Quinazoline derivatives as modulators of mutant KRAS, HRAS or NRAS
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 , R 5 , L 1 , L 2 , E, 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 or stereoisomer thereof, wherein:
G 1 and G 2 are each independently N or CH;
L 1 is a bond or —NR 6 —;
L 2 is a bond or alkylene;
R 1 is aryl or heteroaryl;
R 2a , R 2b and R 2c are each independently H, amino, cyano, halo, hydroxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkylaminyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, heteroaryl or aryl;
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 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R 3a and R 3b join to form oxo, a carbocyclic or heterocyclic ring; or R 3a is H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R 3b joins with R 4b to form a carbocyclic or heterocyclic ring;
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 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R 4a and R 4b join to form oxo, a carbocyclic or heterocyclic ring; or R 4a is H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 hydroxylalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R 4b joins with R 3b to form a carbocyclic or heterocyclic ring;
R 5 is —NR 6 S(O 2 )R 7 or —S(O 2 )R 7 ;
R 6 is, at each occurrence, independently H or C 1 -C 6 alkyl;
R 7 is amino, C 1 -C 6 alkyl, C 1 -C 6 alkylaminyl, aminylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl;
m 1 and m 2 are each independently 1, 2 or 3; 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, alkylene, aryl, aralkyl, heteroaryl, heteroarylalkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, alkylaminyl, haloalkyl, hydroxylalkyl, alkoxy, alkoxyalkyl, haloalkoxy, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonyl, aminylcarbonylalkyl, and carbocyclic and heterocyclic rings 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 2 , wherein the compound has one of the following structures (I′b), (I′c), (I'd) or (I′e):
4. The compound of claim 1 , wherein R 1 is aryl.
5. The compound of claim 4 , 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, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, phosphate, phosphoalkoxy, boronic acid, boronic acid ester, —OC(═O)R or C 1 -C 6 alkylcarbonyloxy, or combinations thereof, wherein R is C 1 -C 6 alkyl.
6. The compound of claim 1 , wherein R′ has one of the following structures:
7. The compound of claim 1 , wherein R 1 is heteroaryl.
8. The compound of claim 7 , wherein R 1 is indazolyl, indolyl, benzoimidazolyl, benzotriazolyl, pyrrolopyridyl or quinolinyl.
9. The compound of claim 7 , wherein R 1 is substituted with cyano, nitro, —NH 2 , —(C═O)NH 2 , hydroxyl, hydroxylalkyl, halo or C 1 -C 6 alkyl, or combinations thereof.
10. The compound of claim 7 , wherein R 1 has one of the following structures:
11. The compound of claim 1 , wherein R 2c is H; and/or wherein R 2a and R 2b are each independently halo, C 1 -C 6 haloalkyl, C 1 -C 6 alkyl, or C 1 -C 6 alkoxy.
12. The compound of claim 1 , wherein R 2a is fluoro, chloro or methoxy; and/or wherein R 2b is chloro, fluoro or CF 3 .
13. The compound of claim 1 , wherein R 6 is H; and/or wherein R 7 is amino.
14. The compound of claim 1 , wherein R 7 is amino.
15. The compound of claim 1 , wherein R 7 is C 1 -C 6 alkyl.
16. The compound of claim 1 , wherein R 7 is cycloalkyl.
17. The compound of claim 1 , wherein at least one of R 3a , R 3b , R 4a and R 4b is not H.
18. The compound of claim 1 , wherein the compound has one of the following structures:
wherein R 3a and R 4a are independently —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, C1-C6 hydroxyalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, C 1 -C 6 cyanoalkyl, C 1 -C 6 carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl.
19. The compound of claim 1 , wherein E has one of the following structures:
20. The compound of claim 1 , wherein L 1 is a bond; and/or wherein L 2 is a bond.
21. The compound of claim 1 , wherein the compound is selected from:
22. A purified atropisomer according to claim 1 .
23. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
24. A method for treatment of cancer, wherein the cancer is mediated by a KRAS G12C, HRAS G12C or NRAS G12C mutation, the method comprising administering an effective amount of the pharmaceutical composition of claim 23 to a subject in need thereof.
25. The method of claim 24 , wherein the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer.