US2019375749A1PendingUtilityA1
Kras g12c inhibitors and methods of using the same
Est. expiryJun 11, 2038(~11.9 yrs left)· nominal 20-yr term from priority
Inventors:Jian Jeffrey ChenNuria A. TamayoLongbin LiuHui-Ling WangBrian Alan LanmanRyan WurzYoungsook ShinVictor J. Cee
A61K 38/16A61P 35/00C07D 471/04A61K 45/06
63
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Claims
Abstract
composition 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.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound having a structure of formula (I)
wherein
E 1 and E 2 are each independently N or CR 1 ;
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 1-6 haloalkyl, —C 1-6 alkoxy, —NH—C 1-6 alkyl, —N(C 1-4 alkyl) 2 , cyano, or halo;
R 2 is halo, —C 1-6 alkyl, —C 1-6 haloalkyl, —OR 2a , —N(R 2a ) 2 , —C 2-6 alkenyl, —C 2-6 alkynyl, —C 0-3 alkylene-C 3-14 cycloalkyl, —C 0-3 alkylene-C 2-14 heterocycloalkyl, aryl, heteroaryl, —C 0-3 alkylene-C 6-14 aryl, or —C 0-3 alkylene-C 2-14 heteroaryl, and each R 2a is independently H, —C 1-6 alkyl, —C 1-6 haloalkyl, —C 3-14 cycloalkyl, —C 2-14 heterocycloalkyl, —C 2-6 alkenyl, —C 2-6 alkynyl, aryl, or heteroaryl, or two R 2a substituents, together with the nitrogen atom to which they are attached, form a 3-7-membered ring;
R 3 is halo, —C 1-6 alkyl, —C 1-6 haloalkyl, —C 1-6 alkoxy, C 3-6 cycloalkyl, —C 2-14 heterocycloalkyl, —C 2-6 alkenyl, —C 2-6 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, —C 1-6 alkylene, —O—C 0-6 alkylene, —S—C 0-6 alkylene, or —NH—C 0-6 alkylene, and for —C 2-6 alkylene, —O—C 2-6 alkylene, —S—C 2-6 alkylene, and NH—C 2-6 alkylene, one carbon atom of the alkylene group can optionally be replaced with O, S, or NH;
R 4a is H, C 1-6 alkyl, C 2-6 alkynyl, C 1-6 alkylene-O—C 1-4 alkyl, C 1-6 alkylene-OH, C 1-6 haloalkyl, cycloalkyl, heterocycloalkyl, C 0-3 alkylene-C 3-14 cycloalkyl, C 0-3 alkylene-C 2-14 heterocycloalkyl, aryl, heteroaryl, C 0-3 alkylene-C 6-14 aryl, or selected from
R 5 and R 6 are each independently H, halo, —C 1-6 alkyl, —C 2-6 alkynyl, —C 1-6 alkylene-O—C 1-4 alkyl, —C 1-6 alkylene-OH, —C 1-6 haloalkyl, —C 1-6 alkyleneamine, —C 0-6 alkylene-amide, —C 1-3 alkylene-C(O)OH, —C 0-3 alkylene-C(O)OC 1-4 alkyl, —C 1-6 alkylene-O-aryl, —C 0-3 alkylene-C(O)C 1-4 alkylene-OH, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, —C 0-3 alkylene-C 3-14 cycloalkyl, —C 0-3 alkylene-C 2-14 heterocycloalkyl, —C 0-3 alkylene-C 6-14 aryl, —C 0-3 alkylene-C 2-14 heteroaryl, or cyano, or R 5 and R 6 , together with the atoms to which they are attached, form a 4-6 membered ring;
R 7 is H or C 1-6 alkyl, or R 7 and R 5 , together with the atoms to which they are attached, form a 4-6 membered ring;
R 8 is H, —C 1-6 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;
wherein the heteroaryl, spiroheterocycloalkyl and heterocycloalkyl groups of any of the R 2 , R 2a , R 3 , R 4 , R 4a , R 5 , R 6 , R 7 , and R 8 substituents 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 SO 2 ;
wherein the —C 1-6 alkyl, —C 2-6 alkenyl, —C 2-6 alkynyl and the —OC 1-6 alkyl of any of the R 1 , R 2 , R 2a , R 3 , R 4 , R 4a , L, R 5 , R 6 , R 7 , and R 8 substituents is unsubstituted or substituted by 1, 2 or 3 R 9 substituents independently selected from OH, —OC 1-6 alkyl, —C 1-6 alkyl-O—C 1-6 alkyl, halo, —O-haloC 1-6 alkyl, —CN, —NR a R b , —(NR a R b R c ) n , —OSO 2 R a , —SO 2 R a , —(CH 2 CH 2 O) n CH 3 , -(═O), —C(═O),
—C(═O)R a , —OC(═O)R a , —C(═O)OR a , —C(═O)NR a R b , —O—SiR a R b R c , —SiR a R b R c , —O-(3- to 10-membered heterocycloakyl), a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 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, 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, spiroheterocycloalkyl, and heterocycloalkyl groups may include a C═O group, and further wherein the spiroheterocycloalkyl, and heterocycloalkyl groups may include a S═O or SO 2 ;
wherein the aryl, heteroaryl, cycloalkyl, and heterocycloalkyl group of any of the R 1 , R 2 , R 2a , R 3 , R 4 , R 4a , R 5 , R 6 , R 7 , R 8 and R 9 substituents can be unsubstituted or substituted with 1, 2, 3 or 4 R 10 substituents independently selected from OH, halo, —NR c R d , —C 1-6 alkyl, —OC 1-6 alkyl, —C 1-6 alkyl-OH, —C 1-6 alkyl-O—C 1-6 alkyl, C 1-6 haloalkyl, —O-haloC 1-6 alkyl, —SO 2 R c , —CN, —C(═O)NR c R d , —C(═O)R c , —OC(═O)R a , —C(═O)OR c , a 6- to 12-membered aryl or heteroaryl, a 5- to 12-membered spirocycloalkyl or spiroheterocycloalkyl, 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, wherein the heteroaryl, spiroheterocycloalkyl, and heterocycloalkyl groups of R 10 have 1, 2, 3 or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl, spirocycloalkyl, and spiroheterocycloalkyl groups of R 10 or the heterocycloalkyl group of R 10 may include a C═O group, and further wherein the spiroheterocycloalkyl and heterocycloalkyl groups may include a S═O or SO 2 ;
wherein each R a , R b , R c and R d is independently hydrogen, OH, —C 1-6 alkyl, —(CH 2 CH 2 O) n CH 3 , —NR 11 R 11 , —C 1-6 alkyl-NR 11 R 11 , phenyl, —C 1-6 alkyl-C(═O)OH, —C 1-6 alkyl-C(═O)—O—C 1-6 alkyl, —C 1-6 alkyl-3- to 12-membered cycloalkyl, —C 1-6 alkyl-3- to 12-membered heterocycloalkyl, —C 1-6 alkyl-6- to 12-membered heteroaryl, a 6- to 12-membered aryl or heteroaryl, a 3- to 12-membered monocyclic or bicyclic cycloalkyl, or a 3- to 12-membered monocyclic or bicyclic heterocycloalkyl group, wherein the heteroaryl group, heterocycloalkyl group of R a , R b , R c , and R d or the heterocycloalkyl group of the —C 1-6 alkyl-heterocycloalkyl group of R a , R b , R c , and R d has from 1, 2, 3, or 4 heteroatoms independently selected from O, N or S, wherein the cycloalkyl and heterocycloalkyl groups of R a , R b , R c , and R d and the heterocycloalkyl group of the —C 1-6 alkyl-heterocycloalkyl groups of R a , R b , R c , and R d may include a double bond, and further wherein the cycloalkyl and heterocycloalkyl groups of R a , R b , R c , and R d and the heterocycloalkyl group of the —C 1-6 alkyl-heterocycloalkyl groups of R a , R b , R c , and R d may contain a C═O group;
the alkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl groups of R a , R b , R c , and R d or the heterocycloalkyl groups of the —C 1-6 alkyl-heterocycloalkyl groups of R a , R b , R c , and R d can be unsubstituted or substituted with from 1, 2, 3, or 4 R 12 substituents, wherein each R 12 is independently selected from H, OH, halo, —C 1-6 alkyl, N(CH 3 ) 2 , —C 1-6 haloalkyl, C(═O)CH 3 , —C(═O)OCH 3 , or —C 1-6 alkyl-O—C 1-6 alkyl; 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.
2 . A compound of claim 1 having a structure of formula (Ia)
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.
3 . The compound of claim 1 wherein E 1 is N.
4 . The compound of claim 1 wherein E 2 is CR 1 .
5 . The compound of claim 4 wherein R 1 is H.
6 . The compound of claim 1 wherein R 2 is selected from a halo, or an unsubstituted or substituted aryl.
7 . The compound of claim 6 wherein R 2 is a substituted aryl.
8 . The compound of claim 6 wherein R 2 is a fluorinated phenyl.
9 . The compound of claim 6 wherein R 2 is Cl.
10 . The compound of claim 6 wherein R 2 is
11 . The compound of claim 6 wherein R 2 is
12 . The compound of claim 1 wherein R 3 is halo.
13 . The compound of claim 12 wherein R 3 is Cl.
14 . The compound of claim 12 wherein R 3 is F.
15 . The compound of claim 1 wherein R 4 is
16 . The compound of claim 15 wherein L is a bond.
17 . The compound of claim 15 wherein ring A is a monocyclic 4-7 membered ring.
18 . The compound of claim 17 wherein A is an unsubstituted or substituted heterocycle.
19 . The compound of claim 1 , wherein R 4 is selected from the group consisting of
20 . The compound of claim 19 , wherein R 4 is
21 . The compound of claim 19 , wherein R 4 is
22 . The compound of claim 19 , wherein R 4 is
23 . The compound of claim 1 wherein R 8 is —C 0-3 alkylene-C 6-14 aryl, or —C 0-3 alkylene-C 3-14 heteroaryl.
24 . The compound of claim 23 wherein R 8 is —C 3-14 heteroaryl.
25 . The compound of claim 23 , wherein R 8 is selected from the group consisting of
26 . A compound having a structure selected from the formula:
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.
27 . The compound of claim 1 in the form of a pharmaceutically acceptable salt.
28 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
29 . A method of inhibiting KRAS G12C in a cell, comprising contacting the cell with the compound of claim 1 .
30 . A method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of the compound of claim 1 .
31 . The method of claim 30 , wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.
32 . The method of claim 31 , wherein the cancer is lung cancer.
33 . The method of claim 31 , wherein the cancer is pancreatic cancer.
34 . The method of claim 31 , wherein the cancer is colorectal cancer.
35 . The method of claim 30 , further comprising administering to the patient in need thereof a therapeutically effective amount of one or more additional pharmaceutically active compounds.
36 . The method of claim 35 , wherein the one or more additional pharmaceutically active compounds is an anti-PD-1 antibody.
37 . The method of claim 36 , wherein the anti-PD-1 antibody is pembrolizumab.
38 . The method of claim 36 , wherein the anti-PD-1 antibody is niolumab.
39 . The method of claim 36 , wherein the anti-PD-1 antibody is AMG 404.
40 . The method of claim 35 , wherein the one or more additional pharmaceutically active compounds is a MEK inhibitor.
41 . The method of claim 35 , wherein the one or more additional pharmaceutically active compounds is daratumumab.
42 . The method of claim 35 , wherein the one or more additional pharmaceutically active compounds is an immunomodulatory agent.
43 . Use of a compound according to claim 1 for treating cancer in a subject.
44 . A compound according to claim 1 in the preparation of a medicament for treating cancer.
45 . The compound according to claim 44 , wherein the cancer is non-small cell lung cancer.Join the waitlist — get patent alerts
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