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) or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein R 1 , R 3a , R 3b , R 4a , R 4b , G 1 , G 2 , G 3 , G 4 , m 1 , m 2 , m 3 , m 4 , L 1 , L 2 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) or (Ib):
or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein:
G 1 , G 2 , G 3 and G 4 are each independently N or CR, where R is H, cyano, halo or C 1 -C 6 alkyl;
R 2a , R 2b and R 2c are independently H, halo, hydroxyl, cyano, aminocarbonyl, formyl, C 1 -C 6 alkyl, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 hydroxylalkyl, C 1 -C 6 alkoxyalkyl, C 1 -C 6 aminoalkyl, aliphatic heterocyclyl, heteroaryl, heteroarylaminyl 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 alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl; or one R 3a and one R 3b join to form a carbocyclic or heterocyclic ring, and each remaining 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 alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl; or one R 3b joins with one R 4b to form a carbocyclic or heterocyclic ring, and each R 3a and each remaining 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 alkynyl, hydroxylalkyl, 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 2 -C 6 alkynyl, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl; or one R 4a and one R 4b join to form a carbocyclic or heterocyclic ring, and each remaining 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, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl; or one R 4b joins with one R 3b to form a carbocyclic or heterocyclic ring, and each R 4a and each remaining 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, hydroxylalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
L 1 is a bond or alkylene;
m 1 , m 2 , m 3 and m 4 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 all valences are satisfied.
2. The compound of claim 1 , wherein the compound has one of the following structures (Ia′) or (Ib′):
wherein:
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, heteroaryl or hydroxylalkyl or R 9 and R 10 join to form a carbocyclic or heterocyclic 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 (Ia″) or (Ib″):
4. The compound of claim 1 , wherein R 2a , R 2b and R 2c are each independently fluoro, chloro, bromo, iodo, hydroxyl, cyano, methyl, ethyl, isopropyl, methyl sulfonyl, methoxy, aminocarbonyl, trifluoromethyl, 2,2,2-trifluorethyl, cyclobutyl, cyclopropyl, pyrimidineaminyl or phenyl, wherein the cyclopropyl and phenyl are optionally substituted with one or more substituents selected from C 1 -C 6 alkyl, halo, hydroxyl and cyano.
5. The compound of claim 1 , wherein R 2a is chloro and R 2b is chloro or cyclopropyl.
6. The compound of claim 5 , wherein R 2c is OH or 2-pyrimidineaminyl.
7. The compound of claim 2 , wherein Q is —C(═O)—.
8. The compound of claim 2 , wherein each of R 9 and R 10 are H.
9. The compound of claim 1 , wherein E 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 each R 3a , R 3b , R 4a and R 4b are H.
12. The compound of claim 1 , wherein the compound has one of the following structures:
13. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
14. A method for therapeutic treatment of a cancer, the method comprising administering an effective amount of the pharmaceutical composition of claim 13 to a subject having the cancer.
15. A method for modulating activity of a KRAS G12C, HRAS G12C or NRAS G12C mutant protein, the method comprising reacting the KRAS G12C, HRAS G12C or NRAS G12C mutant protein with the compound of claim 1 .
16. A method for inhibiting proliferation of a cell population, the method comprising contacting the cell population with the compound of claim 1 .
17. A method for therapeutically treating a disorder mediated by a KRAS G12C, HRAS G12C or NRAS G12C-mutation in a subject having the disorder, the method comprising:
determining if the subject has a KRAS G12C, HRAS G12C or NRAS G12C mutation; and
if the subject is determined to have the KRAS G12C, HRAS G12C or NRAS G12C mutation, then administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 13 .
18. A method for preparing a labeled KRAS G12C, HRAS G12C or NRAS G12C mutant protein, the method comprising reacting the KRAS G12C, HRAS G12C or NRAS G12C mutant protein with a compound of claim 1 , to result in the labeled KRAS G12C, HRAS G12C or NRAS G12C mutant protein.
19. A method for inhibiting tumor metastasis, the method comprising administering an effective amount of the pharmaceutical composition of claim 13 to a subject in need thereof.
20. The method of claim 14 , wherein the cancer is a hematological cancer, pancreatic cancer, MYH associated polyposis, colorectal cancer or lung cancer.