Compounds and methods of use thereof for treatment of 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, stereoisomer, isotopic form or prodrug thereof, wherein R 1 , R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , L 1 , L 2 , E, X, Y, Z, m 1 and m 2 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 the following structure (I):
or a pharmaceutically acceptable salt, isotopic form, stereoisomer or prodrug thereof, wherein:
G 1 and G 2 are each N;
L 1 is a bond;
L 2 is a bond;
X is C—CN;
Y is CR′;
Z is N;
R′ is, at each occurrence, independently H, amino, cyano, hydroxyl, C 1 -C 6 alkyl, C 2 -C 6 alkynyl; C 1 -C 6 haloalkyl, C 1 -C 6 hydroxylalkly, C 1 -C 6 cyanoalkyl, alkoxy, aminylalkyl, aminylalkyloxy, aminylalkynyl, alkoxyalkyl, alkoxyalkynyl, alkylcarbonylaminyl, aminylalkylcarbonylaminyl, aminylcarbonylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonylalkyl, aryl, aralkyl, heteroaryl, heteroarylalkyl; —NR a R b , C 1 -C 6 alkylphosphoryl, C 1 -C 6 alkylphosphorylaminyl, heteroarylalkyloxy or heteroarylalkylaminyl, wherein R a is H or C 1 -C 6 alkyl, and R b is C 1 -C 6 alkyl;
R 1 has the following structure:
wherein:
each represents an aromatic ring;
A 1 , A 2 , A 3 and A 4 are each C;
B 1 is N, NH or CR 1e ;
B 2 is N, NH or CR 1f ;
B 3 is CR 1g or NR 1g′ ;
R 1a is a covalent bond to the carbon marked with *, and R 1b , R 1c and R 1d are each independently H, amino, cyano, halo, hydroxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, alkylaminyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy; cycloalkyl, heterocyclyl, aminylalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
R 1e and R 1f are each H;
R 1g and R 1g′ are each independently C 1 -C 6 alkyl or C 3 -C 8 cycloalkyl;
R 2a , R 2b and R 2c are each independently H or halo;
R 3a and R 3b are, at each occurrence, independently H, C 1 -C 6 alkyl or C 1 -C 6 cyanoalkyl;
R 4a and R 4b are, at each occurrence, independently H, C 1 -C 6 alkyl or C 1 -C 6 cyanoalkyl;
m 1 and m 2 are each 2; and
E is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS, HRAS or NRAS G12C mutant protein,
wherein each occurrence of alkyl, alkynyl, alkenyl, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, alkylaminyl, haloalkyl, hydroxylalkyl, alkoxy, alkoxyalkyl, haloalkoxy, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonyl and aminylcarbonylalkyl is optionally substituted with one or more substituents unless otherwise specified.
2. The compound of claim 1 , wherein the compound has the following structure (I′a):
wherein:
represents a double or triple bond;
Q is —C(═O)—, —C(═NR 8′ )—, —NR 8 C(═O)—, —S(═O) 2 — or —NR 8 S(═O) 2 —;
R 8 is H, C 1 -C 6 alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, C 3 -C 8 cycloalkyl or heterocyclylalkyl;
R 8′ is H, —OH, —CN or C 1 -C 6 alkyl;
when is a double bond then R 9 and R 10 are each independently H, halo, cyano, carboxyl, C 1 -C 6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl or hydroxylalkyl, or R 9 and R 10 join to form a carbocyclic, heterocyclic or heteroaryl ring; 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,
wherein each occurrence of alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, cycloalkyl, heterocyclylalkyl, alkoxycarbonyl, heteroaryl, and carbocyclic, heterocyclic and heteroaryl rings is optionally substituted with one or more substituents unless otherwise specified.
3. The compound of claim 1 , wherein B 1 is NH, B 2 is N and B 3 is CR 1g .
4. The compound of claim 1 , wherein B 1 is NH, B 2 is CR 1f and B 3 is CR 1g .
5. The compound of claim 1 , wherein R 1b , R 1c and R 1d are each independently H, amino, halo, hydroxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, alkylaminyl or cycloalkyl.
6. The compound of claim 1 , wherein R 1 has one of the following structures:
7. The compound of claim 1 , wherein R 2c is H.
8. The compound of claim 1 , wherein R 2a and R 2b are each independently fluoro or chloro.
9. The compound of claim 1 , wherein X is C—CN, Y is CH and Z is N.
10. The compound of claim 2 , wherein the compound has one of the following structures:
wherein R 3a and R 4a are independently C 1 -C 6 alkyl or cyanoalkyl.
11. The compound of claim 2 , wherein Q is —C(═O)—.
12. The compound of claim 1 , wherein E has one of the following structures:
13. The compound of claim 1 , wherein the compound has one of the following structures:
14. A substantially purified atropisomer according to claim 1 .
15. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.