Inhibitors of EGFR and methods of use thereof
The application relates to a compound having Formula Ia or Ib: or a pharmaceutically acceptable salt, hydrate, or solvate thereof, 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 Ia:
or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
Z is a bond, O, NH, or S;
A 1 is phenyl or heteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the phenyl or heteroaryl is substituted with one or more R A1 ;
each R A1 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, OH, halogen, CN, phenyl, C 3 -C 6 cycloalkyl, heteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, or heterocyclyl comprising one 5- or 6-membered ring and 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 C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, OH, and halogen, or
two R A1 , together with the adjacent atoms to which they are attached, form phenyl, C 3 -C 6 cycloalkyl, or a 5- or 6-membered heteroaryl or heterocyclyl ring 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 C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, OH, and halogen;
n is 0, 1, 2, or 3;
each R 2 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, OH, halogen, or CN;
each m is independently 0, 1, 2, or 3;
A 2 is phenyl or heteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, wherein the phenyl or heteroaryl is optionally substituted with one or more R A2 ;
each R A2 is independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, OH, halogen, CN, phenyl, C 3 -C 6 cycloalkyl, heteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, or heterocyclyl comprising one 5- or 6-membered ring and 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 C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, OH, and halogen, or
two R A2 , together with the adjacent atoms to which they are attached, form phenyl, C 3 -C 6 cycloalkyl, or a 5- or 6-membered heteroaryl or heterocyclyl ring 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 C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, OH, and halogen;
X 1 , X 2 , X 3 , and X 4 are each independently N or CR X , provided that at least two of X 1 , X 2 , X 3 , and X 4 are CR X ;
X 5 , X 6 , X 7 , and X 8 are each independently N or CR X ;
each R X is independently H, NR n1 R n2 , NR 3 C(O)R 4 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, OH, halogen, CN, phenyl, C 3 -C 6 cycloalkyl, heteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, or heterocyclyl comprising one 5- or 6-membered ring and 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 C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, OH, and halogen;
each R n1 and each R n2 are independently H or C 1 -C 4 alkyl;
each R 3 is independently H or C 1 -C 4 alkyl;
each R 4 is independently C 1 -C 4 alkyl;
R 1 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, OH, halogen, CN, or (CH 2 ) m -A 3 ; and
A 3 is phenyl, C 3 -C 6 cycloalkyl, heteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, or heterocyclyl comprising one 5- or 6-membered ring and 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 C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, OH, and halogen.
2. The compound of claim 1 , wherein Z is a bond or O.
3. The compound of claim 1 , wherein A 1 is phenyl.
4. The compound of claim 1 , wherein A 1 is heteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S.
5. The compound of claim 1 , wherein at least one R A1 is phenyl, C 3 -C 6 cycloalkyl, heteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S, or heterocyclyl comprising one 5- or 6-membered ring and 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 C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, OH, and halogen; or
two R A1 , together with the adjacent atoms to which they are attached, form phenyl, C 3 -C 6 cycloalkyl, or a 5- or 6-membered heteroaryl or heterocyclyl ring 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 C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, OH, and halogen.
6. The compound of claim 1 , wherein n is 0.
7. The compound of claim 1 , wherein A 2 is unsubstituted phenyl or phenyl substituted with one or more R A2 .
8. The compound of claim 1 , wherein A 2 is unsubstituted heteroaryl comprising one 5- or 6-membered ring and 1-3 heteroatoms selected from N, O, and S.
9. The compound of claim 1 , wherein at least one R A2 is C 1 -C 4 straight-chain or C 3 -C 4 branched alkyl, C 1 -C 4 straight-chain or C 3 -C 4 branched haloalkyl, C 1 -C 4 straight-chain or C 3 -C 4 branched alkoxy, C 1 -C 4 straight-chain or C 3 -C 4 branched haloalkoxy, OH, halogen, or CN.
10. The compound of claim 1 , wherein two R A2 , together with the adjacent atoms to which they are attached, form phenyl, C 3 -C 6 cycloalkyl, or a 5- or 6-membered heteroaryl or heterocyclyl ring 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 C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, OH, and halogen.
11. The compound of claim 1 , wherein each m is independently 0 or 1.
12. The compound of claim 1 , wherein R 1 is H.
13. The compound of claim 1 , wherein X 1 , X 2 , X 3 , and X 4 are each CR X ; or
one of X 1 , X 2 , X 3 , and X 4 is N, and the remainder of X 1 , X 2 , X 3 , and X 4 are each CR X .
14. The compound of claim 1 , wherein X 5 , X 6 , X 7 , and X 8 are each CR X .
15. The compound of claim 1 , wherein each R X is independently H, NR n1 R n2 , NR 3 C(O)R 4 , C 1 -C 6 straight-chain or C 3 -C 6 branched alkyl, C 1 -C 6 straight-chain or C 3 -C 6 branched haloalkyl, C 1 -C 6 straight-chain or C 3 -C 6 branched alkoxy, C 1 -C 6 straight-chain or C 3 -C 6 branched haloalkoxy, OH, halogen, or CN.
16. The compound of claim 1 , of Formula IIIa, IIIb, IIIc, IIId, or IIIe:
or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
p is 0, 1, 2, or 3;
q is 0, 1, 2, 3, 4, or 5; and
r is 0, 1, 2, 3, 4, or 5.
17. The compound of claim 1 , of Formula IVa, IVb, IVc, IVd, or IVe:
or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
p is 0, 1, 2, or 3;
q is 0, 1, 2, 3, 4, or 5; and
r is 0, 1, 2, 3, 4, or 5.
18. The compound of claim 1 , of Formula Va, Vb, Vc, Vd, or Ve:
or a pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein:
p is 0, 1, 2, or 3; and
q is 0, 1, 2, 3, 4, or 5.
19. The compound of claim 1 , selected from
20. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier, optionally further comprising a second agent that prevents EGFR dimer formation, and a pharmaceutically acceptable carrier.
21. A kit comprising a compound of claim 1 , or a pharmaceutically acceptable salt, hydrate, or solvate thereof, optionally further comprising a second agent that prevents EGFR dimer formation, and a pharmaceutically acceptable carrier.
22. The compound of claim 1 , wherein the compound of Formula Ia is
or a pharmaceutically acceptable salt thereof.