to 4 h time frame. The reaction rate at each concentration of compound was converted to percent inhibition using controls (i.e., reaction with no test compound and reaction with a known inhibitor) and IC50 values were calculated by fitting a four-parameter sigmoidal curve to the data using Prism (GraphPad software). A-Raf protein sequence residues 273-end containing Y301D and Y302D mutations with N-terminal GST-tag (SEQ. ID No: 1) MSPILGYWKIKGLVQPTRLLLEYLEEKYEEHLYERDEGDKWRNKKFELGLEFPNLPY YIDGDVKLTQSMAIIRYIADKHNMLGGCPKERAEISMLEGAVLDIRYGVSRIAYSKDF ETLKVDFLSKLPEMLKMFEDRLCHKTYLNGDHVTHPDFMLYDALDVVLYMDPMCL DAFPKLVCFKKRIEAIPQIDKYLKSSKYIAWPLQGWQATFGGGDHPPKSDLEVLFQG PEFKSPAEQRERKSLADDKKKVKNLGYRDSGDDWEVPPSEVQLLKRIGTGSFGTVFR GRWHGDVAVKVLKVSQPTAEQAQAFKNEMQVLRKTRHVNILLFMGFMTRPGFAIIT QWCEGSSLYHHLHVADTRFDMVQLIDVARQTAQGMDYLHAKNIIHRDLKSNNIFLH EGLTVKIGDFGLATVKTRWSGAQPLEQPSGSVLWMAAEVIRMQDPNPYSFQSDVYA YGVVLYELMTGSLPYSHIGCRDQIIFMVGRGYLSPDLSKISSNCPKAMRRLLSDCLKF QREERPLFPQILATIELLQRSLPKIERSASEPSLHRTQADELPACLLSAARLVP Biochemical assay for B-Raf (1) [000348] Activity of B-Raf kinase (SEQ. ID NO: 2) was determined spectroscopically using a coupled pyruvate kinase/lactate dehydrogenase assay that continuously monitors the ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al., Science, 2000, 289, 1938-1942). Assays were conducted in 384-well plates (100 µL final volume) using 0.13 nM B-Raf (Sigma), 1.5 units pyruvate kinase, 2.1 units lactate dehydrogenase, 1 mM phosphoenol pyruvate, 0.28 mM NADH, 30.1 nM MEK (SignalChem), and 1 mM ATP in assay buffer (100 mM Tris, Ph 7.5, 15 mM MgCl2, 0.5 mM DTT, 0.1% octyl-glucoside, 0.002% (w/v) BSA, and 0.002% Triton X-100). Inhibition of B-Raf was measured by adding serial diluted test compound (final assay concentration of 1% DMSO). A decrease in absorption at 340 nm was monitored continuously for 6 h at 30 ºC on a multi-mode microplate reader (BioTek). The reaction rate was calculated using the 4 to 5 h time frame. The reaction rate at each concentration of compound was converted to percent inhibition using controls (i.e., reaction with no test compound and reaction with a known inhibitor) and IC50 values were calculated by fitting a four-parameter sigmoidal curve to the data using Prism (GraphPad software). Biochemical assay for B-Raf (2) [000349] Activity of B-Raf kinase (SEQ. ID NO: 2) was determined spectroscopically using a coupled pyruvate kinase/lactate dehydrogenase assay that continuously monitors the ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al., Science, 2000, 289, 1938-1942). Assays were conducted in 384-well plates (25 µL final volume) using 2 nM B- Raf (Sigma), 1.5 units pyruvate kinase, 2.1 units lactate dehydrogenase, 1 mM phosphoenol pyruvate, 0.7 mM NADH, 50 nM MEK (SignalChem), and 1 mM ATP in assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl2, 0.5 mM DTT, 0.1% octyl-glucoside, 0.002% (w/v) BSA, and 0.002% Triton X-100). Inhibition of B-Raf was measured by adding serial diluted test compound (final assay concentration of 1% DMSO). A decrease in absorption at 340 nm was monitored hourly for 4 h at 30 ºC on a multi-mode microplate reader (BioTek). The reaction rate was calculated using the 2 to 3 h time frame. The reaction rate at each concentration of compound was converted to percent inhibition using controls (i.e., reaction with no test compound and reaction with a known inhibitor) and IC50 values were calculated by fitting a four-parameter sigmoidal curve to the data using Prism (GraphPad software). B-Raf protein sequence residues 416-766 with N-terminal GST-tag (SEQ. ID NO: 2) LQKSPGPQRERKSSSSSEDRNRMKTLGRRDSSDDWEIPDGQITVGQRIGSGSFGTVYK GKWHGDVAVKMLNVTAPTPQQLQAFKNEVGVLRKTRHVNILLFMGYSTKPQLAIV TQWCEGSSLYHHLHIIETKFEMIKLIDIARQTAQGMDYLHAKSIIHRDLKSNNIFLHED LTVKIGDFGLATVKSRWSGSHQFEQLSGSILWMAPEVIRMQDKNPYSFQSDVYAFGI VLYELMTGQLPYSNINNRDQIIFMVGRGYLSPDLSKVRSNCPKAMKRLMAECLKKK RDERPLFPQILASIELLARSLPKIHRSASEPSLNRAGFQTEDFSLYACASPKTPIQAGGY GAFPVH Biochemical assay for C-Raf (1) [000350] Activity of C-Raf kinase (SEQ. ID NO: 3) was determined spectroscopically using a coupled pyruvate kinase/lactate dehydrogenase assay that continuously monitors the ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al., Science, 2000, 289, 1938-1942). Assays were conducted in 384-well plates (100 µL final volume) using 0.43 nM C-Raf (Sigma), 1.5 units pyruvate kinase, 2.1 units lactate dehydrogenase, 1 mM phosphoenol pyruvate, 0.28 mM NADH, 30.1 nM MEK (SignalChem), and 1 mM ATP in assay buffer (100 mM Tris, Ph 7.5, 15 mM MgCl 2 , 0.5 mM DTT, 0.1% octyl-glucoside, 0.002% (w/v) BSA, and 0.002% Triton X-100). Inhibition of C-Raf was measured by adding serial diluted test compound (final assay concentration of 1% DMSO). A decrease in absorption at 340 nm was monitored continuously for 6 h at 30 ºC on a multi-mode microplate reader (BioTek). The reaction rate was calculated using the 4 to 5 h time frame. The reaction rate at each concentration of compound was converted to percent inhibition using controls (i.e., reaction with no test compound and reaction with a known inhibitor) and IC50 values were calculated by fitting a four-parameter sigmoidal curve to the data using Prism (GraphPad software). Biochemical assay for C-Raf (2) [000351] Activity of C-Raf kinase (SEQ. ID NO: 3) was determined spectroscopically using a coupled pyruvate kinase/lactate dehydrogenase assay that continuously monitors the ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al., Science, 2000, 289, 1938-1942). Assays were conducted in 384-well plates (25 µL final volume) using 3.84 nM C- Raf (Eurofins), 1.5 units pyruvate kinase, 2.1 units lactate dehydrogenase, 1 mM phosphoenol pyruvate, 0.7 mM NADH, 50 nM MEK (SignalChem), and 1 mM ATP in assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl 2 , 0.5 mM DTT, 0.1% octyl-glucoside, 0.002% (w/v) BSA, and 0.002% Triton X-100). Inhibition of C-Raf was measured by adding serial diluted test compound (final assay concentration of 1% DMSO). A decrease in absorption at 340 nm was monitored hourly for 4 h at 30 ºC on a multi-mode microplate reader (BioTek). The reaction rate was calculated using the 2 to 3 h time frame. The reaction rate at each concentration of compound was converted to percent inhibition using controls (i.e., reaction with no test compound and reaction with a known inhibitor) and IC 50 values were calculated by fitting a four-parameter sigmoidal curve to the data using Prism (GraphPad software). C-Raf residues 306-end; Y340D, Y341D with N-terminal GST-tag (SEQ. ID NO: 3) QPKTPVPAQRERAPVSGTQEKNKIRPRGQRDSSDDWEIEASEVMLSTRIGSGSFGTVY KGKWHGDVAVKILKVVDPTPEQFQAFRNEVAVLRKTRHVNILLFMGYMTKDNLAI VTQWCEGSSLYKHLHVQETKFQMFQLIDIARQTAQGMDYLHAKNIIHRDMKSNNIF LHEGLTVKIGDFGLATVKSRWSGSQQVEQPTGSVLWMAPEVIRMQDNNPFSFQSDV YSYGIVLYELMTGELPYSHINNRDQIIFMVGRGYASPDLSKLYKNCPKAMKRLVADC VKKVKEERPLFPQILSSIELLQHSLPKINRSASEPSLHRAAHTEDINACTLTTSPRLPVF Biochemical assay for B-Raf (V600E) (1) [000352] Activity of B-Raf (V600E) (SEQ. ID NO: 4) kinase was determined spectroscopically using a coupled pyruvate kinase/lactate dehydrogenase assay that continuously monitors the ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al., Science, 2000, 289, 1938-1942). Assays were conducted in 384-well plates (100 µL final volume) using 0.03 nM B-Raf (SignalChem), 1.5 units pyruvate kinase, 2.1 units lactate dehydrogenase, 1 mM phosphoenol pyruvate, 0.28 mM NADH, 30.1 nM MEK (SignalChem), and 1 mM ATP in assay buffer (100 mM Tris, Ph 7.5, 15 mM MgCl 2 , 0.5 mM DTT, 0.1% octyl-glucoside, 0.002% (w/v) BSA, and 0.002% Triton X-100). Inhibition of B- Raf (V600E) was measured by adding serial diluted test compound (final assay concentration of 1% DMSO). A decrease in absorption at 340 nm was monitored continuously for 6 h at 30 ºC on a multi-mode microplate reader (BioTek). The reaction rate was calculated using the 3 to 4 h time frame. The reaction rate at each concentration of compound was converted to percent inhibition using controls (i.e., reaction with no test compound and reaction with a known inhibitor) and IC 50 values were calculated by fitting a four-parameter sigmoidal curve to the data using Prism (GraphPad software). Biochemical assay for B-Raf (V600E) (2) [000353] Activity of B-Raf (V600E) (SEQ. ID NO: 4) kinase was determined spectroscopically using a coupled pyruvate kinase/lactate dehydrogenase assay that continuously monitors the ATP hydrolysis-dependent oxidation of NADH (e.g., Schindler et al., Science, 2000, 289, 1938-1942). Assays were conducted in 384-well plates (25 µL final volume) using 0.5 nM B-Raf (deCode), 1.5 units pyruvate kinase, 2.1 units lactate dehydrogenase, 1 mM phosphoenol pyruvate, 0.7 mM NADH, 100 nM MEK (SignalChem), and 1 mM ATP in assay buffer (100 mM Tris, pH 7.5, 15 mM MgCl 2 , 0.5 mM DTT, 0.1% octyl-glucoside, 0.002% (w/v) BSA, and 0.002% Triton X-100). Inhibition of B-Raf (V600E) was measured by adding serial diluted test compound (final assay concentration of 1% DMSO). A decrease in absorption at 340 nm was monitored hourly for 4 h at 30 ºC on a multi-mode microplate reader (BioTek). The reaction rate was calculated using the 3 to 4 h time frame. The reaction rate at each concentration of compound was converted to percent inhibition using controls (i.e., reaction with no test compound and reaction with a known inhibitor) and IC50 values were calculated by fitting a four-parameter sigmoidal curve to the data using Prism (GraphPad software). B-Raf (V600E) residues 416-766 with a N-terminal GST-tag (SEQ. ID NO: 4) LQKSPGPQRERKSSSSSEDRNRMKTLGRRDSSDDWEIPDGQITVGQRIGSGSFGTVYK GKWHGDVAVKMLNVTAPTPQQLQAFKNEVGVLRKTRHVNILLFMGYSTKPQLAIV TQWCEGSSLYHHLHIIETKFEMIKLIDIARQTAQGMDYLHAKSIIHRDLKSNNIFLHED LTVKIGDFGLATEKSRWSGSHQFEQLSGSILWMAPEVIRMQDKNPYSFQSDVYAFGI VLYELMTGQLPYSNINNRDQIIFMVGRGYLSPDLSKVRSNCPKAMKRLMAECLKKK RDERPLFPQILASIELLARSLPKIHRSASEPSLNRAGFQTEDFSLYACASPKTPIQAGGY GAFPVH Table J. Inhibition of biochemical activity of BRAF, CRAF, ARAF and BRAF V600E kinases by exemplary compounds (“Exp. No.”).
For Table J, “+” refers to an IC50 less than or equal to 100 nM; “++” refers to an IC50 greater than 100 nM and less than or equal to 500 nM; “+++” refers to an IC50 greater than 500 nM and less than or equal to 1000 nM; and “++++” refers to an IC50 greater than 1000 nM and less than or equal to 10000 nM. A375 Cell Proliferation Assay (1) [000354] A375 cells (catalog (#CRL-1619) are obtained from the American Type Culture Collect (ATTC, Manassas, VA). Briefly, cells were grown in DMEM High Glucose supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA) and 1% Penicillin/Streptomycin/L-Glutamine at 37 ºC, 5% CO 2 , and 95% humidity. Cells are expanded until reaching 70-95% confluency at which point they are sub-cultured or harvested for assay use. A serial dilution of test compound is dispensed into a 96-well black clear bottom plate in triplicate. Two thousand five hundred cells are added per well in 200 µL complete growth medium in the 96-well plate. Plates are incubated for 67-72 h at 37 ºC, 5% CO 2 , and 95% humidity. At the end of the incubation, 40 µL of a 440 ^M solution of resazurin (Sigma, St. Louis, MO) in PBS is added to each well of the plate and plates are incubated for an additional 5-6 h at 37 ºC, 5% CO2, and 95% humidity. Plates are read on a Synergy2 or equivalent reader (Biotek, Winooski VT) using an excitation of 540 nm and an emission of 600 nm. Data is analyzed using Prism software (GraphPad, San Diego, CA) to calculate IC 50 values. A375 Cell Proliferation Assay (2) [000355] A375 cells (catalog (#CRL-1619) are obtained from the American Type Culture Collect (ATTC, Manassas, VA). Briefly, cells were grown in DMEM High Glucose supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA) and 1% Penicillin/Streptomycin/L-Glutamine at 37 ºC, 5% CO2, and 95% humidity. Cells are expanded until reaching 70-95% confluency at which point they are sub-cultured or harvested for assay use. Using the Beckman Coulter Echo 650, a serial dilution of test compound is dispensed into a 384-well black clear bottom plate in triplicate. Six hundred twenty-five cells are added per well in 50 µL complete growth medium in the 384-well plate. Plates are incubated for 67-72 h at 37 ºC, 5% CO 2 , and 95% humidity. At the end of the incubation, 10 µL of a 440 ^M solution of resazurin (Sigma, St. Louis, MO) in PBS is added to each well of the plate and plates are incubated for an additional 3-6 h at 37 ºC, 5% CO 2 , and 95% humidity. Plates are read on a Synergy2 or equivalent reader (Biotek, Winooski VT) using an excitation of 540 nm and an emission of 600 nm. Data is analyzed using Prism software (GraphPad, San Diego, CA) to calculate IC50 values. WM3928 Cell Proliferation Assay (1) [000356] WM3928 cells (#WM3928-01-0001) are obtained from Rockland Immunochemicals Inc (Gilbertsville, PA). Briefly, cells were grown in MCDB 153 medium (Sigma, #M7403, St. Louis, MO) supplemented with 20% Leibovitz’s L-15 (ThermoFisher #11415-064, Waltham, MA), 2% heat inactivated fetal bovine serum (ThermoFisher, #A3840001, Waltham, MA), 5µg/mL Insulin (Bovine Pancreas) (Sigma, #I0516, St. Louis, MO), 1.68 mM Calcium Chloride (Sigma, #C-34006, St. Louis, MO) and 1% Penicillin/Streptomycin/L-Glutamine (ThermoFisher #10378016, Waltham, MA) at 37 ºC, 5% CO2, and 95% humidity. Cells are expanded until reaching 70-95% confluency at which point they are subcultured or harvested for assay use. A serial dilution of test compound is dispensed into a 96-well black clear bottom plate in triplicate. Three thousand cells are added per well in 200 µL complete growth medium in the 96-well plate. Plates are incubated for 67-72 hours at 37 ºC, 5% CO2, and 95% humidity. At the end of the incubation, 40 µL of a 440 µM solution of resazurin (Sigma, #199303, St. Louis, MO) in PBS is added to each well of the plate and plates are incubated for an additional 6-7 hours at 37 ºC, 5% CO2, and 95% humidity. Plates are read on a Synergy2 or equivalent reader (Biotek, Winooski VT) using an excitation of 540 nm and an emission of 600 nm. Data is analyzed using Prism software (GraphPad, San Diego, CA) to calculate IC 50 values. WM3928 Cell Proliferation Assay (2) [000357] WM3928 cells (#WM3928-01-0001) are obtained from Rockland Immunochemicals Inc (Gilbertsville, PA). Briefly, cells were grown in MCDB 153 medium (Sigma, #M7403, St. Louis, MO) supplemented with 20% Leibovitz’s L-15 (ThermoFisher #11415-064, Waltham, MA), 2% heat inactivated fetal bovine serum (ThermoFisher, #A3840001, Waltham, MA), 5µg/mL Insulin (Bovine Pancreas) (Sigma, #I0516, St. Louis, MO), 1.68 mM Calcium Chloride (Sigma, #C-34006, St. Louis, MO) and 1% Penicillin/Streptomycin/L-Glutamine (ThermoFisher #10378016, Waltham, MA) at 37 ºC, 5% CO 2 , and 95% humidity. Cells are expanded until reaching 70-95% confluency at which point they are sub-cultured or harvested for assay use. Using the Beckman Coulter Echo 650, a serial dilution of test compound is dispensed into a 384-well black clear bottom plate in triplicate. Seven hundred fifty cells are added per well in 50 µL complete growth medium in the 384-well plate. Plates are incubated for 67-72 hours at 37 ºC, 5% CO 2 , and 95% humidity. At the end of the incubation, 10 µL of a 440 µM solution of resazurin (Sigma, #199303, St. Louis, MO) in PBS is added to each well of the plate and plates are incubated for an additional 3-6 hours at 37 ºC, 5% CO2, and 95% humidity. Plates are read on a Synergy2 or equivalent reader (Biotek, Winooski VT) using an excitation of 540 nm and an emission of 600 nm. Data is analyzed using Prism software (GraphPad, San Diego, CA) to calculate IC50 values. WM3629 Cell Proliferation Assay (1) [000358] WM3629 cells (#WM3629-01-0001) are obtained from Rockland Immunochemicals Inc (Gilbertsville, PA). Briefly, cells were grown in MCDB 153 medium (Sigma, #M7403, St. Louis, MO) supplemented with 20% Leibovitz’s L-15 (ThermoFisher #11415-064, Waltham, MA), 2% heat inactivated fetal bovine serum (ThermoFisher, #A3840001, Waltham, MA), 5µg/mL Insulin (Bovine Pancreas) (Sigma, #I0516, St. Louis, MO), 1.68 mM Calcium Chloride (Sigma, #C-34006, St. Louis, MO) and 1% Penicillin/Streptomycin/L-Glutamine (ThermoFisher #10378016, Waltham, MA) at 37 ºC, 5% CO2, and 95% humidity. Cells are expanded until reaching 70-95% confluency at which point they are subcultured or harvested for assay use. A serial dilution of test compound is dispensed into a 96-well black clear bottom plate in triplicate. Four thousand five hundred cells are added per well in 200 µL complete growth medium in the 96-well plate. Plates are incubated for 67- 72 hours at 37 ºC, 5% CO2, and 95% humidity. At the end of the incubation, 40 µL of a 440 µM solution of resazurin (Sigma, #199303, St. Louis, MO) in PBS is added to each well of the plate and plates are incubated for an additional 6-7 hours at 37 ºC, 5% CO2, and 95% humidity. Plates are read on a Synergy2 or equivalent reader (Biotek, Winooski VT) using an excitation of 540 nm and an emission of 600 nm. Data is analyzed using Prism software (GraphPad, San Diego, CA) to calculate IC 50 values. WM3629 Cell Proliferation Assay (2) [000359] WM3629 cells (#WM3629-01-0001) are obtained from Rockland Immunochemicals Inc (Gilbertsville, PA). Briefly, cells were grown in MCDB 153 medium (Sigma, #M7403, St. Louis, MO) supplemented with 20% Leibovitz’s L-15 (ThermoFisher #11415-064, Waltham, MA), 2% heat inactivated fetal bovine serum (ThermoFisher, #A3840001, Waltham, MA), 5µg/mL Insulin (Bovine Pancreas) (Sigma, #I0516, St. Louis, MO), 1.68 mM Calcium Chloride (Sigma, #C-34006, St. Louis, MO) and 1% Penicillin/Streptomycin/L-Glutamine (ThermoFisher #10378016, Waltham, MA) at 37 ºC, 5% CO2, and 95% humidity. Cells are expanded until reaching 70-95% confluency at which point they are sub-cultured or harvested for assay use. Using the Beckman Coulter Echo 650, a serial dilution of test compound is dispensed into a 384-well black clear bottom plate in triplicate. One thousand one hundred twenty-five cells are added per well in 50 µL complete growth medium in the 384-well plate. Plates are incubated for 67-72 hours at 37 ºC, 5% CO2, and 95% humidity. At the end of the incubation, 10 µL of a 440 µM solution of resazurin (Sigma, #199303, St. Louis, MO) in PBS is added to each well of the plate and plates are incubated for an additional 3-6 hours at 37 ºC, 5% CO2, and 95% humidity. Plates are read on a Synergy2 or equivalent reader (Biotek, Winooski VT) using an excitation of 540 nm and an emission of 600 nm. Data is analyzed using Prism software (GraphPad, San Diego, CA) to calculate IC50 values. H2405 Cell Proliferation Assay (1) [000360] H2405 cells (catalog #CRL-5994) are obtained from the American Type Culture Collect (ATTC, Manassas, VA). Briefly, cells were grown in RPMI 1640 supplemented with 5% characterized fetal bovine serum (Invitrogen, Carlsbad, CA) and 1% Penicillin/Streptomycin/L-Glutamine at 37 ºC, 5% CO2, and 95% humidity. Cells are expanded until reaching 70-95% confluency at which point they are sub-cultured or harvested for assay use. A serial dilution of test compound is dispensed into a 96-well black clear bottom plate in triplicate. Three thousand cells are added per well in 200 µL complete growth medium in the 96-well plate. Plates are incubated for 67-72 h at 37 ºC, 5% CO2, and 95% humidity. At the end of the incubation, 40 µL of a 440 µM solution of resazurin (Sigma, St. Louis, MO) in PBS is added to each well of the plate and plates are incubated for an additional 5-6 h at 37 ºC, 5% CO 2 , and 95% humidity. Plates are read on a Synergy2 or equivalent reader (Biotek, Winooski VT) using an excitation of 540 nm and an emission of 600 nm. Data is analyzed using Prism software (GraphPad, San Diego, CA) to calculate IC 50 values. H2405 Cell Proliferation Assay (2) [000361] H2405 cells (catalog #CRL-5994) are obtained from the American Type Culture Collect (ATTC, Manassas, VA). Briefly, cells were grown in RPMI 1640 supplemented with 5% characterized fetal bovine serum (Invitrogen, Carlsbad, CA) and 1% Penicillin/Streptomycin/L-Glutamine at 37 ºC, 5% CO2, and 95% humidity. Cells are expanded until reaching 70-95% confluency at which point they are sub-cultured or harvested for assay use. A serial dilution of test compound is dispensed into a 384-well black clear bottom plate in triplicate. Seven hundred fifty cells are added per well in 50 µL complete growth medium in the 384-well plate. Plates are incubated for 67-72 h at 37 ºC, 5% CO2, and 95% humidity. At the end of the incubation, 10 µL of a 440 µM solution of resazurin (Sigma, St. Louis, MO) in PBS is added to each well of the plate and plates are incubated for an additional 5-6 h at 37 ºC, 5% CO2, and 95% humidity. Plates are read on a Synergy2 or equivalent reader (Biotek, Winooski VT) using an excitation of 540 nm and an emission of 600 nm. Data is analyzed using Prism software (GraphPad, San Diego, CA) to calculate IC50 values MiaPaca-2 Cell Proliferation Assay (1) [000362] Miapaca-2 cells (catalog #CRL-1420) are obtained from the American Type Culture Collect (ATTC, Manassas, VA). Briefly, cells were grown in DMEM supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 2.5% New Zealand sourced horse serum and 1% Penicillin/Streptomycin/L-Glutamine at 37 ºC, 5% CO2, and 95% humidity. Cells are expanded until reaching 70-95% confluency at which point they are sub- cultured or harvested for assay use. A serial dilution of test compound is dispensed into a 96- well black clear bottom plate in triplicate. Three thousand cells are added per well in 200 µL complete growth medium in the 96-well plate. Plates are incubated for 67-72 h at 37 ºC, 5% CO 2 , and 95% humidity. At the end of the incubation, 40 µL of a 440 µM solution of resazurin (Sigma, St. Louis, MO) in PBS is added to each well of the plate and plates are incubated for an additional 5-6 h at 37 ºC, 5% CO 2 , and 95% humidity. Plates are read on a Synergy2 or equivalent reader (Biotek, Winooski VT) using an excitation of 540 nm and an emission of 600 nm. Data is analyzed using Prism software (GraphPad, San Diego, CA) to calculate IC 50 values. MiaPaca-2 Cell Proliferation Assay (2) [000363] Miapaca-2 cells (catalog #CRL-1420) are obtained from the American Type Culture Collect (ATTC, Manassas, VA). Briefly, cells were grown in DMEM supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 2.5% New Zealand sourced horse serum and 1% Penicillin/Streptomycin/L-Glutamine at 37 ºC, 5% CO2, and 95% humidity. Cells are expanded until reaching 70-95% confluency at which point they are sub- cultured or harvested for assay use. A serial dilution of test compound is dispensed into a 384- well black clear bottom plate in triplicate. Seven hundred fifty cells are added per well in 50 µL complete growth medium in the 384-well plate. Plates are incubated for 67-72 h at 37 ºC, 5% CO 2 , and 95% humidity. At the end of the incubation, 10 µL of a 440 µM solution of resazurin (Sigma, St. Louis, MO) in PBS is added to each well of the plate and plates are incubated for an additional 5-6 h at 37 ºC, 5% CO 2 , and 95% humidity. Plates are read on a Synergy2 or equivalent reader (Biotek, Winooski VT) using an excitation of 540 nm and an emission of 600 nm. Data is analyzed using Prism software (GraphPad, San Diego, CA) to calculate IC50 values. MiaPaca-2 Combination Cell proliferation Assay (1) [000364] Miapaca-2 cells (catalog #CRL-1420) are obtained from the American Type Culture Collect (ATCC, Manassas, VA). Briefly, cells were grown in DMEM supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 2.5% New Zealand sourced horse serum and 1% Penicillin/Streptomycin/L-Glutamine at 37 ºC, 5% CO2, and 95% humidity. Cells are expanded until reaching 70-95% confluency at which point they are subcultured or harvested for assay use. A serial dilution of test compound was dispensed into multiple 96-well black clear bottom plates in triplicate. A serial dilution of complete growth medium containing cobimetinib was prepared at twice the final concentration and 100 µL was dispensed across the test compound titration in triplicate. Three thousand cells are added per well in 100 µL complete growth medium in each 96-well plate. Plates are incubated for 67-72 hours at 37 ºC, 5% CO2, and 95% humidity. At the end of the incubation, 40 µL of a 440 µM solution of resazurin (Sigma, St. Louis, MO) in PBS is added to each well of the plate and plates are incubated for an additional 5-7 hours at 37 ºC, 5% CO2, and 95% humidity. Plates are read on a Synergy2 or equivalent reader (Biotek, Winooski VT) using an excitation of 540 nm and an emission of 600 nm. Drug synergy was assessed via BLISS analysis in the Combenefit software (Cancer Research UK Cambridge Institute, Cambridge, UK). Data is analyzed using Prism software (Graphpad, San Diego, CA) to calculate IC50 values. Shifts in test compound IC 50 values are reported from top-constrained combination therapy curves. MiaPaca-2 Combination Cell proliferation Assay (2) [000365] Miapaca-2 cells (catalog #CRL-1420) are obtained from the American Type Culture Collect (ATCC, Manassas, VA). Briefly, cells were grown in DMEM supplemented with 10% characterized fetal bovine serum (Invitrogen, Carlsbad, CA), 2.5% New Zealand sourced horse serum and 1% Penicillin/Streptomycin/L-Glutamine at 37 ºC, 5% CO 2 , and 95% humidity. Cells are expanded until reaching 70-95% confluency at which point they are subcultured or harvested for assay use. Using the Beckman Coulter Echo 650, a threefold, 8- point serial dilution of compound was spotted column wise into a 384 well black, clear bottom, tissue culture treated plate. Likewise, a threefold, 8-point serial dilution of cobimetinib was spotted row wise into the 384 well black, clear bottom plate containing compound. DMSO concentration was constant across all wells at 0.4%. Seven hundred fifty cells are added per well in 50 µL complete growth medium in each 384-well plate. Plates are incubated for 67-72 hours at 37 ºC, 5% CO2, and 95% humidity. At the end of the incubation, 10 µL of a 440 µM solution of resazurin (Sigma, St. Louis, MO) in PBS is added to each well of the plate and plates are incubated for an additional 4-6 hours at 37 ºC, 5% CO2, and 95% humidity. Plates are read on a Synergy2 or equivalent reader (Biotek, Winooski VT) using an excitation of 540 nm and an emission of 600 nm. Drug synergy was assessed via BLISS analysis in the Combenefit software (Cancer Research UK Cambridge Institute, Cambridge, UK). Data is analyzed using Prism software (Graphpad, San Diego, CA) to calculate IC50 values. Shifts in test compound IC 50 values are reported from top-constrained combination therapy curves. Table K. Inhibition of cell proliferation in A375 (1), H2405 (1), WM3928 (1), WM3629 (1), MiaPaca-2 (1), and combination with cobimetinib in MiaPaca-2 (1) by exemplary compounds (“Ex. No.”). 438 For Table K, “+” refers to an IC50 less than or equal to 100 nM; “++” refers to an IC50 greater than 100 nM and less than or equal to 500 nM; “+++” refers to an IC 50 greater than 500 nM and less than or equal to 1000 nM; and “++++” refers to an IC50 greater than 1000 nM and less than or equal to 10000 nM. Table L. Inhibition of cell proliferation in A375 (2), H2405 (2), WM3928 (2), WM3629 (2), MiaPaca-2 (2), and combination with cobimetinib in MiaPaca-2 (2) by exemplary compounds (“Ex. No.”).
For Table L, “+” refers to an IC 50 less than or equal to 100 nM; “++” refers to an IC 50 greater than 100 nM and less than or equal to 500 nM; “+++” refers to an IC50 greater than 500 nM and less than or equal to 1000 nM; and “++++” refers to an IC 50 greater than 1000 nM and less than or equal to 10000 nM. EQUIVALENTS [000366] While specific embodiments have been discussed, the above specification is illustrative and not restrictive. Many variations of the embodiments will become apparent to those skilled in the art upon review of this specification. The full scope of what is disclosed should be determined by reference to the claims, along with their full scope of equivalents, and the specification, along with such variations. [000367] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in this specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained.
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