Inhibitors of EGFR and methods of use thereof
The disclosure relates to a compound having Formula (I′): and in particular, Compound I-126: which modulates the activity of EGFR, a pharmaceutical composition comprising the compound, and a method of treating or preventing a disease in which EGFR plays a role.
1. A compound of Formula (I′):
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein:
R 1 is
optionally substituted with one or more R 11 ;
each R 11 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(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 alkyl, 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 (C 1 -C 3 ) alkyl or
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
substituted with one to three R 19 ;
R 5′ is H or (C 1 -C 4 ) alkyl;
each R 19 is independently selected from 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 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 20 ; or
two Rig 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, 1, 2, 3 or 4;
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 one R 19 is phenyl or heteroaryl comprising one or two 5- to 7-membered rings 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 .
4. The compound of claim 1 , wherein R 1 is
optionally 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.
5. The compound of claim 4 , wherein R 1 is
6. The compound of claim 1 , wherein R 4 is phenyl optionally substituted with two or more R 7 .
7. The compound of claim 1 , of Formula (I):
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer 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, 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, or CN.
8. A method of inhibiting epidermal growth factor receptor (EGFR), comprising administering to a subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof.
9. The compound of claim 1 , wherein n is 0.
10. The compound of claim 1 , wherein n is 1.
11. The compound of claim 1 , wherein p is 2.
12. 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.
13. 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.
14. The compound of claim 1 , wherein R 4 is phenyl substituted with two or more R 7 .
15. 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.
16. A method of inhibiting epidermal growth factor receptor (EGFR), comprising administering to a subject in need thereof an effective amount of a compound of Formula (I′):
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof, wherein:
R 1 is
optionally substituted with one or more R 11 ;
each R 11 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(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 alkyl, 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 (C 1 -C 3 ) alkyl or
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
substituted with one to three R 19 ;
R 5′ is H or (C 1 -C 4 ) alkyl;
each R 19 is independently selected from 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 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 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, 1, 2, 3 or 4;
provided that R 4 is not 4-fluoro-2-hydroxyphenyl.
17. A method of inhibiting epidermal growth factor receptor (EGFR), comprising administering to a subject in need thereof an effective amount of:
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof.
18. A method of inhibiting epidermal growth factor receptor (EGFR), comprising administering to a subject in need thereof an effective amount of a compound selected from:
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, or tautomer thereof.