Inhibitors of EGFR and methods of use thereof

1. A compound of Formula (I′):

or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof, wherein:

R 1 is (C 6 -C 10 ) 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 R 11 ;

each R 11 is independently selected from (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, NO 2 , OH, CN, C(O)R 13 , C(O)OR 13 , C(O)NR 13 R 14 , NR 13 R 14 , (C 3 -C 7 ) cycloalkyl, heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S, (C 6 -C 10 ) 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 R 12 ;

each R 12 is independently selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, NO 2 , OH, CN, (C 3 -C 7 ) cycloalkyl, heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S, (C 6 -C 10 ) 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 (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, NH 2 , NH(C 1 -C 4 ) alkyl, N((C 1 -C 4 ) alkyl) 2 , (C 3 -C 7 ) cycloalkyl, and heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S;

each R 13 is independently selected from H, (C 1 -C 4 ) alkyl, (C 3 -C 7 ) 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 (C 1 -C 4 ) alkyl, halogen, OH, NH 2 , NH(C 1 -C 4 ) alkyl, N((C 1 -C 4 ) alkyl) 2 , and heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S;

each R 14 is independently H or (C 1 -C 3 ) alkyl;

R 2 is H or (C 1 -C 3 ) alkyl;

R 3 is H or (C 1 -C 3 ) alkyl;

R 4 is

X 1 is N or CR 6 ;

R 6 is H, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, NO 2 , NH 2 , (CH 2 ) q OH, S(O) r R 23 , or CN;

each R 7 is independently selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, NO 2 , NH 2 , (CH 2 ) q OH, S(O) r R 23 , and CN;

R 5 is NR 15 R 16 ;

R 5′ is H or (C 1 -C 4 ) alkyl;

R 15 is H or (C 1 -C 3 ) alkyl;

R 16 is (C 6 -C 10 ) 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 R 18 ; or

R 15 and R 16 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 R 19 ;

each R 18 is independently selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, C(O)O(C 1 -C 4 ) alkyl, NO 2 , C(O)NH(C 1 -C 4 ) alkyl, NH 2 , NH(C 1 -C 4 ) alkyl, and N((C 1 -C 4 ) alkyl) 2 , wherein the alkyl is optionally substituted with one or more substituents independently selected from halogen, OH, NH 2 , NH(C 1 -C 4 ) alkyl, and N((C 1 -C 4 ) alkyl) 2 ;

each R 19 is independently selected from halogen, O(CH 2 ) 1-3 —OH, (C 3 -C 7 ) cycloalkyl, (C 4 -C 7 ) cycloalkenyl, (C 6 -C 10 ) aryl, NH—(C 6 -C 10 ) 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 R 20 ; or

two R 19 together with the atoms to which they are attached form a (C 6 -C 10 ) aryl optionally substituted with one or more R 20 ;

each R 20 is independently selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, C(O)OH, C(O)O(C 1 -C 4 ) alkyl, C(O)NR 21 R 22 , O(CH 2 ) 1-3 —OH, NH 2 , OH, CN, O(CH 2 ) 0-3 —(C 6 -C 10 ) aryl, and (CH 2 ) 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 (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) haloalkoxy, halogen, NH 2 , NH(C 1 -C 4 ) alkyl, N((C 1 -C 4 ) alkyl) 2 , S(O) 2 NH 2 , (CH 2 ) s OH, C(O)(CH 2 ) s OH, and C(O)O(C 1 -C 4 ) alkyl);

R 21 is H or (C 1 -C 3 ) alkyl;

R 22 is H or (C 1 -C 4 ) alkyl optionally substituted with one or more substituents independently selected from NH 2 , NH(C 1 -C 4 ) alkyl, N((C 1 -C 4 )alkyl) 2 , and heterocyclyl comprising a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S; or

R 21 and R 22 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;

R 23 is H or NH 2 ;

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, R 15 and R 16 together with the nitrogen atom to which they are attached form an unsubstituted isoindolinone, and R 6 is H, then R 1 is not

and

provided that R 4 is not 4-fluoro-2-hydroxyphenyl.

2. The compound of claim 1 , wherein m is 0.

3. The compound of claim 1 , wherein R 5 is

optionally substituted with one to three R 19 .

4. The compound of claim 1 , wherein one R 19 is phenyl or heteroaryl comprising one or two 5- to 7-membered ring and 1-4 heteroatoms selected from N, O, and S, wherein the phenyl and heteroaryl are each optionally substituted with one or more R 20 .

5. The compound of claim 1 , wherein R 20 is halogen, O(CH 2 ) 1-3 —OH, or optionally substituted (CH 2 ) 0-3 -heterocyclyl which comprises a 5- to 7-membered ring and 1-3 heteroatoms selected from N, O, and S.

6. The compound of claim 1 , wherein R 20 is piperazinyl or piperazinyl substituted with one or more substituents independently selected from (C 1 -C 4 ) alkyl, S(O) 2 NH 2 , (CH 2 ) s OH, and C(O)(CH 2 ) s OH.

7. The compound of claim 1 , wherein R 1 is

8. The compound of claim 1 , wherein R 4 is phenyl substituted with two or more R 7 .

9. The compound of claim 1 , wherein at least one R 7 is halogen or at least one R 7 is halogen and at least one R 7 is OH.

10. The compound of claim 1 , wherein n is 0.

11. The compound of claim 1 , wherein n is 1.

12. A compound of the following structure

or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof.

13. A pharmaceutical composition comprising a compound of claim 12 , and a pharmaceutically acceptable carrier.

14. A pharmaceutical composition comprising a compound of claim 1 , and a pharmaceutically acceptable carrier.

15. The compound of claim 1 , of Formula (I):

or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof, wherein R 6 is H, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, NO 2 , NH 2 , OH, or CN; and each R 7 is independently selected from (C 1 -C 4 ) alkyl, (C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) haloalkoxy, halogen, NO 2 , NH 2 , OH, and CN.

16. The compound of claim 1 , wherein R 5 is

17. The compound of claim 1 , wherein R 1 is

substituted with one or more substituents independently selected from (C 1 -C 4 ) haloalkyl, halogen, C(O)R 13 , C(O)OR 13 , C(O)NR 13 R 14 , and heteroaryl.

18. The compound of claim 1 , wherein R 4 is unsubstituted phenyl.

19. The compound of claim 1 , wherein p is 0 or 2.

20. The compound of claim 12 , of the following structure

21. A compound selected from:

or pharmaceutically acceptable salts, hydrates, solvates, stereoisomers, or tautomers thereof.