Inhibitors of EGFR and methods of use thereof

A compound of Formula I:

• or a pharmaceutically acceptable salt, hydrate, solvate, or stereoisomer thereof, wherein:
• A1 is phenyl or 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O, and S, wherein the phenyl or heteroaryl is optionally substituted with one or more R0;
• each R0 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, CN, phenyl, C3-C6 cycloalkyl, 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O, and S, or 5- or 6-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, wherein the phenyl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, and halogen, or
• two R0, taken together with the adjacent atoms to which they are attached, form phenyl, C5-C6 cycloalkyl, 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O, and S, or 5- or 6-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, wherein the phenyl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, and halogen;
• R1 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or (CH2)m-A2;
• A2 is phenyl, C3-C6 cycloalkyl, 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O, and S, or 5- or 6-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, wherein the phenyl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, and halogen;
• m is 0, 1, 2, or 3;
• R2 is H or C1-C6 alkyl;
• R3 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
• or
• R2 and R3, taken together with the intervening atoms, form a 5- or 6-membered heterocyclyl ring comprising 0-2 additional heteroatoms selected from N, O, and S, or a 5- or 6-membered heteroaryl ring comprising 0-2 additional heteroatoms selected from N, O, and S, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more substituents independently selected from oxo, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, and C1-C6 haloalkoxy;
• L1 is a bond, a straight or branched bivalent C1-C6 alkylene chain, —C(O)—, —C(O)(CH2)n—, —C(S)—, —C(S)(CH2)n—, —C(S)NH—, —C(S)N(C1-C6 alkyl)-, —C(S)NH(CH2)n—, —C(S)N(C1-C6 alkyl)(CH2)n—, —(CH2)pNH—, —(CH2)pN(C1-C6 alkyl)-, or —(CH2)pO—;
• n is 1 or 2;
• p is 1, 2, or 3;
• X1, X2, X3, and X4 are each independently N or CR4, provided that at least two of X1, X2, X3, and X4 are CR4;
• each R4 is independently H, NR5R6, NR7C(O)R8, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, CN, phenyl, C3-C6 cycloalkyl, 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O, and S, or 5- or 6-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, wherein the phenyl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, and halogen;
• each R5 and each R6 are independently H or C1-C4 alkyl;
• each R7 is independently H or C1-C4 alkyl;
• each R8 is independently C1-C4 alkyl;
• X5, X6, X7, and X8 are each independently N, CR9, or CR10, provided that at least one of X5, X6, X7, and X8 is CR9 and at least one of X5, X6, X7, and X8 is CR10;
• each R9 is independently H, halogen, OH, CN, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, or C1-C6 haloalkoxy;
• each R10 is independently phenyl, C3-C6 cycloalkyl, 5- or 6-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, or 5- or 6-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, wherein the phenyl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or more R11;
• each R11 is independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, halogen, CN, phenyl, C3-C6 cycloalkyl, 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O, and S, or 5- or 6-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, wherein the phenyl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, and halogen, or
• two R11, taken together with the adjacent atoms to which they are attached, form phenyl, C5-C6 cycloalkyl, 5- or 6-membered heteroaryl comprising 1-3 heteroatoms selected from N, O, and S, or 5- or 6-membered heterocyclyl comprising 1-3 heteroatoms selected from N, O, and S, wherein the phenyl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or more substituents independently selected from C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, OH, and halogen.