Inhibitors of KRAS G12C mutant proteins
Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof wherein Z, Y R 3a , R 3b , R 4a , R 4b , G 1 , G 2 , G 3 , G 4 , L 1 , m 1 , m 2 , m 3 , m 4 , n and E are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.
1. A compound having one of the following structures: (Ia″); (Ib″); (Ic″); (Id″); (Ie″); (If″); (Ig″); (Ih″); (Ii″); (Ij″) or (Ik″):
or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein:
R 1 is aryl optionally substituted with one or more substituents independently selected from halo, hydroxyl, cyano, aminocarbonyl, formyl, C 1 -C 6 alkyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxylalkyl, C 1 -C 6 alkoxyalkyl and C 1 -C 6 aminoalkyl;
R 3a is, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonyl alkyl or aminocarbonyl;
R 4a is, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonyl alkyl or aminocarbonyl;
L 1 is a bond or alkylene;
L 2 is a bond, O or NH;
=represents a double or triple bond;
Q is —C(═O)—, —C(═NR 7 )—, —NR 8 C(═O)—, —S(═O) 2 — or —NR 8 S(═O) 2 —;
R 7 is H, —OH, —CN or C 1 -C 6 alkyl;
R 8 is H, C 1 -C 6 alkyl or hydroxylalkyl;
when is a double bond then R 9 and R 10 are each independently H, cyano, carboxyl, C 1 -C 6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, or hydroxylalkyl; and
when is a triple bond then R 9 is absent and R 10 is H, C 1 -C 6 alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl.
2. The compound of claim 1 , wherein R 1 is substituted aryl.
3. The compound of claim 2 , wherein R 1 is substituted with one or more substituents selected from halo, hydroxyl, C 1 -C 6 alkyl and C 3 -C 8 cycloalkyl.
4. The compound of claim 3 , wherein the one or more substituents are selected from hydroxyl, chloro and cyclopropyl.
5. The compound of claim 1 , wherein R 1 has one of the following structure:
6. The compound of claim 1 , wherein L 2 is a bond or NH.
7. The compound of claim 1 , wherein Q is —C(═O)—.
8. The compound of claim 1 , wherein each of R 9 and R 10 are H.
9. The compound claim 1 , wherein
has one of the following structures:
10. The compound of claim 1 , wherein L 1 is a bond.
11. The compound of claim 1 , wherein R 3a and R 4a are each H.
12. A compound having one of the following structures:
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
14. The compound of claim 1 , wherein R 1 is phenyl optionally substituted with one or more substituents selected from halo, hydroxyl and C 3 -C 8 cycloalkyl.
15. The compound of claim 1 , wherein Q is —C(═O)—and R 9 and R 10 are each H.