US 12,234,244 B2
Substituted piperazines as inhibitors of KRAS G12C
Liansheng Li, San Diego, CA (US); Jun Feng, San Diego, CA (US); Tao Wu, Carlsbad, CA (US); Pingda Ren, San Diego, CA (US); Yi Liu, San Diego, CA (US); Yuan Liu, San Diego, CA (US); and Yun Oliver Long, San Diego, CA (US)
Assigned to Araxes Pharma LLC, San Diego, CA (US)
Filed by Araxes Pharma LLC, San Diego, CA (US)
Filed on Apr. 8, 2022, as Appl. No. 17/716,707.
Application 17/125,955 is a division of application No. 16/449,967, filed on Jun. 24, 2019, granted, now 10,927,125, issued on Feb. 23, 2021.
Application 16/449,967 is a division of application No. 15/805,716, filed on Nov. 7, 2017, granted, now 10,370,386, issued on Aug. 6, 2019.
Application 15/805,716 is a division of application No. 14/511,425, filed on Oct. 10, 2014, granted, now 9,840,516, issued on Dec. 12, 2017.
Application 17/716,707 is a continuation of application No. 17/125,955, filed on Dec. 17, 2020, granted, now 11,878,985.
Claims priority of provisional application 62/052,366, filed on Sep. 18, 2014.
Claims priority of provisional application 62/034,619, filed on Aug. 7, 2014.
Claims priority of provisional application 61/889,460, filed on Oct. 10, 2013.
Prior Publication US 2022/0242875 A1, Aug. 4, 2022
Prior Publication US 2023/0212183 A9, Jul. 6, 2023
This patent is subject to a terminal disclaimer.
Int. Cl. A61K 31/517 (2006.01); C07D 215/46 (2006.01); C07D 215/54 (2006.01); C07D 217/22 (2006.01); C07D 239/84 (2006.01); C07D 239/94 (2006.01); C07D 239/95 (2006.01); C07D 241/44 (2006.01); C07D 401/04 (2006.01); C07D 401/12 (2006.01); C07D 403/04 (2006.01); C07D 409/04 (2006.01); C07D 487/04 (2006.01); C07D 495/04 (2006.01)
CPC C07D 495/04 (2013.01) [C07D 215/46 (2013.01); C07D 215/54 (2013.01); C07D 217/22 (2013.01); C07D 239/84 (2013.01); C07D 239/94 (2013.01); C07D 239/95 (2013.01); C07D 241/44 (2013.01); C07D 401/04 (2013.01); C07D 401/12 (2013.01); C07D 403/04 (2013.01); C07D 409/04 (2013.01); C07D 487/04 (2013.01)] 12 Claims
 
1. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound having the following structure:

OG Complex Work Unit Chemistry
or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof,
wherein:
R1 is aryl;
wherein the aryl is monocyclic or bicyclic; and
wherein the aryl is optionally substituted with one or more substituents independently selected from the group consisting of halo, cyano, C1-C6 alkyl, C1-C6 haloalkyl, cyano-C1-C6 alkyl, aminylcarbonyl-C1-C6 alkyl, hydroxy-C1-C6 alkyl, alkoxy-C1-C6 alkyl, C3-C8 cycloalkyl-alkyl, C2-C6 alkynyl, aminylcarbonyl, C1-C6 alkyl-aminylcarbonyl, C3-C8 cycloalkyl-aminylcarbonyl, C1-C6 alkylaminyl, C1-C6 alkyl-carbonylaminyl, hydroxy, C1-C6 alkoxy, C1-C6 haloalkoxy, aminylsulfone, C3-C8 cycloalkyl, cyano-C3-C8 cycloalkyl, C1-C6 alkyl-cycloalkyl, aminylcarbonyl-C3-C8 cycloalkyl, fused C3-C8 cycloalkyl, and heteroaryl;
R2a is halo;
A is CR2b, or N;
R2b is H, F, Cl, methyl, CH2N(CH3)2, OH, C1-C6 alkoxy, or monocyclic heteroaryl, wherein the monocyclic heteroaryl is optionally substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, cyano, methyl, CH2N(CH3)2, trifluoromethyl, ethyl, ethynyl C(═O)NH2, NH2, alkylaminyl, heterocyclylaminyl, pyrazolylaminyl, OH, alkoxy, heterocyclyloxy, aryloxy, cyclopropyl, piperidinyl, morpholinyl, aryl, and heteroaryl;
Y is CR6, —C(O)—, N, or —NR5—;
Z is CR6, N, or —NH—;
R5 is H or C1-C6 alkyl;
each R6 is independently H, F, Cl, cyano, methyl, CH2N(CH3)2, NH2, C1-C6 alkylaminyl, monocyclic heterocyclylalkylaminyl, monocyclic heterocyclylaminyl, monocyclic heteroarylalkylaminyl, monocyclic heteroarylaminyl, OH, C1-C6 alkoxy, oxo, monocyclic heterocyclylalkyloxy, monocyclic heteroarylalkyloxy, monocyclic heterocyclyloxy, monocyclic heteroaryloxy, unsubstituted pyrazolyl, or unsubstituted thiazolyl, wherein each monocyclic heterocyclylalkylaminyl, monocyclic heterocyclylaminyl, monocyclic heteroarylalkylaminyl, monocyclic heteroarylaminyl, monocyclic heterocyclylalkyloxy, monocyclic heteroarylalkyloxy, monocyclic heterocyclyloxy, and monocyclic heteroaryloxy is optionally and independently substituted with at least one substituent independently selected from the group consisting of methyl and CH2CF3;
L1 is a bond;
each R3a is independently H, halo, cyano, C1-C6 alkyl, cyanoalkyl, aminylcarbonylalkyl, carboxyalkyl, aminylalkyl, alkylaminylalkyl, hydroxyalkyl, C2-C6 alkynyl, aminylcarbonyl, CO2H, NH2, or OH;
each R3b is independently H, halo, cyano, C1-C6 alkyl, cyanoalkyl, aminylcarbonylalkyl, carboxyalkyl, aminylalkyl, alkylaminylalkyl, hydroxyalkyl, C2-C6 alkynyl, aminylcarbonyl, CO2H, NH2, or OH;
each R4a is independently H, halo, cyano, C1-C6 alkyl, cyanoalkyl, aminylcarbonylalkyl, carboxyalkyl, aminylalkyl, alkylaminylalkyl, hydroxyalkyl, C2-C6 alkynyl, aminylcarbonyl, CO2H, NH2, or OH;
each R4b is independently H, halo, cyano, C1-C6 alkyl, cyanoalkyl, aminylcarbonylalkyl, carboxyalkyl, aminylalkyl, alkylaminylalkyl, hydroxyalkyl, C2-C6 alkynyl, aminylcarbonyl, CO2H, NH2, or OH;
L2 is a bond;

OG Complex Work Unit Chemistry
and
custom character is a single bond or double bond;
with the proviso that if Z is —NH—, then Y is —C(O)—.