US 11,053,226 B2
KRAS G12C inhibitors and methods of using the same
Youngsook Shin, Thousand Oaks, CA (US); Victor J. Cee, Thousand Oaks, CA (US); Christopher M. Tegley, Thousand Oaks, CA (US); Brian Alan Lanman, Thousand Oaks, CA (US); Ryan Paul Wurz, Thousand Oaks, CA (US); Kevin C. Yang, Thousand Oaks, CA (US); Vu Van Ma, Thousand Oaks, CA (US); Daniel Erlanson, San Francisco, CA (US); Joon Won Jeong, Belmont, CA (US); Raymond V. Fucini, San Bruno, CA (US); and Jeffrey Iwig, Albany, CA (US)
Assigned to AMGEN INC., Thousand Oaks, CA (US)
Filed by Amgen Inc., Thousand Oaks, CA (US)
Filed on Nov. 18, 2019, as Appl. No. 16/687,546.
Claims priority of provisional application 62/769,497, filed on Nov. 19, 2018.
Prior Publication US 2020/0165231 A1, May 28, 2020
Int. Cl. C07D 403/14 (2006.01); C07D 401/14 (2006.01); C07D 403/12 (2006.01); C07D 417/14 (2006.01); C07D 471/04 (2006.01); C07D 487/04 (2006.01); C07D 498/04 (2006.01); A61P 35/00 (2006.01)
CPC C07D 403/14 (2013.01) [A61P 35/00 (2018.01); C07D 401/14 (2013.01); C07D 403/12 (2013.01); C07D 417/14 (2013.01); C07D 471/04 (2013.01); C07D 487/04 (2013.01); C07D 498/04 (2013.01)] 48 Claims
 
1. A compound having a structure of formula (I)

OG Complex Work Unit Chemistry
wherein
R1, R1A and R1B are independently H, —C1-6alkyl, —C1-6alkylene-OH, —C1-6alkylene-O—C1-6alkyl, or C1-6alkylene-NR10R11;
R2 is independently H, or —C1-6alkyl;
R3 is independently H, —C1-6alkyl, or —C1-6alkyl-OH;
R4 is independently H, or —C1-6alkyl;
R4A is independently H, or —C1-6alkyl; or
R4 and R4A, together with the atoms to which they are attached, form a 6- to 12-membered aryl or heteroaryl, a 3- to 8-membered monocyclic or bicyclic cycloalkyl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 8-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl group may include a S═O or SO2;
R4B is independently H, or —C1-6alkyl;
R5 is independently H, halo, —C1-6alkyl, or —C1-6alkyl-CN;
R6 is independently H, halo or —C1-6alkyl, a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl group may include a S═O or SO2;
R7 is independently H, halo or —C1-6alkyl, —O—C1-6alkyl, —S—C1-6alkyl, —NO2, —CN, —CF3, a 6- to 12-membered aryl, 5- to 12-membered heteroaryl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl, and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO2;
R8 is independently H, halo or —C1-6alkyl;
R9 is independently selected from H, OH, —C1-6alkyl, —OC1-6alkyl, —C1-6alkyl-O—C1-6alkyl, halo, —O-haloC1-6alkyl, —CN, —C1-6alkyl-C(═O)—NRaRb, —NRaRb, —(NRaRbRc)n, —OSO2Ra, —SO2Ra, —(CH2CH2O)nCH3, —(═O), —C(═O), —C(═O)Ra, —OC(═O)Ra, —C(═O)ORa, —C(═O)C(═O)ORa, —C(═O)NRaRb, —O—SiRaRbRc, —SiRaRbRc, —O-(3- to 12-membered cycloakyl), —O-(3- to 12-membered heterocycloakyl), —C(═O)-6- to 12-membered aryl, —C(═O)-5- to 12-membered heteroaryl, —C(═O)-3- to 12-membered cycloalkenyl, —C(═O)-3- to 12-membered monocyclic or bicyclic cycloalkyl, —C(═O)-3- to 12-membered monocyclic or bicyclic heterocycloalkyl, —C(═O)-5- to 12-membered spirocycloalkyl, —C(═O)-5- to 12-membered spiroheterocycloalkyl, —C1-6alkyl-C(═O)-6- to 12-membered aryl, —C1-6alkyl-C(═O)-5- to 12-membered heteroaryl, a —C1-6alkyl-C(═O)-3- to 12-membered monocyclic or bicyclic cycloalkyl, a —C1-6alkyl-C(═O)-3- to 12-membered monocyclic or bicyclic heterocycloalkyl, —C1-6alkyl-C(═O)-5- to 12-membered monocyclic or bicyclic spirocycloalkyl, —C1-6alkyl-C(═O)-5- to 12-membered spiroheterocycloalkyl group, 6- to 12-membered aryl, 5- to 12-membered heteroaryl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, a 5- to 12-membered monocyclic or bicyclic spirocycloalkyl, or a 5- to 12-membered monocyclic or bicyclic spiroheterocycloalkyl group, wherein the heteroaryl, heterocycloalkyl and spiroheterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO2; and still further wherein two adjacent carbon atoms or an adjacent carbon atom and adjacent N atom on a R9 group that includes a cycloalkyl, heterocycloalkyl, aryl, heteroaryl, spirocycloalkyl, or a spiroheterocycloalkyl group may join together to form a 5-6 membered cycloalkyl, heterocycloalkyl, aryl, heteroaryl spirocycloalkyl, or a spiroheterocycloalkyl ring that is unsubstituted or is substituted with 1, 2, or 3 R11 groups;
R10 is independently H, halo, —OH, —NH—C1-8alkyl, —N(C1-8alkyl)2, —NH—C0-3alkylene-C6-14aryl, —NH—C0-3alkylene-C2-14heteroaryl, —NH—C0-3alkylene-C3-14cycloalkyl, —NH—C0-3 alkylene-C2-14heterocycloalkyl, cyano, or C1-6alkylene-amine, —C1-6alkyl, —C(═O)NRaRb, —C(═O)ORa, —C(═O), —C0-3alkylene-C3-14cycloalkyl, —C0-3alkylene-C6-14aryl, —C0-3alkylene-C3-14heteroaryl, —C0-3 alkylene-C3-14cycloalkyl, —C0-3alkylene-C2-14heterocycloalkyl, —C1-6alkoxy, —O—C0-3 alkylene-C6-14aryl, —O—C0-3alkylene-C3-14heteroaryl, —O—C0-3 alkylene-C3-14cycloalkyl, —O—C0-3 alkylene-C2-14heterocycloalkyl, —C(═O)-(3- to 10-membered heterocycloakyl), —C(═O)-6- to 12-membered aryl, —C(═O)-5- to 12-membered heteroaryl, —C(═O)-3- to 12-membered cycloalkenyl, —C(═O)-3- to 12-membered monocyclic or bicyclic cycloalkyl, —C(═O)-3- to 12-membered monocyclic or bicyclic heterocycloalkyl, a —C(═O)-5- to 12-membered bicyclic spirocycloalkyl, a —C(═O)-5- to 12-membered spiroheterocycloalkyl, a 6- to 12-membered aryl, 5- to 12-membered heteroaryl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl, a 5- to 12-membered monocyclic or bicyclic spirocycloalkyl, or a 5- to 12-membered monocyclic or bicyclic spiroheterocycloalkyl group, wherein the heteroaryl, heterocycloalkyl and spiroheterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO2;
or R9 and R10, together with the atoms to which they are attached, form a ring selected from a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, a 3-8 membered cycloalkyl, or a 3- to 8-membered heterocycloalkyl group, wherein the heteroaryl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein when R9 and R10 form the ring, the ring is unsubstituted or substituted with 1, 2, or 3 R11 groups; further wherein when the ring is a cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, or heterocycloalkyl group, the ring may further include a C═O group;
R11 is independently selected from H, —OH, halo, cyano, —C1-8alkyl, —C1-6haloalkyl, —C1-6alkyl-OH, —C2-C6 alkenyl, —C2-C6 alkynyl, —(CH2CH2O)nRa, —CSRa, —CS(═O)Ra, —SRa, —SORa, —OSO2Ra, —SO2Ra, —(CH2CH2O)nCH3, —(═O), —C(═O), —O—Ra, —C(═O)Ra, —(CH2)n—NRaRb, NRaRb; —C(═O)NRaRb, —C(═O)ORa, —CH(═O), —C0-3alkylene-C3-14cycloalkyl, —C0-3alkylene-C2-14heterocycloalkyl, —C0-3alkylene-C6-14aryl, —C0-3alkylene-C3-14heteroaryl, —C1-6-alkylene-amine, —C1-6alkoxy, —O—C0-3 alkylene-C6-14aryl, —O—C0-3alkylene-C3-14heteroaryl, —O—C0-3 alkylene-C3-14cycloalkyl, —O—C0-3 alkylene-C2-14heterocycloalkyl, —NH—C1-8alkyl, —N(C1-8alkyl)2, —NH—C0-3alkylene-C6-14aryl, —NH—C0-3alkylene-C2-14heteroaryl, —NH—C0-3alkylene-C3-14cycloalkyl, —NH—C0-3 alkylene-C2-14heterocycloalkyl, —C1-6alkylene-amine-C(═O)-(3- to 10-membered heterocycloakyl), —C(═O)-6- to 12-membered aryl, —C(═O)-5- to 12-membered heteroaryl, —C(═O)-3- to 12-membered cycloalkenyl, —C(═O)-3- to 12-membered monocyclic or bicyclic cycloalkyl, —C(═O)-3- to 12-membered monocyclic or bicyclic heterocycloalkyl, a —C(═O)-5- to 12-membered bicyclic spirocycloalkyl, a —C(═O)-5- to 12-membered spiroheterocycloalkyl, a 6- to 12-membered aryl, 5- to 12-membered heteroaryl, a 3- to 12-membered cycloalkenyl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, a 5- to 12-membered monocyclic or bicyclic spirocycloalkyl, or a 5- to 12-membered monocyclic or bicyclic spiroheterocycloalkyl group, wherein the heteroaryl, heterocycloalkyl and spiroheterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO2;
wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups of any of the R4, R4A, R6, R7, R9, R10, and R11 substituents have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO2;
wherein the —C1-6alkyl, —C2-6alkenyl, —C2-6alkynyl and the —OC1-6alkyl of any of the R1, R2, R3, R4, R4a, R4B, R5, R6, R7, R8, R9, R10 and R11 substituents is unsubstituted or substituted by 1, 2 or 3 R12 substituents independently selected from OH, —OC1-6alkyl, —C1-6alkyl-O—C1-6alkyl, halo, —O-haloC1-6alkyl, —CN, —NRaRb, —(NRaRb)n, —OSO2Ra, —SO2Ra, —(CH2CH2O)nCH3, —(═O), —C(═O), —C(═O)Ra, —OC(═O)Ra, —C(═O)ORa, —C(═O)NRaRb, —O—SiRaRbRc, —SiRaRbRc, —O-(3- to 10-membered heterocycloalkyl), 6- to 12-membered aryl or heteroaryl, 3- to 12-membered cycloalkenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, 3- to 12-membered monocyclic or bicyclic heterocycloalkyl or 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO2;
wherein the aryl, heteroaryl, cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups of any of the R4, R4A, R4B, R6, R7, R9, R10, R11, and R12 substituents can be unsubstituted or substituted with 1, 2, 3 or 4 R13 substituents independently selected from OH, halo, —NRcRd, —ORa, —C1-6alkyl, —OC1-6alkyl, —C1-6alkyl-OH, —C1-6alkyl-O—C1-6alkyl, C1-6haloalkyl, —O-haloC1-6alkyl, —SO2Rc, —CN, —C1-6alkyl-NRcRd, —C(═O)NRcRd, —C(═O)Rc, —OC(═O)Ra, —C(═O)ORc, —C1-6alkyl-6- to 12-membered aryl, —C1-6alkyl-5- to 12-membered heteroaryl, —C1-6alkyl-3- to 12-membered cycloalkenyl, —C1-6alkyl-3- to 12-membered monocyclic or bicyclic cycloalkyl, —C1-6alkyl-3- to 12-membered monocyclic or bicyclic heterocycloalkyl, 6- to 12-membered aryl, 5- to 12-membered heteroaryl, 3- to 12-membered cycloalkenyl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, 3- to 12-membered monocyclic or bicyclic heterocycloalkyl, 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, —C(═O)-5- to 12-membered bicyclic spirocycloalkyl, —C(═O)-5- to 12-membered spiroheterocycloalkyl group, wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups of R13 have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl or heterocycloalkyl group of R13 may include a C═O group, and further wherein the heterocycloalkyl and spiroheterocycloalkyl groups may include a S═O or SO2; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, spirocycloalkyl, or spiroheterocycloalkyl groups of R13 may be unsubstituted or substituted by 1, 2 or 3 Ra substituents;
wherein each Ra, Rb, Rc and Rd is independently hydrogen, OH, O, cyano, —C1-6alkyl, —C1-6alkyl(halo)n, —(CH2CH2O)nCH3, —O—C1-6alkyl, —NO2, —NR14R14, —C1-6alkyl-NR14R14, phenyl, —C1-6alkyl-C(═O)OH, —C1-6alkyl-C(═O)—O—C1-6alkyl, —C1-6alkyl-C(═O)—NH—C1-6alkyl-6- to 12-membered aryl, —C1-6alkyl-C(═O)—NH—6- to 12-membered aryl, —C1-6alkyl-3- to 12-membered cycloalkyl, —C1-6alkyl-3- to 12-membered heterocycloalkyl, —C1-6alkyl-6- to 12-membered aryl, —C1-6alkyl-5- to 12-membered heteroaryl, —C1-6alkyl-O-3- to 12-membered cycloalkyl, —C1-6alkyl-O-3- to 12-membered heterocycloalkyl, —C1-6alkyl-O-6- to 12-membered aryl, —C1-6alkyl-O-5- to 12-membered heteroaryl, 6- to 12-membered aryl, 5- to 12-membered heteroaryl, 3- to 12-membered monocyclic or bicyclic cycloalkyl, 3- to 12-membered monocyclic or bicyclic heterocycloalkyl, or 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl group, wherein the heteroaryl group, heterocycloalkyl or spiroheterocycloalkyl group of Ra, Rb, Rc, and Rd or the heterocycloalkyl group of the —C1-6alkyl-heterocycloalkyl group of Ra, Rb, Rc, and Rd has from 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups of Ra, Rb, Rc, and Rd and the heterocycloalkyl group of the —C1-6alkyl-heterocycloalkyl groups of Ra, Rb, Rc, and Rd may include a double bond, and further wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl and heterocycloalkyl groups of Ra, Rb, Rc, and Rd and the heterocycloalkyl group of the —C1-6alkyl-heterocycloalkyl groups of Ra, Rb, Rc, and Rd may contain a C═O group; and
the alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycloalkyl and spiroheterocycloalkyl groups of Ra, Rb, Rc, and Rd or the heterocycloalkyl groups of the —C1-6alkyl-heterocycloalkyl groups of Ra, Rb, Rc, and Rd can be unsubstituted or substituted with from 1, 2, 3, or 4 R14 substituents, wherein each R14 is independently selected from H, OH, halo, —C1-6alkyl, —CN, —C1-6alkyl(halo)n, —N(CH3)2, —C(O)NH2, —C(O)N(CH3)2, —C1-6haloalkyl, —C(═O)CH3, —C(═O)OH, —C(═O)OCH3, —O—C1-6alkyl or —C1-6alkyl-O—C1-6alkyl, —C1-6alkyl-N(CH3)2, —C(═O)-3- to 12-membered cycloalkyl, 5- to 12-membered heteroaryl, —C1-6alkyl-6- to 12-membered aryl or -6- to 12-membered aryl;
wherein n is 0, 1, 2, or 3; or
a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof.