Inhibitors of kras g12c mutant proteins
AssigneeAraxes Pharma LLC
InventorsLiansheng Li, Jun Feng, Yun Oliver Long, Yuan Liu, Pingda Ren, Yi Liu
Life of this patent
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Abstract
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 A, R1, R3a, R3b, R4a, R4b, G2, G3, G4, m1, m2, m3, m4, L1, L2 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.
Claims60
A compound having the following structure (I):
- or a pharmaceutically acceptable salt, tautomer, stereoisomer or prodrug thereof, wherein:
- A is an aryl or heteroaryl ring;
- G2, G3 and G4 are each independently N or CR, where R is H, cyano, halo or C1-C6alkyl;
- R1 is aryl or heteroaryl;
- R3a and R3b are, at each occurrence, independently H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C1-C6 alkynyl, hydroxylalkly, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl;
- or one R3a and one R3b join to form a carbocyclic or heterocyclic ring, and each remaining R3a and R3b are, at each occurrence, independently H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C1-C6 alkynyl, hydroxylalkly, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl;
- or one R3b joins with one R4b to form a carbocyclic or heterocyclic ring, and each R3a and each remaining R3b are, at each occurrence, independently H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C1-C6 alkynyl, hydroxylalkly, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
- R4a and R4b are, at each occurrence, independently H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C1-C6 alkynyl, hydroxylalkly, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl;
- or one R4a and one R4b join to form a carbocyclic or heterocyclic ring, and each remaining R4a and R4b are, at each occurrence, independently H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C1-C6 alkynyl, hydroxylalkly, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminocarbonylalkyl or aminocarbonyl;
- or one R4b joins with one R3b to form a carbocyclic or heterocyclic ring, and each R4a and each remaining R4b are, at each occurrence, independently H, —OH, —NH2, —CO2H, halo, cyano, C1-C6 alkyl, C1-C6 alkynyl, hydroxylalkly, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl;
- L1 is a bond or alkylene;
- L2 is a linker of one two or three atoms in length, the linker comprising carbon or nitrogen atoms or combinations thereof;
- m1 and m2, are each independently 1 or 2;
- m3 and m4 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.
Dependencies are inferred from the claim text.