Inhibitors of egfr and methods of use thereof

A compound of Formula (I′):

• or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof, wherein:
• R1 is (C6-C10) aryl, or heteroaryl comprising one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are each optionally substituted with one or more R11;
• each R11 is independently selected from (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, NO2, OH, CN, C(O)R13, C(O)OR13, C(O)NR13R14, NR13R14, (C3-C7) cycloalkyl, heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S, (C6-C10) aryl, and heteroaryl comprising one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more R12;
• each R12 is independently selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, NO2, OH, CN, (C3-C7) cycloalkyl, heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S, (C6-C10) aryl, and heteroaryl comprising one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are each optionally substituted with one or more substituents independently selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, halogen, NH2, NH(C1-C4) alkyl, N((C1-C4) alkyl)2, (C3-C7) cycloalkyl, and heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S;
• each R13 is independently selected from H, (C1-C4) alkyl, (C3-C7) cycloalkyl, and heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more substituents independently selected from (C1-C4) alkyl, halogen, OH, NH2, NH(C1-C4) alkyl, N((C1-C4) alkyl)2, and heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S;
• each R14 is independently H or (C1-C3) alkyl;
• R2 is H or (C1-C3) alkyl;
• R3 is H or (C1-C3) alkyl;
• R4 is (C1-C3) alkyl or
• X1 is N or CR6;
• R6 is H, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, NO2, NH2, (CH2)qOH, S(O)rR23, or CN;
• each R7 is independently selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, NO2, NH2, (CH2)qOH, S(O)rR23, and CN;
• R5 is NR15R16;
• R5′ is H or (C1-C4) alkyl;
• R15 is H or (C1-C3) alkyl;
• R16 is (C6-C10) aryl, or heteroaryl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are each optionally substituted with one or more R18;
• or
• R15 and R16 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl optionally comprising 1 or 2 additional heteroatoms selected from N, O, and S and optionally substituted with one or more oxo groups, wherein the heterocyclyl is fused with a phenyl ring which is optionally substituted with one or more R19;
• each R18 is independently selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, halogen, C(O)O(C1-C4) alkyl, NO2, C(O)NH(C1-C4) alkyl, NH2, NH(C1-C4) alkyl, and N((C1-C4) alkyl)2, wherein the alkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, NH(C1-C4) alkyl, and N((C1-C4) alkyl)2;
• each R19 is independently selected from halogen, O(CH2)1-3—OH, (C3-C7) cycloalkyl, (C4-C7) cycloalkenyl, (C6-C10) aryl, NH—(C6-C10) aryl, and heteroaryl comprising one or two 5- to 7-membered ring and 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are each optionally substituted with one or more R20;
• or
• two R19 together with the atoms to which they are attached form a (C6-C10) aryl optionally substituted with one or more R20;
• each R20 is independently selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, halogen, C(O)OH, C(O)O(C1-C4) alkyl, C(O)NR21R22, O(CH2)1-3—OH, NH2, OH, CN, O(CH2)0-3—(C6-C10) aryl, and (CH2)0-3-heterocyclyl which comprises a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with one or more substituents independently selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, halogen, NH2, NH(C1-C4) alkyl, N((C1-C4) alkyl)2, S(O)2NH2, (CH2)sOH, C(O)(CH2)sOH, and C(O)O(C1-C4) alkyl);
• R21 is H or (C1-C3) alkyl;
• R22 is H or (C1-C4) alkyl optionally substituted with one or more substituents independently selected from NH2, NH(C1-C4) alkyl, N((C1-C4) alkyl)2, and heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S;
• or
• R21 and R22 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl optionally containing 1-2 additional heteroatoms selected from N, O, and S;
• R23 is H or NH2;
• m is 0 or 1;
• n is 0;
• each r and each q are independently 0, 1, or 2;
• each s is 1 or 2;
• and
• p is 0, 1, 2, 3, or 4;
• provided that when m is 0, n is 0, p is 0, R15 and R16 together with the nitrogen atom to which they are attached form an unsubstituted isoindolinone, and R6 is H, then R1 is not
• and
• provided that R4 is not 4-fluoro-2-hydroxyphenyl.

A compound of Formula (I′):

• or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof, wherein:
• R1 is (C6-C10) aryl, or heteroaryl comprising one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are each optionally substituted with one or more R11;
• each R11 is independently selected from (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, NO2, OH, CN, C(O)R13, C(O)OR13, C(O)NR13R14, NR13R14, (C3-C7) cycloalkyl, heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S, (C6-C10) aryl, and heteroaryl comprising one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more R12;
• each R12 is independently selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, NO2, OH, CN, (C3-C7) cycloalkyl, heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S, (C6-C10) aryl, and heteroaryl comprising one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are each optionally substituted with one or more substituents independently selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, halogen, NH2, NH(C1-C4) alkyl, N((C1-C4) alkyl)2, (C3-C7) cycloalkyl, and heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S;
• each R13 is independently selected from H, (C1-C4) alkyl, (C3-C7) cycloalkyl, and heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more substituents independently selected from (C1-C4) alkyl, halogen, OH, NH2, NH(C1-C4) alkyl, N((C1-C4) alkyl)2, and heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S;
• each R14 is independently H or (C1-C3) alkyl;
• R2 is H or (C1-C3) alkyl;
• R3 is H or (C1-C3) alkyl;
• R4 is (C1-C3) alkyl or
• X1 is N or CR6;
• R6 is H, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, NO2, NH2, (CH2)qOH, S(O)rR23, or CN;
• each R7 is independently selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, NO2, NH2, (CH2)qOH, S(O)rR23, and CN;
• R5 is NR15R16;
• R5′ is H or (C1-C4) alkyl;
• R15 is H or (C1-C3) alkyl;
• R16 is (C6-C10) aryl, or heteroaryl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are each optionally substituted with one or more R18;
• or
• R15 and R16 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl optionally comprising 1 or 2 additional heteroatoms selected from N, O, and S and optionally substituted with one or more oxo groups, wherein the heterocyclyl is fused with a phenyl ring which is optionally substituted with one or more R19;
• each R18 is independently selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, halogen, C(O)O(C1-C4) alkyl, NO2, C(O)NH(C1-C4) alkyl, NH2, NH(C1-C4) alkyl, and N((C1-C4) alkyl)2, wherein the alkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, NH(C1-C4) alkyl, and N((C1-C4) alkyl)2;
• each R19 is independently selected from halogen, O(CH2)1-3—OH, (C3-C7) cycloalkyl, (C4-C7) cycloalkenyl, (C6-C10) aryl, NH—(C6-C10) aryl, and heteroaryl comprising one or two 5- to 7-membered ring and 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are each optionally substituted with one or more R20;
• or
• two R19 together with the atoms to which they are attached form a (C6-C10) aryl optionally substituted with one or more R20;
• each R20 is independently selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, halogen, C(O)OH, C(O)O(C1-C4) alkyl, C(O)NR21R22, O(CH2)1-3—OH, NH2, OH, CN, O(CH2)0-3—(C6-C10) aryl, and (CH2)0-3-heterocyclyl which comprises a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with one or more substituents independently selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, halogen, NH2, NH(C1-C4) alkyl, N((C1-C4) alkyl)2, S(O)2NH2, (CH2)sOH, C(O)(CH2)sOH, and C(O)O(C1-C4) alkyl);
• R21 is H or (C1-C3) alkyl;
• R22 is H or (C1-C4) alkyl optionally substituted with one or more substituents independently selected from NH2, NH(C1-C4) alkyl, N((C1-C4) alkyl)2, and heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S;
• or
• R21 and R22 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl optionally containing 1-2 additional heteroatoms selected from N, O, and S;
• R23 is H or NH2;
• m is 0 or 1;
• n is 0;
• each r and each q are independently 0, 1, or 2;
• each s is 1 or 2;
• and
• p is 0, 2, 3, or 4;
• provided that when m is 0, n is 0, p is 0, R15 and R16 together with the nitrogen atom to which they are attached form an unsubstituted isoindolinone, and R6 is H, then R1 is not
• and
• provided that R4 is not 4-fluoro-2-hydroxyphenyl.

A method of inhibiting epidermal growth factor receptor (EGFR) or treating or preventing a disease, comprising administering to a subject in need thereof an effective amount of a compound of Formula (I′):

• or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof, wherein:
• R1 is (C6-C10) aryl, or heteroaryl comprising one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are each optionally substituted with one or more R11;
• each R11 is independently selected from (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, NO2, OH, CN, C(O)R13, C(O)OR13, C(O)NR13R14, NR13R14, (C3-C7) cycloalkyl, heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S, (C6-C10) aryl, and heteroaryl comprising one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, and heteroaryl are each optionally substituted with one or more R12;
• each R12 is independently selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, NO2, OH, CN, (C3-C7) cycloalkyl, heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S, (C6-C10) aryl, and heteroaryl comprising one or two 5- to 7-membered rings and 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are each optionally substituted with one or more substituents independently selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, halogen, NH2, NH(C1-C4) alkyl, N((C1-C4) alkyl)2, (C3-C7) cycloalkyl, and heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S;
• each R13 is independently selected from H, (C1-C4) alkyl, (C3-C7) cycloalkyl, and heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the alkyl, cycloalkyl, and heterocyclyl are each optionally substituted with one or more substituents independently selected from (C1-C4) alkyl, halogen, OH, NH2, NH(C1-C4) alkyl, N((C1-C4) alkyl)2, and heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S;
• each R14 is independently H or (C1-C3) alkyl;
• R2 is H or (C1-C3) alkyl;
• R3 is H or (C1-C3) alkyl;
• R4 is
• X1 is N or CR6;
• R6 is H, (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, NO2, NH2, (CH2)qOH, S(O)rR23, or CN;
• each R7 is independently selected from (C1-C4) alkyl, (C1-C4) haloalkyl, (C1-C4) alkoxy, (C1-C4) haloalkoxy, halogen, NO2, NH2, (CH2)qOH, S(O)rR23, and CN;
• R5 is NR15R16;
• R5′ is H or (C1-C4) alkyl;
• R15 is H or (C1-C3) alkyl;
• R16 is (C6-C10) aryl, or heteroaryl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are each optionally substituted with one or more R18;
• or
• R15 and R16 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl optionally comprising 1 or 2 additional heteroatoms selected from N, O, and S and optionally substituted with one or more oxo groups, wherein the heterocyclyl is fused with a phenyl ring which is optionally substituted with one or more R19;
• each R18 is independently selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, halogen, C(O)O(C1-C4) alkyl, NO2, C(O)NH(C1-C4) alkyl, NH2, NH(C1-C4) alkyl, and N((C1-C4) alkyl)2, wherein the alkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH2, NH(C1-C4) alkyl, and N((C1-C4) alkyl)2;
• each R19 is independently selected from halogen, O(CH2)1-3—OH, (C3-C7) cycloalkyl, (C4-C7) cycloalkenyl, (C6-C10) aryl, NH—(C6-C10) aryl, and heteroaryl comprising one or two 5- to 7-membered ring and 1-4 heteroatoms selected from N, O, and S, wherein the aryl and heteroaryl are each optionally substituted with one or more R20;
• or
• two R19 together with the atoms to which they are attached form a (C6-C10) aryl optionally substituted with one or more R20;
• each R20 is independently selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, halogen, C(O)OH, C(O)O(C1-C4) alkyl, C(O)NR21R22, O(CH2)1-3—OH, NH2, OH, CN, O(CH2)0-3—(C6-C10) aryl, and (CH2)0-3-heterocyclyl which comprises a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the heterocyclyl is optionally substituted with one or more substituents independently selected from (C1-C4) alkyl, (C1-C4) alkoxy, (C1-C4) haloalkyl, (C1-C4) haloalkoxy, halogen, NH2, NH(C1-C4) alkyl, N((C1-C4) alkyl)2, S(O)2NH2, (CH2)sOH, C(O)(CH2)sOH, and C(O)O(C1-C4) alkyl);
• R21 is H or (C1-C3) alkyl;
• R22 is H or (C1-C4) alkyl optionally substituted with one or more substituents independently selected from NH2, NH(C1-C4) alkyl, N((C1-C4) alkyl)2, and heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S;
• or
• R21 and R22 together with the nitrogen atom to which they are attached form a 5- or 6-membered heterocyclyl optionally containing 1-2 additional heteroatoms selected from N, O, and S;
• R23 is H or NH2;
• m and n are each independently 0 or 1;
• m and n are each independently 0 or 1;
• each r and each q are independently 0, 1, or 2;
• each s is 1 or 2;
• and
• p is 0, 2, 3 or 4;
• provided that when m is 0, n is 0, p is 0, R15 and R16 together with the nitrogen atom to which they are attached form an unsubstituted isoindolinone, and R6 is H, then R1 is not
• and
• provided that R4 is not 4-fluoro-2-hydroxyphenyl.