KRAS G12C inhibitors and methods of using the same
Provided herein are KRAS G12C inhibitors, compounds of formula (II), or a pharmaceutically acceptable salt thereof: compositions of the same, and methods of using the same. These inhibitors are useful for treating a number of disorders, including pancreatic, colorectal, and lung cancers.
1. A compound having a structure of formula (II)
wherein
E 1 is N;
E 2 is CR 1 ;
J is NR 10 ;
M is N;
is a single or double bond as necessary to give every atom its normal valence;
R 1 is independently H, hydroxy, C 1-6 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, NH—C 1-4 alkyl, N(C 1-4 alkyl) 2 , cyano, or halo;
R 2 is halo, C 1-6 alkyl, C 1-6 haloalkyl, OR′, N(R′) 2 , C 2-3 alkenyl, C 2-3 alkynyl, C 0 -3 akylene-C 3-14 cycloalkyl, C 0-3 alkylene-C 2-14 heterocycloalkyl, aryl, heteroaryl, C 0-3 akylene-C 6-14 aryl, or C 0-3 akylene-C 2-14 heteroaryl, and each R′ is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C 2-14 heterocycloalkyl, C 2-3 alkenyl, C 2-3 alkynyl, aryl, or heteroaryl, or two R′ substituents, together with the nitrogen atom to which they are attached, form a 3-7-membered ring;
R 3 is halo, C 1-3 alkyl, C 1-2 haloalkyl, C 1-3 alkoxy, C 3-4 cycloalkyl, C 2-14 heterocycloalkyl, C 2-3 alkenyl, C 2-3 alkynyl, aryl, or heteroaryl;
R 4 is
ring A is a monocyclic 4-7 membered ring or a bicyclic, bridged, fused, or spiro 6-11 membered ring;
L is a bond;
R 5 and R 6 are each;
Q is C═O;
R 10 is selected from C 1-6 alkyl, C 0-3 alkylene-C 3-14 cycloalkyl, C 0-3 alkylene-C 2-14 heterocycloalkyl, C 1-6 alkylene-amine, i-Pr, t-Bu, benzyl, OCH 3 , Cl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
or a pharmaceutically acceptable salt thereof.
2. A compound having a structure of formula (II)
wherein
E 1 is N;
E 2 is CR 1 ;
J is NR 10 ;
M is N;
is a single or double bond as necessary to give every atom its normal valence;
R 1 is independently H, hydroxy, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, NH—C 1-4 alkyl, N(C 1-4 alkyl ) 2 , cyano, or halo;
R 2 is halo, C 1-6 alkyl , C 1-6 haloalkyl , OR′, N(R′) 2 , C 2-3 alkenyl, C 2-3 alkynyl, C 0-3 alkylene-C 3-14 cycloalkyl, C 0-3 alkylene-C 2-14 heterocycloalkyl, heteroaryl, C 0-3 alkylene-C 6-14 aryl, or C 0-3 alkylene-C 2-14 heteroaryl, and each R′ is independently H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-14 cycloalkyl, C 2-14 heterocycloalkyl, C 2-3 alkenyl, C 2-3 alkynyl, aryl, or heteroaryl, or two R′ substituents, together with the nitrogen atom to which they are attached, form a 3-7-membered ring;
R 3 is halo, C 1-3 alkyl, C 1-2 haloalkyl, C 1-3 alkoxy, C 3-4 cycloalkyl, C 2-3 alkenyl, C 2-3 alkynyl, aryl, or heteroaryl;
R 4 is
Q is C═O; and
R 10 is C 1-8 alkyl, C 0-3 alkylene-C 6-14 aryl, C 0-3 alkylene-C 3-14 heteroaryl, C 0-3 alkylene-C 3-14 cycloalkyl, C 0-3 alkylene-C 2-14 heterocycloalkyl, C 1-6 alkoxy, O—C 0-3 alkylene-C 6-14 aryl, O—C 0-3 alkylene-C 3-14 heteroaryl, O—C 0-3 alkylene-C 3-14 cycloalkyl, O—C 0-3 alkylene-C 2-14 heterocycloalkyl, NH—C 1-8 alkyl, N(C 1-8 alkyl) 2 , NH—C 0-3 alkylene-C 6-14 aryl, NH—C 0-3 alkylene-C 2-14 heteroaryl, NH—C 0-3 alkylene-C 3-14 cycloalkyl, NH—C 0-3 alkylene-C 2-14 heterocycloalkyl, halo, cyano, or C 1-6 alkylene-amine, or a pharmaceutically acceptable salt thereof.
3. The compound of any one of claims 1 - 2 , wherein R 10 is C 0-3 alkylene-C 3-14 cycloalkyl.
4. The compound of any one of claim 1 or 2 , wherein R 1 is H.
5. The compound of claim 1 , wherein R 2 is aryl.
6. The compound of claim 1 , wherein R 2 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidine, pyrrolidine, azetidine, phenyl, naphthyl, pyridyl, indazolyl, indolyl, azaindolyl, indolinyl, benzotriazolyl, benzoxadiazolyl, imidazolyl, cinnolinyl, imidazopyridyl, pyrazolopyridyl, quinolinyl, isoquinolinyl, quinazolinyl, quinazolinonyl, indolinonyl, isoindolinonyl, tetrahydronaphthyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl.
7. The compound of claim 1 , wherein R 2 is selected from the group consisting of Cl, Br, CF 3 , OCH 3 , OCH 2 CH 3 , phenyl,
8. The compound of claim 1 , wherein R 2 is selected from the group consisting of bromine,
9. The compound of any one of claim 1 or 2 wherein R 3 is halo.
10. The compound of claim 9 , wherein R 3 is Cl.
11. The compound of claim 1 , wherein ring A is selected from the group consisting of
12. The compound of any one of claim 1 - 2 in the form of a pharmaceutically acceptable salt.
13. A pharmaceutical formulation comprising the compound of any one of claim 1 - 2 and a pharmaceutically acceptable excipient.