FUSED N-HETEROCYCLIC COMPOUNDS AND METHODS OF USE THEREOF
Compounds having activity as inhibitors of G12C mutant KRAS protein are provided. The compounds have the following structure (I): or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein A, B, E, L 1 , R a . R b , R c and are as defined herein. Methods associated with preparation and use of such compounds, pharmaceutical compositions comprising such compounds and methods to modulate the activity of G12C mutant KRAS protein for treatment of disorders, such as cancer, are also provided.
1 . A compound having the following structure (I):
or a pharmaceutically acceptable salt, isotopic form, stereoisomer or prodrug thereof, wherein:
A is a five or six-membered, nitrogen containing heterocyclyl or heteroaryl substituted with -L-R 1 and optionally substituted with 1, 2 or 3 additional substituents selected from the group consisting of R 2a , R 2b and R 2c ;
B is C or N;
R a , R b and R c are, at each occurrence, independently H, amino, cyano, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy; C 3 -C 8 cycloalkyl, heterocycylalkyl, C 1 -C 6 alkynyl, C 1 -C 6 alkenyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, heteroaryl or aryl;
R 1 is cycloalkyl, heterocyclyl, aryl or heteroaryl;
R 2a , R 2b and R 2c are, at each occurrence, independently H, amino, cyano, halo, hydroxyl, C 1 -C 6 alkyl, C 1 -C 6 alkylamino, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy; C 3 -C 8 cycloalkyl, heterocycylalkyl, C 1 -C 6 alkynyl, C 1 -C 6 alkenyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, aminylcarbonyl, heteroaryl or aryl;
L is, at each occurrence, independently absent or a linker selected from the group consisting of —O—, —NR d —, —NR d C(═O)—, —NR d S(═O) 2 — and —S(═O) 2 —, wherein R d is H or C 1 -C 6 alkyl;
L 1 is alkylene, heteroalkylene, heterocyclylene, aminylheterocyclylene alkylheterocyclylene or heteroalkylheterocyclylene;
indicates an aromatic ring; and
E is an electrophilic moiety capable of forming a covalent bond with the cysteine residue at position 12 of a KRAS, HRAS or NRAS G 12 C mutant protein.
2 . The compound of claim 1 , having the following structure (Ia):
3 . The compound of claim 1 , wherein L 1 is heterocyclylene, alkylheterocyclylene or heteroalkylheterocyclylene.
4 . The compound of claim 1 , having the following structure (Ib):
wherein:
G 1 and G 2 are each independently N or CH, provided one of G 1 and G 2 is N;
R 3a and R 3b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R 3a and R 3b join to form oxo, a carbocyclic ring or a heterocyclic ring; or R 3a is H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R 3b joins with R 4b to form a carbocyclic or heterocyclic ring;
R 4a and R 4b are, at each occurrence, independently H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl; or R 4a and R 4b join to form oxo, a carbocyclic ring or a heterocyclic ring; or R 4a is H, —OH, —NH 2 , —CO 2 H, halo, cyano, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, C 1 -C 6 alkynyl, hydroxylalkly, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl or aminylcarbonyl, and R 4b joins with R 3b to form a carbocyclic or heterocyclic ring; and
m 1 and m 2 are each independently 1, 2 or 3.
5 . The compound of claim 4 , having the following structure (Ic):
wherein
represents a double or triple bond;
L 2 is a bond or alkylene;
Q is —C(═O)—, —C(═NR 7 )—, —NR 8 C(═O)—, —S(═O) 2 — or —NR 8 S(═O) 2 —;
when is a double bond then R 5 and R 6 are each independently H, halo, cyano, carboxyl, C 1 -C 6 alkyl, alkoxycarbonyl, aminylalkyl, alkylaminylalkyl, aryl, heterocyclyl, heterocyclylalkyl, heteroaryl or hydroxylalkyl, or R 5 and R 6 join to form a carbocyclic, heterocyclic or heteroaryl ring;
when is a triple bond then R 5 is absent and R 6 is H, C 1 -C 6 alkyl, aminylalkyl, alkylaminylalkyl or hydroxylalkyl;
R 7 is H, —OH, —CN or C 1 -C 6 alkyl;
R 8 is H, C 1 -C 6 alkyl, hydroxylalkyl, aminoalkyl, alkoxyalkyl, aminylalkyl, alkylaminylalkyl, cyanoalkyl, carboxyalkyl, aminylcarbonylalkyl, C 3 -C 8 cycloalkyl or heterocyclylalkyl.
6 . The compound of claim 5 , having the following structure (Id):
7 . (canceled)
8 . (canceled)
9 . The compound of claim 1 , wherein A has one of the following structures:
10 . The compound of claim 4 , having one of the following structures (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), (Ip), (Iq), (Ir), (Is), (It) or (Iu).
wherein R 2a is H or C 1 -C 6 alkyl.
11 .- 16 . (canceled)
17 . The compound of claim 16 , wherein R 1 is substituted with halo, hydroxyl, C 1 -C 6 alkyl, cyano, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, alkylaminyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, phosphate, phosphoalkoxy, boronic acid, boronic acid ester, —OC(═O)R or C 1 -C 6 alkylcarbonyloxy, or combinations thereof, wherein R is C 1 -C 6 alkyl.
18 . (canceled)
19 . The compound of claim 1 , wherein R 1 has one of the following structures:
20 . The compound of claim 19 , wherein R 1 has one of the following structures:
21 . The compound of claim 1 , wherein R a is, at each occurrence, independently H, cyano, —C(═O)NH 2 ,
22 . (canceled)
23 . (canceled)
24 . The compound of claim 1 , wherein E has one of the following structures:
25 . The compound of claim 24 , wherein E is
26 . The compound of claim 5 , wherein L 2 is a bond.
27 . The compound of claim 1 , wherein L is absent.
28 . (canceled)
29 . The compound of claim 4 , wherein each R 3a , R 3b , R 4a and R 4b is H.
30 .- 32 . (canceled)
33 . The compound of claim 1 , having one of the following structures:
34 . (canceled)
35 . A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
36 . (canceled)
37 . (canceled)
38 . A method for treatment of cancer, the method comprising administering an effective amount of the pharmaceutical composition of claim 35 to a subject in need thereof.
39 .- 48 . (canceled)