US RE50,527 E1
Covalent inhibitors of KRAS G12C
Pingda Ren, San Diego, CA (US); Yi Liu, San Diego, CA (US); Liansheng Li, San Diego, CA (US); Jun Feng, San Diego, CA (US); and Tao Wu, Carlsbad, CA (US)
Assigned to Araxes Pharma LLC, San Diego, CA (US)
Filed by Araxes Pharma LLC, San Diego, CA (US)
Filed on Feb. 14, 2023, as Appl. No. 18/109,726.
Application 18/109,726 is a division of application No. 15/891,304, filed on Feb. 7, 2018, granted, now 10,273,207, issued on Apr. 30, 2019.
Application 15/891,304 is a division of application No. 14/933,734, filed on Nov. 5, 2015, granted, now 9,926,267, issued on Mar. 27, 2018.
Application 14/933,734 is a division of application No. 14/212,656, filed on Mar. 14, 2014, granted, now 9,227,978, issued on Jan. 5, 2016.
Application 18/109,726 is a reissue of application No. 16/355,258, filed on Mar. 15, 2019, granted, now 10,919,850, issued on Feb. 16, 2021.
Claims priority of provisional application 61/889,480, filed on Oct. 10, 2013.
Claims priority of provisional application 61/852,123, filed on Mar. 15, 2013.
Int. Cl. C07D 205/04 (2006.01); C07D 211/56 (2006.01); C07D 211/58 (2006.01); C07D 211/60 (2006.01); C07D 211/62 (2006.01); C07D 213/64 (2006.01); C07D 213/74 (2006.01); C07D 231/40 (2006.01); C07D 237/04 (2006.01); C07D 285/14 (2006.01); C07D 285/16 (2006.01); C07D 295/16 (2006.01); C07D 401/04 (2006.01); C07D 401/12 (2006.01); C07D 403/04 (2006.01); C07D 403/06 (2006.01); C07D 403/12 (2006.01); C07D 405/06 (2006.01); C07D 419/12 (2006.01); C07D 471/04 (2006.01); C07D 487/04 (2006.01); C07D 487/10 (2006.01); G01N 33/58 (2006.01)
CPC C07D 205/04 (2013.01) [C07D 211/56 (2013.01); C07D 211/58 (2013.01); C07D 211/60 (2013.01); C07D 211/62 (2013.01); C07D 213/64 (2013.01); C07D 213/74 (2013.01); C07D 231/40 (2013.01); C07D 237/04 (2013.01); C07D 285/14 (2013.01); C07D 285/16 (2013.01); C07D 295/16 (2013.01); C07D 401/04 (2013.01); C07D 401/12 (2013.01); C07D 403/04 (2013.01); C07D 403/06 (2013.01); C07D 403/12 (2013.01); C07D 405/06 (2013.01); C07D 419/12 (2013.01); C07D 471/04 (2013.01); C07D 487/04 (2013.01); C07D 487/10 (2013.01); G01N 33/58 (2013.01)] 39 Claims
 
1. A method for treating a cancer mediated by a K-Ras G12C, H-Ras G12C or N-Ras G12C mutation, the method comprising administering an effective amount of a compound having the following structure (VI):

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt, tautomer, stereoisomer [ , solvate, isotopically-labeled derivative ] or prodrug thereof, to a subject in need thereof, wherein:
A is CR37b, N or NR38a;
B is CR37c, N, NR38b or S;
C is CR37d, N, NR38c or S;
G3 and G4 are each independently N or CR, wherein R is H, cyano, halo or C1-C6alkyl [ C1-C6alkyl] ;
L1a is a bond, —NH—, alkylene or heteroalkylene;
L2 is a bond or alkylene;
R32a and R32b are, at each occurrence, independently H, —OH, —NH2, —CO2H, cyano, cyanoalkyl, C1-C6alkyl, C3-C8cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R32a and R32b join to form a carbocyclic or heterocyclic ring; or R32a is H, —OH, —NH2, —CO2H, cyano, C1-C6alkyl, C3-C8cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R32b joins with R33b to form a carbocyclic or heterocyclic ring;
R33a and R33b are, at each occurrence, independently H, —OH, —NH2, —CO2H, cyano, cyanoalkyl, C1-C6alkyl, C3-C8cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl; or R33a and R33b join to form a carbocyclic or heterocyclic ring; or R33a is H, —OH, —NH2, —CO2H, cyano, C1-C6alkyl, C3-C8cycloalkyl, hydroxylalkyl, aminoalkyl, carboxylalkyl or aminocarbonyl and R33b joins with R32b to form a carbocyclic or heterocyclic ring;
R37a, R37b, R37c, R37d and R37e are each independently H, halo, oxo, hydroxyl, cyano, aminocarbonyl, formyl, C1-C6alkyl, C1-C6alkylsulfonyl, C1-C6haloalkyl, C3-C8cycloalkyl, C1-C6alkoxy, C1-C6hydroxylalkyl, C1-C6alkoxyalkyl, C1-C6aminoalkyl, heterocyclyl or aryl [ -OH, fluoro, chloro, bromo, iodo, oxo, methyl, methoxy, heteroaryl or aryl] ;
R38a, R38b and R38c are each independently H, C1-C6alkyl or aryl;
n3 and n4 are each independently 1, 2 or 3;
m is 0 or 1;
custom character is a single or double bond such that all valences are satisfied; and
E is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a K-Ras, H-Ras or N-Ras G12C mutant protein.