Substituted quinazoline compounds and methods of use thereof
Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have one of the following structures (I), (II) or (III): or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein R 1 , R 2a , R 2b , R 2c , R 3a , R 3b , R 4a , R 4b , R 5a , R 5b , R 6 , A, B, G 1 , G 2 , L 1 , L 2 , m 1 , m 2 , n, x, y, X 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 the following structure (I):
or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein:
A is N;
G 1 and G 2 are each independently N or CH;
L 1 is a bond or NR 7 ;
L 2 is a bond or alkylene;
R 1 is heteroaryl;
R 2a , R 2b and R 2c are each independently H, amino, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkylaminyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 3 -C 8 cycloalkyl, heteroaryl or aryl;
R 3a , R 3b , 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 alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
R 5a and R 5b are, at each occurrence, independently H, hydroxyl, halo or C 1 -C 6 alkyl, or R 5a and R 5b join to form oxo;
R 6 is heterocyclyl;
R 7 is H, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl or heterocyclylalkyl;
m 1 and m 2 are each independently 1, 2 or 3;
n is 0;
X is a bond; 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, alkylene, aryl, heteroaryl, heterocyclyl, alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, alkylaminyl, haloalkyl, alkoxy, cycloalkyl and heterocyclylalkyl is optionally substituted with one or more substituents unless otherwise specified, the optional substituents being selected from the group consisting of aminyl, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, aminylsulfonyl, aminylcarbonyl, C 1 -C 12 alkyl, C 1 -C 6 alkylaminylcarbonyl, aminylcarbonylC 1 -C 6 alkyl, C 1 -C 12 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkoxyalkyl, C 1 -C 6 haloalkoxyalkyl, cyanoC 1 -C 6 alkyl, C 1 -C 6 alkylcycloalkyl, C 1 -C 6 alkylheterocycloalkyl, C 2 -C 6 alkynyl, C 1 -C 6 alkylaminyl, C 1 -C 6 alkylcarbonylaminyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkenylcarbonylaminyl, C 1 -C 6 thioalkyl, aryl, aralkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylalkyl, aminylcarbonylC 3 -C 8 cycloalkyl, C 3 -C 8 cycloalkylaminylcarbonyl, C 3 -C 8 fused cycloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, N-heteroaryl and heteroarylalkyl, and
wherein: i) each aryl comprises a 6- to 18-membered carbocyclic aromatic ring radical; ii) each heterocyclyl comprises a 3- to 18-membered non-aromatic ring radical having one to twelve ring carbon atoms and from one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur; and iii) each heteroaryl comprises a 5- to 14-membered ring radical comprising hydrogen atoms, one to thirteen ring carbon atoms, one to six ring heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring.
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 heterocycloalkyl;
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.
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 comprises nitrogen.
5. The compound of claim 4 , wherein R 1 is indazolyl or quinolinyl.
6. The compound of claim 1 , wherein R 1 is substituted with one or more substituents.
7. The compound of claim 6 , 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, boronic acid, —OC(═O)R, phosphate, phosphoalkoxy or C 1 -C 6 alkylcarbonyloxy, or combinations thereof, wherein R is C 1 -C 6 alkyl.
8. The compound of claim 6 , wherein R 1 is substituted with hydroxyl or C 1 -C 6 alkyl, or both.
9. The compound of claim 1 , wherein R 1 has one of the following structures:
10. The compound of claim 1 , wherein R 2c is H.
11. The compound of claim 1 , wherein R 2a and R 2b are each halo.
12. The compound of claim 1 , wherein R 2a is fluoro.
13. The compound of claim 1 , wherein R 2b is chloro.
14. The compound of claim 1 , wherein R 6 is azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl.
15. The compound of claim 14 , wherein R 6 is substituted.
16. The compound of claim 15 , wherein R 6 is substituted with C 1 -C 6 alkyl, C 1 -C 6 alkylaminyl, heterocyclyl or spiro-heterocyclyl, or combinations thereof.
17. The compound of claim 1 , wherein R 6 has one of the following structures:
18. The compound of claim 2 , wherein Q is —C(═O)—.
19. The compound of claim 2 , wherein each of R 9 and R 10 are H.
20. The compound of claim 1 , wherein E has one of the following structures:
21. The compound of claim 1 , wherein L 1 is a bond.
22. The compound of claim 1 , wherein L 2 is a bond.
23. The compound of claim 1 , wherein R 3a , R 3b , R 4a and R 4b are, at each occurrence, independently H or C 1 -C 6 alkyl.
24. The compound of claim 1 , wherein the compound has one of the following structures:
25. A substantially purified atropisomer of the compound of claim 1 .
26. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
27. A method for treatment of cancer, the method comprising administering an effective amount of the pharmaceutical composition of claim 26 to a subject in need thereof.
28. The method of claim 27 , wherein the cancer is mediated by a KRAS G12C, HRAS G12C or NRAS G12C mutation.
29. The method of claim 27 , wherein the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer.