US2022168280A1PendingUtilityA1
Kras g12c inhibitors and methods of using the same
Est. expiryDec 22, 2036(~10.4 yrs left)· nominal 20-yr term from priority
Inventors:Brian Alan LanmanVictor J. CeeAlexander J. PickrellAnthony B. ReedKevin YangDavid John KopeckyHui-Ling WangPatricia LopezKate AshtonShon BookerChristopher M. Tegley
G06Q 30/0207G06Q 10/109G01C 21/34C07D 401/14C07D 401/04C07D 239/95C07D 239/80C07D 487/04C07D 487/10C07D 417/14C07D 417/12A61P 35/00A61K 31/428A61K 31/502C07D 417/04C07D 275/04A61K 31/5025A61K 31/496C07D 471/08C07D 403/04C07D 513/04A61P 35/02C07D 471/04A61K 31/519A61K 31/517A61P 35/04Y02A50/30C07D 403/14C07D 237/34
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Claims
Abstract
Provided herein are KRAS G12C inhibitors, 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:
1 . A compound having a structure of formula (I)
wherein
E 1 and E 2 are each independently N or CR 1 ;
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 1-6 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, aryl, 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
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 0-5 alkylene, —S—C 0-5 alkylene, or —NH—C 0-5 alkylene, and for C 2-6 alkylene, —O—C 2-5 alkylene, —S—C 2-5 alkylene, and NH—C 2-5 alkylene, one carbon atom of the alkylene group can optionally be replaced with O, S, or NH;
R 4′ 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, cycloalklyl, heterocycloalkyl, C 0-3 alkylene-C 3-4 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 0-3 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; and
R 7 is H or C 1-8 alkyl, or R 7 and R 5 , together with the atoms to which they are attached, form a 4-6 membered ring; or
a pharmaceutically acceptable salt thereof.
2 . A compound having a structure of formula (I)
wherein
E 1 and E 2 are each independently N or CR 1 ;
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′, 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, aryl, 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 2-3 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 3-14 cycloalkyl, 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, C 1-6 alkylene, —O—C 0-5 alkylene, —S—C 0-5 alkylene, or —NH—C 0-5 alkylene, and for C 2-6 alkylene, —O—C 2-5 alkylene, —S—C 2-5 alkylene, and NH—C 2-5 alkylene, one carbon atom of the alkylene group can optionally be replaced with O, S, or NH;
R 5 and R 6 are each independently H, halo, C 1-8 alkyl, C 2-8 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 0-3 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; and
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; or
a pharmaceutically acceptable salt thereof.
3 . A compound having a structure of formula (II)
wherein
E 1 and E 2 are each independently N or CR 1 ;
J is N, NR 10 , or CR 10 ;
M is N, NR 13 , or CR 13 ;
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 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′ 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, C 1-6 alkylene, —O—C 0-5 alkylene, —S—C 0-5 alkylene, or —NH—C 0-5 alkylene, and for C 2-6 alkylene, —O—C 2-5 alkylene, —S—C 2-5 alkylene, and NH—C 2-5 alkylene, one carbon atom of the alkylene group can optionally be replaced with O, S, or NH;
R 4′ is H, C 1-8 alkyl, C 2-8 alkynyl, C 1-6 alkylene-O—C 1-4 alkyl, C 1-6 alkylene-OH, C 1-6 haloalkyl, cycloalklyl, 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 0-3 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 1-8 alkyl, or R 7 and R 5 , together with the atoms to which they are attached, form a 4-6 membered ring;
Q is CR 8 R 9 , C═CR 8 R 9 , C═O, C═S, or C═NR 8 ;
R 8 and R 9 are each independently H, C 1-3 alkyl, hydroxy, C 1-3 alkoxy, cyano, nitro, or C 3-6 cycloalkyl, or R 8 and R 9 , taken together with the carbon atom to which they are attached, can form a 3-6 membered ring;
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; and
R 13 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyleneamine, or C 3-14 cycloalkyl; or
a pharmaceutically acceptable salt thereof,
with the proviso that
(1) when J is NR 10 , M is N or CR 13 ;
(2) when M is NR 13 , J is N or CR 10 ;
(3) when J is CR 10 , M is N or NR 13 ; and
(4) when M is CR 13 , J is N or NR 10 .
4 . A compound having a structure of formula (II)
wherein
E 1 and E 2 are each independently N or CR 1 ;
J is N, NR 10 , or CR 10 ;
M is N, NR 13 , or CR 13 ;
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, aryl, 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
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 0-5 alkylene, —S—C 0-5 alkylene, or —NH—C 0-5 alkylene, and for C 2-6 alkylene, —O—C 2-5 alkylene, —S—C 2-5 alkylene, and NH—C 2-5 alkylene, one carbon atom of the alkylene group can optionally be replaced with O, S, or NH;
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 0-3 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 1-8 alkyl, or R 7 and R 5 , together with the atoms to which they are attached, form a 4-6 membered ring;
Q is CR 8 R 9 , C═CR 8 R 9 , C═O, C═S, or C═NR 8 ;
R 8 and R 9 are each independently H, C 1-3 alkyl, hydroxy, C 1-3 alkoxy, cyano, nitro, or C 3-6 cycloalkyl, or R 8 and R 9 , taken together with the carbon atom to which they are attached, can form a 3-6 membered ring;
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; and
R 13 is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyleneamine, or C 3-14 cycloalkyl; or
a pharmaceutically acceptable salt thereof,
with the proviso that
(1) when J is NR 10 , M is N or CR 13 ;
(2) when M is NR 13 , J is N or CR 10 ;
(3) when J is CR 10 , M is N or NR 13 ; and
(4) when M is CR 13 , J is N or NR 10 .
5 . The compound of claim 3 or 4 , wherein when Q is C═O; and E 1 and E 2 are each CR 1 ; then either
(1) R 10 is C 1-3 alkylene-C 6-14 aryl, C 1-3 alkylene-C 3-14 heteroaryl, C 0-3 alkylene-C 3-8 cycloalkyl, C 1-3 alkylene-C 2-7 heterocycloalkyl, or halo; or
(2) R 13 is C 1-3 haloalkyl or C 3-5 cycloalkyl.
6 . The compound of claim 3 or 4 , wherein J is NR 10 and M is CR 13 .
7 . The compound of claim 3 or 4 , wherein J is CR 10 and M is NR 13 .
8 . The compound of claim 3 or 4 , wherein J is N and M is NR 13 .
9 . The compound of claim 3 or 4 , wherein J is NR 10 and M is N.
10 . A compound having a structure of formula (III) or (III′):
wherein
E 1 and E 2 are each independently N or CR 1 ;
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 -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, aryl, 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 2-14 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, C 1-6 alkylene, —O—C 0-5 alkylene, —S—C 0-5 alkylene, or —NH—C 0-5 alkylene, and for C 2-6 alkylene, —O—C 2-5 alkylene, —S—C 2-5 alkylene, and NH—C 2-5 alkylene, one carbon atom of the alkylene group can optionally be replaced with O, S, or NH;
R 4′ is H, C 1-8 alkyl, C 2-8 alkynyl, C 1-6 alkylene-O—C 1-4 alkyl, C 1-6 alkylene-OH, C 1-6 haloalkyl, cycloalklyl, 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 0-3 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 1-8 alkyl, or R 7 and R 5 , together with the atoms to which they are attached, form a 4-6 membered ring;
Q is CR 8 R 9 , C═CR 8 R 9 , C═O, C═S, or C═NR 8 ;
R 8 and R 9 are each independently H, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, cyano, nitro, or C 3-14 cycloalkyl, or R 8 and R 9 , taken together with the carbon atom to which they are attached, can form a 3-6 membered ring;
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.
11 . A compound having a structure of formula (III) or (III′):
wherein
E 1 and E 2 are each independently N or CR 1 ;
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 -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, aryl, 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 2-14 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, C 1-6 alkylene, —O—C 0-5 alkylene, —S—C 0-5 alkylene, or —NH—C 0-5 alkylene, and for C 2-6 alkylene, —O—C 2-5 alkylene, —S—C 2-5 alkylene, and NH—C 2-5 alkylene, one carbon atom of the alkylene group can optionally be replaced with O, S, or NH;
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 0-3 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 1-8 alkyl, or R 7 and R 5 , together with the atoms to which they are attached, form a 4-6 membered ring;
Q is CR 8 R 9 , C═CR 8 R 9 , C═O, C═S, or C═NR 8 ;
R 8 and R 9 are each independently H, C 1-6 alkyl, hydroxy, C 1-6 alkoxy, cyano, nitro, or C 3-14 cycloalkyl, or R 8 and R 9 , taken together with the carbon atom to which they are attached, can form a 3-6 membered ring;
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.
12 . The compound of claim 10 or 11 , having a structure of formula (III).
13 . The compound of claim 10 or 11 , having a structure of formula (III′).
14 . The compound of any one of claims 3 to 12 , wherein Q is C═O.
15 . The compound of any one of claims 3 to 12 , wherein Q is C═S.
16 . The compound of any one of claims 3 to 12 , wherein Q is C═NR 8 .
17 . The compound of claim 16 , wherein R 8 is C 1-2 alkyl.
18 . The compound of any one of claims 3 to 12 , wherein Q is CR 8 R 9 .
19 . The compound of any one of claims 3 to 12 , wherein Q is C═CR 8 R 9 .
20 . The compound of claim 18 or 19 , wherein R 8 and R 9 , taken together with the carbon atom to which they are attached, form a 3-4 membered ring.
21 . The compound of claim 18 or 19 , wherein R 8 is C 1-2 alkyl, and R 9 is H.
22 . A compound having a structure of formula (IV) or (IV′):
wherein
E 1 and E 2 are each independently CR 1 or N;
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 1-6 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, aryl, 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 1-2 haloalkyl, C 1-3 alkoxy, C 3-4 cycloalkyl, 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, C 1-6 alkylene, —O—C 0-5 alkylene, —S—C 0-5 alkylene, or —NH—C 0-5 alkylene, and for C 2-6 alkylene, —O—C 2-5 alkylene, —S—C 2-5 alkylene, and NH—C 2-5 alkylene, one carbon atom of the alkylene group can optionally be replaced with O, S, or NH;
R 4′ is H, C 1-8 alkyl, C 2-8 alkynyl, C 1-6 alkylene-O—C 1-4 alkyl, C 1-6 alkylene-OH, C 1-6 haloalkyl, cycloalklyl, 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 0-3 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 1-8 alkyl, or R 7 and R 1 , together with the atoms to which they are attached, form a 4-6 membered ring;
R 8 is H, C 1-3 alkyl, hydroxy, C 1-3 alkoxy, halo, cyano, nitro, C 3-14 cycloalkyl, or NR 11 R 12 ;
R 11 and R 12 are each independently H, C 1-8 alkyl, or C 3-14 cycloalkyl; and
R 10 is C 1-8 alkyl, C 0-3 alkylene-C 6-14 aryl, C 0-3 alkylene-C 2-14 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 2-14 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, N—C 0-3 alkylene-C 3-14 cycloalkyl, N—C 0-3 alkylene-C 2-14 heterocycloalkyl, halo, cyano, or C 1-6 alkylene-amine; or
a pharmaceutically acceptable salt thereof.
23 . A compound having a structure of formula (IV) or (IV′):
wherein
E 1 and E 2 are each independently CR 1 or N;
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 1-6 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, aryl, 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 1-2 haloalkyl, C 1-3 alkoxy, C 3-14 cycloalkyl, 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, C 1-6 alkylene, —O—C 0-5 alkylene, —S—C 0-5 alkylene, or —NH—C 0-5 alkylene, and for C 2-6 alkylene, —O—C 2-5 alkylene, —S—C 2-5 alkylene, and NH—C 2-5 alkylene, one carbon atom of the alkylene group can optionally be replaced with O, S, or NH;
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 -alkylene-OH, C 1-6 haloalkyl, C 1-6 alkyleneamine, C 0-6 alkylene-amide, C 0-3 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 1-8 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 1-3 alkyl, hydroxy, C 1-3 alkoxy, halo, cyano, nitro, C 3-14 cycloalkyl, or NR 11 R 12 ;
R 11 and R 12 are each independently H, C 1-8 alkyl, or C 3-15 cycloalkyl; 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.
24 . The compound of claim 22 or 23 , having a structure of formula (IV).
25 . The compound of claim 22 or 23 , having a structure of formula (IV′).
26 . The compound of any one of claims 22 to 25 , wherein E 1 and E 2 are each CR 1 , and R 8 is hydroxy, halo, nitro, or C 3-6 cycloalkyl.
27 . The compound of any one of claims 22 to 25 , wherein R 8 is methyl.
28 . A compound having a structure of formula (V):
wherein
E 1 and E 2 are each independently CR 1 or N;
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 1-6 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, aryl, 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 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-14 cycloalkyl, 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 0-5 alkylene, —S—C 0-5 alkylene, or —NH—C 0-5 alkylene, and for C 2-6 alkylene, —O—C 2-5 alkylene, —S—C 2-5 alkylene, and NH—C 2-5 alkylene, one carbon atom of the alkylene group can optionally be replaced with O, S, or NH;
R 4′ is H, C 1-8 alkyl, C 2-8 alkynyl, C 1-6 alkylene-O—C 1-4 alkyl, C 1-6 alkylene-OH, C 1-6 haloalkyl, cycloalklyl, 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 0-3 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 1-8 alkyl, or R 7 and R 5 , together with the atoms to which they are attached, form a 4-6 membered ring; 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.
29 . A compound having a structure of formula (V):
wherein
E 1 and E 2 are each independently CR 1 or N;
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 1-6 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, aryl, 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 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-14 cycloalkyl, C 2-8 alkenyl, C 2-8 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 0-5 alkylene, —S—C 0-5 alkylene, or —NH—C 0-5 alkylene, and for C 2-6 alkylene, —O—C 2-5 alkylene, —S—C 2-5 alkylene, and NH—C 2-5 alkylene, one carbon atom of the alkylene group can optionally be replaced with O, S, or NH;
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 0-3 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 1-8 alkyl, or R 7 and R 5 , together with the atoms to which they are attached, form a 4-6 membered ring; 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.
30 . The compound of any one of claims 1 to 29 , wherein each of E 1 and E 2 is CR 1 .
31 . The compound of any one of claims 1 , 2 , 3 , 4 , 6 to 29 wherein E 1 is CR 1 and E 2 is N.
32 . The compound of any one of claims 1 , 2 , 3 , 4 , 6 to 29 , wherein E 1 is N and E 2 is CR 1 .
33 . The compound of any one of claims 1 , 2 , 3 , 4 , 6 to 29 , wherein each of E 1 and E 2 is N.
34 . The compound of any one of claims 1 , 2 , 3 , 4 , 6 to 33 , wherein R 10 is C 1-6 alkyl, aryl, heteroaryl, C 3-14 cycloalkyl, C 2-15 heterocycloalkyl, C 1-4 alkoxy, O—C 0-3 alkylene-C 6-14 aryl, O—C 0-3 alkylene-C 2-14 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 3-14 aryl, NH—C 0-3 alkylene-C 2-14 heteroaryl, NH—C 0-3 alkylene-C 3-14 cycloalkyl, or NH—C 0-3 alkylene-C 2-14 heterocycloalkyl.
35 . The compound of claim 28 or 29 , wherein E 1 and E 2 are each CR 1 , and R 10 is C 1-3 alkylene-C 6-14 aryl, C 1-3 alkylene-C 2-14 heteroaryl, C 0-3 alkylene-C 3-14 cycloalkyl, C 1-3 alkylene-C 2-14 heterocycloalkyl, or halo.
36 . The compound of any one of claims 3 to 33 , wherein R 10 is C 1-8 alkyl.
37 . The compound of any one of claims 3 to 33 , wherein R 10 is C 0-3 alkylene-C 6-14 aryl.
38 . The compound of any one of claims 3 to 34 , wherein R 10 is C 0-3 alkylene-C 3-14 heteroaryl.
39 . The compound of any one of claims 3 to 35 , wherein R 10 is C 0-3 alkylene-C 3-14 cycloalkyl.
40 . The compound of any one of claims 3 to 24 , 26 , 27 , and 30 to 33 , wherein R 10 is C 0-3 alkylene-C 2-14 heterocycloalkyl.
41 . The compound of any one of claims 3 to 33 , wherein R 10 is C 0-6 alkylene-amine.
42 . The compound of any one of claims 3 to 33 , wherein R 10 is selected from the group consisting of i-Pr, t-Bu, phenyl, benzyl, OCH 3 , Cl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
43 . The compound of any one of claims 3 to 33 , wherein R 10 comprises ortho-substituted aryl, ortho-substituted heteroaryl, or 2-substituted cyclohexyl.
44 . The compound of claim 43 , wherein R 10 is selected from the group consisting of
45 . The compound of any one of claims 1 to 44 , wherein R 1 is H.
46 . The compound of any one of claims 1 to 44 , wherein R 1 is F.
47 . The compound of any one of claims 1 to 44 , wherein R 1 is methyl.
48 . The compound of any one of claims 1 to 47 , wherein R 2 is aryl.
49 . The compound of any one of claims 1 to 47 , wherein R 2 is heteroaryl.
50 . The compound of any one of claims 1 to 47 , 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.
51 . The compound of any one of claims 1 to 47 , wherein R 2 is selected from the group consisting of Cl, Br, CF 3 , OCH 3 , OCH 2 CH 3 , phenyl
52 . The compound of any one of claims 1 to 47 , wherein R 2 is selected from the group consisting of bromine,
53 . The compound of any one of claims 1 to 52 , wherein R 3 is halo.
54 . The compound of claim 53 , wherein R 3 is Cl.
55 . The compound of any one of claims 1 to 52 , wherein R 3 is C 1-2 alkyl.
56 . The compound of claim 55 , wherein R 3 is methyl.
57 . The compound of any one of claims 1 to 52 , wherein R 3 is C 1-2 haloalkyl.
58 . The compound of claim 57 , wherein R 3 is CF 3 .
59 . The compound of any one of claims 1 to 58 , wherein R 4 is
60 . The compound of claim 59 , wherein ring A is
61 . The compound ofany one of claims 1 to 58 , wherein R 4 is
62 . The compound of claim 61 , wherein ring A is selected from the group consisting of
63 . The compound of any one of claims 1 to 58 , wherein R 4 is
64 . The compound of any one of claims 1 to 58 , wherein R 4 is
65 . The compound of claim 64 , wherein ring A is selected from the group consisting of
66 . The compound of any one of claims 59 to 65 , wherein
is selected from the group consisting of
67 . The compound of any one of claims 59 to 66 , wherein L is a bond.
68 . The compound of any one of claims 59 to 66 , wherein L is C 1-2 alkylene.
69 . The compound of claim 59 , 60 , 62 , 63 , or 66 , wherein L is O.
70 . The compound of claim 59 , 60 , 62 , 63 , or 66 , wherein L is S.
71 . The compound of claim 59 , 61 , 64 , 65 , or 66 , wherein L is NH.
72 . The compound of any one of claims 1 to 59 , 61 , 63 , 64 and 66 , wherein ring A comprises piperidinyl, piperazinyl, pyrrolidinyl, or azetidinyl.
73 . The compound of claim 72 , wherein ring A comprises piperidinyl.
74 . The compound of any one of claims 1 to 59 , 61 , 63 , 64 and 65 , wherein R 5 is H or halo.
75 . The compound of any one of claims 1 to 59 , 61 , 63 , 64 and 65 , wherein R 5 is H, Br, Cl, F, CN, CH 3 , CF 3 , CH 2 Br, CH 2 OH, CH 2 CH 2 OH, CH 2 OCH 2 phenyl, cyclopropyl, phenyl, CH 2 phenyl, CH 2 OCH 3 , CH 2 N(CH 3 ) 2 , CH 2 N(CH 2 CH 3 ) 2 , CH 2 CO 2 H, CH 2 CO 2 CH 3 , CH 2 NHC(O)CH 3 , CH 2 C(O)NHCH 3 , CH 2 OC(O)CH 3 , or
76 . The compound of any one of claims 1 to 65 and 67 to 75 , wherein R 6 is H, C 1-3 alkyl, C 1-3 alkylene-O—C 1-2 alkyl, C 1-3 alkylene-OH, C 1-3 haloalkyl, C 1-3 alkylene-amine, C 0-3 alkylene-amide, C 0-1 alkylene C(O)OC 1-3 alkyl, C 0-1 alkylene-C 2-7 heterocycloalkyl, C 0-1 alkylene-C 3-8 cycloalkyl, or C 0-3 alkylene-C 6-14 aryl.
77 . The compound of claim 76 , wherein R 6 is C 1-3 alkylene-amine or C 1-3 alkylene-amide and is selected from the group consisting of CH 2 NH 2 , CH(CH 3 )NH 2 , CH(CH 3 ) 2 NH 2 , CH 2 CH 2 NH 2 , CH 2 CH 2 N(CH 3 ) 2 , CH 2 NHCH 3 , C(O)NHCH 3 , C(O)N(CH 3 ) 2 , CH 2 C(O)NHphenyl, CH 2 NHC(O)CH 3 , CH 2 NHCH 2 CH 2 OH, CH 2 NHCH 2 CO 2 H, CH 2 NH(CH 3 )CH 2 CO 2 CH 3 , CH 2 NHCH 2 CH 2 OCH 3 , CH 2 NH(CH 3 )CH 2 CH 2 OCH 3 , CH 2 NH(CH 3 )CH 2 C(O)N(CH 3 ) 2 , CH 2 NH(CH 3 )CH 2 C(O)NHCH 3 , CH 2 NMe 2 , CH 2 NH(CH 3 )CH 2 CH 2 OH, CH 2 NH(CH 3 )CH 2 CH 2 F, CH 2 N + (CH 3 ) 3 , CH 2 NHCH 2 CHF 2 , CH 2 NHCH 2 CH 3
78 . The compound of any one of claims 1 to 65 and 67 to 75 , wherein R 6 is phenyl, cyclopropyl, CH 3 , CF 3 , CH 2 CH 3 , CH 2 NH 2 , CH(CH 3 )NH 2 , CH(CH 3 ) 2 NH 2 , CH 2 Cl, CH 2 Br, CH 2 OCH 3 , CH 2 Ophenyl, CH 2 OH, CO 2 H, CO 2 CH 2 CH 3 , CH 2 CO 2 H, CH 2 CH 2 NH 2 , CH 2 CH 2 OH, CH 2 CH 2 N(CH 3 ) 2 , CH 2 NHCH 3 , C(O)NHCH 3 , C(O)N(CH 3 ) 2 , CH 2 C(O)NHphenyl, CH 2 CHF 2 , CH 2 F, CHF 2 , CH 2 NHC(O)CH 3 , CH 2 NHCH 2 CH 2 OH, CH 2 NHCH 2 CO 2 H, CH 2 NH(CH 3 )CH 2 CO 2 CH 3 , CH 2 NHCH 2 CH 2 OCH 3 , CH 2 NH(CH 3 )CH 2 CH 2 OCH 3 , CH 2 NH(CH 3 )CH 2 C(O)N(CH 3 ) 2 , CH 2 NH(CH 3 )CH 2 C(O)NHCH 3 , CH 2 CH 2 CCH, CH 2 NMe 2 , CH 2 NH(CH 3 )CH 2 CH 2 OH, CH 2 NH(CH 3 )CH 2 CH 2 F, CH 2 N + (CH 3 ) 3 , CH 2 NHCH 2 CHF 2 , CH 2 NHCH 2 CH 3 ,
79 . The compound of any one of claims 1 to 65 and 67 to 73 , wherein R 5 and R 6 together are
80 . The compound of any one of claims 1 to 65 and 67 to 73 , wherein each of R 5 and R 6 is H.
81 . The compound of any one of claims 1 to 58 and 63 to 80 , wherein R 7 is H.
82 . The compound of any one of claims 1 to 58 and 63 to 80 , wherein R 7 is methyl.
83 . The compound of any one of claims 1 to 58 , 63 to 65 , 67 - 73 and 76 to 78 , wherein R 7 and R 5 together are —CH 2 — or —C(O)CH 2 —.
84 . The compound of any one of claims 1 to 58 , wherein R 4 is selected from the group consisting of
85 . A compound as recited in Table 1.
86 . The compound of any one of claims 1 to 85 in the form of a pharmaceutically acceptable salt.
87 . A pharmaceutical formulation comprising the compound of any one of claims 1 to 86 and a pharmaceutically acceptable excipient.
88 . A method of inhibiting KRAS G12C in a cell, comprising contacting the cell with the compound of any one of claims 1 to 86 or the composition of claim 87 .
89 . A method of treating cancer in a subject comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1 to 86 or the composition of claim 87 .
90 . The method of claim 89 , wherein the cancer is lung cancer, pancreatic cancer, or colorectal cancer.
91 . A compound having a structure selected from:
92 . The compounds of claim 91 in the form of a pharmaceutically acceptable salt.
93 . A pharmaceutical formulation comprising the compounds of claim 91 or 92 and a pharmaceutically acceptable excipient.Cited by (0)
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