RAS INHIBITORS
The invention features macrocyclic compounds, and pharmaceutical compositions and protein complexes thereof, capable of inhibiting Ras proteins, and their uses in the treatment of cancers.
1 - 12 . (canceled)
13 . A compound, or pharmaceutically acceptable salt thereof, having the structure of Formula III:
wherein P is —(CO)R 9 , —(PO)(OH) 2 , or —Si(R 10 ) 3 ;
W is a cross-linking group comprising an aziridine, an epoxide, a carbodiimide, an oxazoline, a thiazoline, a chloroethyl urea, a chloroethyl thiourea, a chloroethyl carbamate, a chloroethyl thiocarbamate, a trifluoromethyl ketone, a boronic acid, a boronic ester, an N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ), an iso-EEDQ or other EEDQ derivative, an oxazolium, or a glycal;
L 1 is optionally substituted 3 to 9-membered heterocycloalkylene or optionally substituted C 2 -C 4 heteroalkylene;
R 4 is optionally substituted C 1 -C 6 alkyl;
R 5 is optionally substituted C 1 -C 6 alkyl or optionally substituted 3 to 6-membered cycloalkyl;
R 9 is optionally substituted C 1 -C 3 alkyl or optionally substituted C 1 -C 3 heteroalkyl; and
each R 10 is, independently, optionally substituted C 1 -C 3 alkyl.
14 . The compound of claim 13 , or pharmaceutically acceptable salt thereof, having the structure of a compound of Table 3.
15 - 20 . (canceled)
21 . The compound of claim 13 , or pharmaceutically acceptable salt thereof, wherein W is a cross-linking group comprising an aziridine.
22 . The compound of claim 21 , or pharmaceutically acceptable salt thereof, wherein W is
23 . The compound of claim 13 , or pharmaceutically acceptable salt thereof, wherein R 4 is:
24 . The compound of claim 13 , or pharmaceutically acceptable salt thereof, wherein R 5 is:
25 . The compound of claim 13 , or pharmaceutically acceptable salt thereof, wherein R 5 is:
26 . The compound of claim 13 , or pharmaceutically acceptable salt thereof,
wherein P is
27 . The compound of claim 13 , or pharmaceutically acceptable salt thereof, wherein P is —(PO)(OH) 2 .
28 . The compound of claim 13 , or pharmaceutically acceptable salt thereof, wherein P is
29 . The compound of claim 13 , or pharmaceutically acceptable salt thereof, wherein L 1 is 3 to 9-membered heterocycloalkylene.
30 . The compound of claim 29 , or pharmaceutically acceptable salt thereof, wherein L 1 is
31 . The compound of claim 13 , or pharmaceutically acceptable salt thereof, wherein L 1 is optionally substituted C 2 -C 4 heteroalkylene.
32 . The compound of claim 31 , or pharmaceutically acceptable salt thereof, wherein L 1 is: