1-(3-(6-(3-hydroxynaphthalen-1-yl)benzofuran-2-yl)azetidin-1 yl)prop-2-en-1-one derivatives and similar compounds as KRAS G12C modulators for treating cancer
Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, wherein A is a five-membered heteroaryl comprising 1 or 2 non-adjacent heteroatoms, inclusive of X and Y; W, X, Y, Z, L, L 1 , E, R 1 , R 2b R 2c and the dotted circle are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and compounds for use in methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided. Preferred compounds are e.g. 1-(3-(6-(3-hydroxynaphthalen-1-yl)benzofuran-2-yl)azetidin-1yl)prop-2-en-1-one derivatives and related compounds such as e.g. the corresponding derivatives with e.g. a benzoimidazole, indole, benzooxazole, imidazopyridine or imidazole core structure, substituted on ring A by e.g. azetidine, pyrrolidine, azepane or bicyclopentane-amine (L 1 ) each substituted by e.g. propenone (E), and the core structure substituted on the six-membered ring with e.g. 3-hydroxynaphthalene or indazole or hydroxy-, alkoxy- and/or fluoro-substituted phenyl (R 1 ).
1. A compound having one of the following structures (Ie) and (Ik):
or a pharmaceutically acceptable salt, isotopic form or stereoisomer thereof, wherein:
R 1 is aryl or heteroaryl;
R 2a , R 2b and R 2c are, at each occurrence, independently H, amino, cyano, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 2 -C 6 alkynyl, C 2 -C 6 alkenyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, alkylcarbonylaminyl or aminylcarbonyl;
R 3a and R 3b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
R 4a and R 4b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 2 -C 6 alkynyl, hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
R 9 is H, oxo, cyano, halo, CF 3 , aminylsulfone, alkylsulfone cyanoalkyl, amino, aminylalkyl, aminylalkylaminyl, aminylcarbonyl, alkylaminyl, haloalkylaminyl, hydroxylalkylaminyl, amidinylalkyl, amidinylalkoxy, amidinylalkylaminyl, guanidinylalkyl, guanidinylalkoxy, guanidinylalkylaminyl, C 1 -C 6 alkoxy, aminylalkoxy, alkylaminylalkoxy, alkylcarbonylaminylalkoxy, C 1 -C 6 alkyl or alkylcarbonylaminyl;
R 10 is H, C 1 -C 6 alkyl, alkylcarbonyl, alkylaminylalkyl or aminylalkyl;
L is, at each occurrence, independently absent or —NR a —, wherein R a is H or C 1 -C 6 alkyl;
G is N;
m 1 and m 2 are each independently 1, 2 or 3;
represents a double or triple bond;
L 2 is a bond;
Q is —C(═O)—;
when is a double bond then R 5 and R 6 are each independently H, halo, cyano, carboxyl, C 1 -C 6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl; and
when is a triple bond then R 5 is absent and R 6 is H, C 1 -C 6 alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl.
2. The compound of claim 1 , having one of the following structures (Ie′) and (Ik′):
3. The compound of claim 1 , wherein:
m 1 and m 2 are both 1;
m 1 and m 2 are both 2;
m 1 is 2 and m 2 is 1;
m 1 is 3 and m 2 is 1; or
m 1 is 3 and m 2 is 2.
4. The compound of claim 1 , wherein R 1 is substituted with halo, amino, hydroxyl, C 1 -C 6 alkyl, cyano, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, alkylaminyl; or C 1 -C 6 alkylcarbonyloxy, or combinations thereof.
5. The compound of claim 1 , wherein R 1 has one of the following structures:
6. The compound of claim 1 , wherein:
R 2a is chloro, fluoro, cyano, hydroxyl, methyl, —C(═O)NH 2 or trifluoromethyl and R 2b and R 2c are each H;
R 2b is chloro, fluoro, cyano, hydroxyl, methyl, —C(═O)NH 2 or trifluoromethyl and R 2a and R 2c are each H; or
R 2c is chloro, fluoro, cyano, hydroxyl, methyl, —C(═O)NH 2 or trifluoromethyl and R 2b and R 2b are each H.
7. The compound of claim 1 , wherein each R 3a , R 3b , R 4a and R 4b is H.
8. The compound of claim 1 , wherein at least one occurrence of R 3a , R 3b , R 4a or R 4b is C 1 -C 6 alkyl.
9. The compound of claim 1 , wherein each of R 5 and R 6 are H.
10. The compound of claim 1 , wherein
has one of the following structures:
11. The compound of claim 1 , wherein the compound has one of the following structures:
12. A substantially purified atropisomer according to claim 1 .
13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.