RAS INHIBITORS
The disclosure features macrocyclic compounds, and pharmaceutical compositions and protein complexes thereof, capable of inhibiting Ras proteins, and their uses in the treatment of cancers.
1 . A compound, or pharmaceutically acceptable salt thereof, having the structure of Formula I:
wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds;
A is —N(H or CH 3 )C(O)—(CH 2 )—where the amino nitrogen is bound to the carbon atom of —CH(R 10 )— optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 10-membered heteroarylene;
B is absent, —CH(R 9 )—, >C═CR 9 R 9′ , or >CR 9 R 9′ where the carbon is bound to the carbonyl carbon of —N(R 11 )C(O)—, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5 to 6-membered heteroarylene;
G is optionally substituted C 1 -C 4 alkylene, optionally substituted C 1 -C 4 alkenylene, optionally substituted C 1 -C 4 heteroalkylene, —C(O)O—CH(R 6 )—where C is bound to —C(R 7 R 8 )—, —C(O)NH—CH(R 6 )— where C is bound to —C(R 7 R 8 )—, optionally substituted C 1 -C 4 heteroalkylene, or 3 to 8-membered heteroarylene;
L is absent or a linker;
W is a cross-linking group comprising a vinyl ketone, a vinyl sulfone, an ynone, or an alkynyl sulfone;
X 1 is optionally substituted C 1 -C 2 alkylene, NR, O, or S(O) n ;
X 2 is O or NH;
X 3 is N or CH;
n is 0, 1, or 2;
R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, C(O)R′, C(O)OR′, C(O)N(R′) 2 , S(O)R′, S(O) 2 R′, or S(O) 2 N(R′) 2 ;
each R′ is, independently, H or optionally substituted C 1 -C 4 alkyl;
Y 1 is C, CH, or N;
Y 2 , Y 3 , Y 4 , and Y 7 are, independently, C or N;
Y 5 is CH, CH 2 , or N;
Y 6 is C(O), CH, CH 2 , or N;
R 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 6 to 10-membered aryl, or optionally substituted 5 to 10-membered heteroaryl, or
R 1 and R 2 combine with the atoms to which they are attached to form an optionally substituted 3 to 14-membered heterocycloalkyl;
R 2 is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5 or 6-membered heteroaryl; R 3 is absent, or
R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or optionally substituted 3 to 14-membered heterocycloalkyl;
R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens;
R 5 is hydrogen, C 1 -C 4 alkyl optionally substituted with halogen, cyano, hydroxy, or C 1 -C 4 alkoxy, cyclopropyl, or cyclobutyl;
R 6 is hydrogen or methyl; R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl, or
R 6 and R 7 combine with the carbon atoms to which they are attached to form an optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heterocycloalkyl;
R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3 to 8-membered cycloalkyl, optionally substituted 3 to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6 to 10-membered aryl, or
R 7 and R 8 combine with the carbon atom to which they are attached to form C═CR 7′ R 8′ ; C═N(OH), C═N(O—C 1 -C 3 alkyl), C═O, C═S, C═NH, optionally substituted 3 to 6-membered cycloalkyl, or optionally substituted 3 to 7-membered heterocycloalkyl;
R 7a and R 8a are, independently, hydrogen, halo, optionally substituted C 1 -C 3 alkyl, or combine with the carbon to which they are attached to form a carbonyl;
R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl; R 8′ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3 to 8-membered cycloalkyl, optionally substituted 3 to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6 to 10-membered aryl, or
R 7′ and R 8′ combine with the carbon atom to which they are attached to form optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heterocycloalkyl;
R 9 is H, F, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, or optionally substituted 3 to 7-membered heterocycloalkyl, or
R 9 and L combine with the atoms to which they are attached to form an optionally substituted 3 to 14-membered heterocycloalkyl;
R 9′ is hydrogen or optionally substituted C 1 -C 6 alkyl; or
R 9 and R 9′ , combined with the atoms to which they are attached, form a 3 to 6-membered cycloalkyl or a 3 to 6-membered heterocycloalkyl;
R 10 is hydrogen, halo, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 alkyl;
R 10a is hydrogen or halo;
R 11 is hydrogen or C 1 -C 3 alkyl; and
R 21 is H or C 1 -C 3 alkyl.
2 - 3 . (canceled)
4 . The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula Ie:
wherein A is —N(H or CH 3 )C(O)—(CH 2 )—where the amino nitrogen is bound to the carbon atom of —CH(R 10 )—, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 6-membered heteroarylene;
B is —CH(R 9 )—where the carbon is bound to the carbonyl carbon of —NHC(O)—, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5 to 6-membered heteroarylene;
L is absent or a linker;
W is a cross-linking group comprising a vinyl ketone, a vinyl sulfone, an ynone, or an alkynyl sulfone;
R 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 6 to 10-membered aryl, or optionally substituted 5 to 10-membered heteroaryl;
R 2 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5 or 6-membered heteroaryl; R 3 is absent, or
R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or optionally substituted 3 to 14-membered heterocycloalkyl;
R 5 is hydrogen, C 1 -C 4 alkyl optionally substituted with halogen, cyano, hydroxy, or C 1 -C 4 alkoxy, cyclopropyl, or cyclobutyl;
R 6 is hydrogen or methyl; R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl, or
R 6 and R 7 combine with the carbon atoms to which they are attached to form an optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heterocycloalkyl;
R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3 to 8-membered cycloalkyl, optionally substituted 3 to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6 to 10-membered aryl, or
R 7 and R 8 combine with the carbon atom to which they are attached to form C═CR 7′ R 8′ ; C═N(OH), C═N(O—C 1 -C 3 alkyl), C═O, C═S, C═NH, optionally substituted 3 to 6-membered cycloalkyl, or optionally substituted 3 to 7-membered heterocycloalkyl;
R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl; R 8′ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3 to 8-membered cycloalkyl, optionally substituted 3 to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6 to 10-membered aryl, or
R 7′ and R 8′ combine with the carbon atom to which they are attached to form optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heterocycloalkyl;
R 9 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, or optionally substituted 3 to 7-membered heterocycloalkyl; and
R 10 is hydrogen, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 alkyl.
5 - 6 . (canceled)
7 . The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein the compound has the structure of Formula Ig:
wherein A is —N(H or CH 3 )C(O)—(CH 2 )—where the amino nitrogen is bound to the carbon atom of —CH(R 10 )—, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 6-membered heteroarylene;
B is —CH(R 9 )—where the carbon is bound to the carbonyl carbon of —NHC(O)—, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5 to 6-membered heteroarylene;
L is absent or a linker;
W is a cross-linking group comprising a vinyl ketone, a vinyl sulfone, an ynone, or an alkynyl sulfone;
R 2 is C 1 -C 6 alkyl, C 1 -C 6 fluoroalkyl, or 3 to 6-membered cycloalkyl;
R 7 is C 1 -C 3 alkyl;
R 8 is C 1 -C 3 alkyl; and
R 9 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, or optionally substituted 3 to 7-membered heterocycloalkyl X e and X f are, independently, N or CH; and
R 12 is optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or optionally substituted 3 to 7-membered heterocycloalkyl.
8 . (canceled)
9 . The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein A is optionally substituted 5 to 6-membered heteroarylene.
10 . (canceled)
11 . The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3 to 6-membered heterocycloalkylene.
12 . The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein B is —CHR 9 — and R 9 is F, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, or optionally substituted 3 to 7-membered heterocycloalkyl.
13 - 15 . (canceled)
16 . The compound, or pharmaceutically acceptable salt thereof, of claim 1 , wherein the linker is the structure of Formula II:
where A 1 is a bond between the linker and B; A 2 is a bond between W and the linker; B 1 , B 2 , B 3 , and B 4 each, independently, is selected from optionally substituted C 1 -C 2 alkylene, optionally substituted C 1 -C 3 heteroalkylene, O, S, and NR N ; R N is hydrogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, optionally substituted 3 to 14-membered heterocycloalkyl, optionally substituted 6 to 10-membered aryl, or optionally substituted C 1 -C 7 heteroalkyl; C 1 and C 2 are each, independently, selected from carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; f, g, h, i, j, and k are each, independently, 0 or 1; and D 1 is optionally substituted C 1 -C 10 alkylene, optionally substituted C 2 -C 10 alkenylene, optionally substituted C 2 -C 10 alkynylene, optionally substituted 3 to 14-membered heterocycloalkylene, optionally substituted 5 to 10-membered heteroarylene, optionally substituted 3 to 8-membered cycloalkylene, optionally substituted 6 to 10-membered arylene, optionally substituted C 2 -C 10 polyethylene glycolene, or optionally substituted C 1 -C 10 heteroalkylene, or a chemical bond linking A 1 -(B 1 ) f —(C 1 ) g —(B 2 ) h — to —(B 3 ) i —(C 2 ) j —(B 4 ) k -A 2 .
17 . (canceled)
18 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the linker has the structure of Formula Ila:
wherein X a is absent or N;
R 14 is absent, hydrogen or optionally substituted C 1 -C 6 alkyl; and
L 2 is absent, —SO 2 —, optionally substituted C 1 -C 4 alkylene or optionally substituted C 1 -C 4 heteroalkylene,
wherein at least one of X a , R 14 , or L 2 is present.
19 . (canceled)
20 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the linker has the structure of Formula IIb:
wherein o is 0 or 1;
R 15 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted 3 to 8-membered cycloalkylene, or optionally substituted 3 to 8-membered heterocycloalkylene;
X 4 is absent, optionally substituted C 1 -C 4 alkylene, O, NCH 3 , or optionally substituted C 1 -C 4 heteroalkylene;
Cy is optionally substituted 3 to 8-membered cycloalkylene, optionally substituted 3 to 8-membered heterocycloalkylene, optionally substituted 6-10 membered arylene, or optionally substituted 5 to 10-membered heteroarylene; and
L 3 is absent, —SO 2 —, optionally substituted C 1 -C 4 alkylene or optionally substituted C 1 -C 4 heteroalkylene.
21 . (canceled)
22 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W has the structure of Formula IIIa:
wherein R 16a , R 16b , and R 16c are, independently, hydrogen, —CN, halogen, or —C 1 -C 3 alkyl optionally substituted with one or more substituents independently selected from —OH, —O—C 1 -C 3 alkyl, —NH 2 , —NH(C 1 -C 3 alkyl), —N(C 1 -C 3 alkyl) 2 , or a 4 to 7-membered saturated heterocycloalkyl.
23 . (canceled)
24 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W has the structure of Formula IIIb:
wherein R 17 is hydrogen, —C 1 -C 3 alkyl optionally substituted with one or more substituents independently selected from —OH, —O—C 1 -C 3 alkyl, —NH 2 , —NH(C 1 -C 3 alkyl), —N(C 1 -C 3 alkyl) 2 , or a 4 to 7-membered saturated cycloalkyl, or a 4 to 7-membered saturated heterocycloalkyl.
25 . (canceled)
26 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W has the structure of Formula IIIc:
wherein R 18a , R 18b , and R 18c are, independently, hydrogen, —CN, or —C 1 -C 3 alkyl optionally substituted with one or more substituents independently selected from —OH, —O—C 1 -C 3 alkyl, —NH 2 , —NH(C 1 -C 3 alkyl), —N(C 1 -C 3 alkyl) 2 , or a 4 to 7-membered saturated heterocycloalkyl.
27 . (canceled)
28 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W has the structure of Formula IIId:
wherein R 19 is hydrogen, —C 1 -C 3 alkyl optionally substituted with one or more substituents independently selected from —OH, —O—C 1 -C 3 alkyl, —NH 2 , —NH(C 1 -C 3 alkyl), —N(C 1 -C 3 alkyl) 2 , or a 4 to 7-membered saturated heterocycloalkyl, or a 4 to 7-membered saturated heterocycloalkyl.
29 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein W has the structure of Formula IIIe:
wherein X e is a halogen; and
R 20 is hydrogen, —C 1 -C 3 alkyl optionally substituted with one or more substituents independently selected from —OH, —O—C 1 -C 3 alkyl, —NH 2 , —NH(C 1 -C 3 alkyl), —N(C 1 -C 3 alkyl) 2 , or a 4 to 7-membered saturated heterocycloalkyl.
30 . (canceled)
31 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
32 . A conjugate, or salt thereof, comprising the structure of Formula IV:
wherein L is a linker;
P is a monovalent organic moiety; and
M has the structure of Formula V:
wherein the dotted lines represent zero, one, two, three, or four non-adjacent double bonds;
A is —N(H or CH 3 )C(O)—(CH 2 )—where the amino nitrogen is bound to the carbon atom of —CH(R 10 )— optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 6-membered heteroarylene;
B is absent, —CH(R 9 )—, >C═CR 9 R 9′ , or >CR 9 R 9′ where the carbon is bound to the carbonyl carbon of —N(R 11 )C(O)—, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, or 5 to 6-membered heteroarylene;
G is optionally substituted C 1 -C 4 alkylene, optionally substituted C 1 -C 4 alkenylene, optionally substituted C 1 -C 4 heteroalkylene, —C(O)O—CH(R 6 )—where C is bound to —C(R 7 R 8 )—, —C(O)NH—CH(R 6 )— where C is bound to —C(R 7 R 8 )—, optionally substituted C 1 -C 4 heteroalkylene, or 3 to 8-membered heteroarylene;
X 1 is optionally substituted C 1 -C 2 alkylene, NR, O, or S(O) n ;
X 2 is O or NH;
X 3 is N or CH;
n is 0, 1, or 2;
R is hydrogen, cyano, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 alkenyl, optionally substituted C 2 -C 4 alkynyl, C(O)R′, C(O)OR′, C(O)N(R′) 2 , S(O)R′, S(O) 2 R′, or S(O) 2 N(R′) 2 ;
each R′ is, independently, H or optionally substituted C 1 -C 4 alkyl;
Y 1 is C, CH, or N;
Y 2 , Y 3 , Y 4 , and Y 7 are, independently, C or N;
Y 5 is CH, CH 2 , or N;
Y 6 is C(O), CH, CH 2 , or N;
R 1 is cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered cycloalkenyl, optionally substituted 3 to 6-membered heterocycloalkyl, optionally substituted 6 to 10-membered aryl, or optionally substituted 5 to 10-membered heteroaryl, or
R 1 and R 2 combine with the atoms to which they are attached to form an optionally substituted 3 to 14-membered heterocycloalkyl;
R 2 is absent, hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 7-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5 or 6-membered heteroaryl; R 3 is absent, or
R 2 and R 3 combine with the atom to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or optionally substituted 3 to 14-membered heterocycloalkyl;
R 4 is absent, hydrogen, halogen, cyano, or methyl optionally substituted with 1 to 3 halogens;
R 5 is hydrogen, C 1 -C 4 alkyl optionally substituted with halogen, cyano, hydroxy, or C 1 -C 4 alkoxy, cyclopropyl, or cyclobutyl;
R 6 is hydrogen or methyl; R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl, or
R 6 and R 7 combine with the carbon atoms to which they are attached to form an optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heterocycloalkyl;
R 8 is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3 to 8-membered cycloalkyl, optionally substituted 3 to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6 to 10-membered aryl, or
R 7 and R 8 combine with the carbon atom to which they are attached to form C═CR 7′ R 8′ ; C═N(OH), C═N(O—C 1 -C 3 alkyl), C═O, C═S, C═NH, optionally substituted 3 to 6-membered cycloalkyl, or optionally substituted 3 to 7-membered heterocycloalkyl;
R 7a and R 8a are, independently, hydrogen, halo, optionally substituted C 1 -C 3 alkyl, or combine with the carbon to which they are attached to form a carbonyl;
R 7 is hydrogen, halogen, or optionally substituted C 1 -C 3 alkyl; R 8′ is hydrogen, halogen, hydroxy, cyano, optionally substituted C 1 -C 3 alkoxy, optionally substituted C 1 -C 3 alkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted 3 to 8-membered cycloalkyl, optionally substituted 3 to 14-membered heterocycloalkyl, optionally substituted 5 to 10-membered heteroaryl, or optionally substituted 6 to 10-membered aryl, or
R 7′ and R 8′ combine with the carbon atom to which they are attached to form optionally substituted 3 to 6-membered cycloalkyl or optionally substituted 3 to 7-membered heterocycloalkyl;
R 9 is H, F, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, or optionally substituted 3 to 7-membered heterocycloalkyl, or
R 9 and L combine with the atoms to which they are attached to form an optionally substituted 3 to 14-membered heterocycloalkyl;
R 9′ is hydrogen or optionally substituted C 1 -C 6 alkyl; or
R 9 and R 9′ , combined with the atoms to which they are attached, form a 3 to 6-membered cycloalkyl or a 3 to 6-membered heterocycloalkyl;
R 10 is hydrogen, halo, hydroxy, C 1 -C 3 alkoxy, or C 1 -C 3 alkyl;
R 10a is hydrogen or halo;
R 11 is hydrogen or C 1 -C 3 alkyl; and
R 21 is H or C 1 -C 3 alkyl.
33 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
34 . (canceled)
35 . The method of claim 33 , wherein the cancer comprises a Ras mutation.
36 - 37 . (canceled)
38 . The method of claim 33 , wherein the method or use further comprises administering an additional anti-cancer therapy.
39 . The method of claim 38 , wherein the additional anti-cancer therapy is an EGFR inhibitor, a second Ras inhibitor, a SHP2 inhibitor, a SOS1 inhibitor, a Raf inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, a PTEN inhibitor, an AKT inhibitor, an mTORC1 inhibitor, a BRAF inhibitor, a PD-L1 inhibitor, a PD-1 inhibitor, a CDK4/6 inhibitor, a HER2 inhibitor, or a combination thereof.
40 . (canceled)