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 having the structure of Formula I′:
wherein:
A is optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3- to 10-membered heterocycloalkylene, optionally substituted C 6-10 arylene, optionally substituted 5 to 6-membered heteroarylene, optionally substituted C 2 -C 6 alkylene, or optionally substituted C 2 -C 6 alkenylene, or -L 1 -L 2 -, wherein L 1 is 3 to 6-membered cycloalkylene or C 1-6 alkylene and L 2 is —O— or C 1-6 alkylene;
L is a bond or —CH(R 20 )—N(R 21 )—C(O)—, wherein R 20 and R 21 are each independently an optionally substituted C 1-6 alkyl; or R 20 and R 21 taken together with the atoms to which they are attached form 4-10 membered heterocycloalkyl;
W is optionally substituted 3 to 10-membered heterocycloalkyl or optionally substituted 3 to 10-membered cycloalkyl;
X 4 is CH 2 or NH;
R 1 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-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 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 5- to 10-membered heteroaryl;
R 3 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 3 heteroalkyl, optionally substituted C 3 -C 6 cycloalkyl, or optionally substituted 4- to 6-membered heterocycloalkyl;
or R 2 and R 3 combine, together with the atoms to which they are attached, to form an optionally substituted 8- to 14-membered heterocycloalkyl;
R 4 , R 5 , R 6 , R 7 , R 5a , R 6a and R 7a are each independently hydrogen, halo or C 1 -C 6 alkyl;
or R 5 and R 7 are taken together to form a methylene or ethylene bridge between the carbon atoms to which they are attached, and R 4 , R 5a , R 6 , Roa, and R 7a are each independently hydrogen, halogen, or C 1-6 alkyl;
or R 4 and R 6 are taken together to form a methylene or ethylene bridge between the carbon atoms to which they are attached, and R 5 , R 5a , R 6a , R 7 and R 7a are each independently hydrogen, halogen, or C 1-6 alkyl;
or R 5 and R 6 taken together with the atoms to which they are attached form optionally substituted 3- to 7-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;
or R 6 and R 7 taken together with the atoms to which they are attached form optionally substituted 3- to 7-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;
or R 5 and R 5a taken together with the atom to which they are attached form optionally substituted 3- to 7-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;
or R 6 and R 6a taken together with the atom to which they are attached form optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;
or R 7 and R 7a taken together with the atom to which they are attached form an optionally 3- to 7-membered substituted cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;
or R 5 and R 6 taken together form a bond;
R 10 is H, —OR 11 or —NR 12 R 13 ;
R 11 , R 12 , and R 13 are each, independently, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 4-14 membered heterocycloalkyl, optionally substituted C 3 -C 10 cycloalkyl or R 12 and R 13 combine to form an optionally substituted 3- to 10-membered heterocycloalkyl;
and
when R 10 is H, then ring A is optionally substituted 2,4-oxazol-diyl or optionally substituted 2,5-oxazol-diyl and R 2 is hydrogen, substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5 or 6-membered heteroaryl;
or a pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 , having the structure of Formula I′:
wherein:
A is optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5 to 6-membered heteroarylene, optionally substituted C 2 -C 4 alkylene, or optionally substituted C 2 -C 4 alkenylene;
L is a bond or —CH(R 20 )—N(R 21 )—C(O)—, wherein R 20 and R 21 are each independently an optionally substituted C 1-6 alkyl; or R 20 and R 21 taken together with the atoms to which they are attached form 4-10 membered heterocycloalkyl;
W is optionally substituted 3 to 10-membered heterocycloalkyl or optionally substituted 3 to 10-membered cycloalkyl;
X 4 is CH 2 or NH;
R 1 is 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 15-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 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5 or 6-membered heteroaryl; and R 3 is hydrogen;
or R 2 and R 3 combine, together with the atoms to which they are attached, to form an optionally substituted 8- to 14-membered heterocycloalkyl;
each of R 4 , R 5 , R 6 , and R 7 are hydrogen; or R 4 and R 6 are hydrogen and R 5 and R 7 combine, together with the atoms to which they are attached, to form an optionally substituted four-membered cycloalkyl; or R 5 and R 7 are hydrogen and R 4 and R 6 combine, together with the atoms to which they are attached, to form an optionally substituted four-membered cycloalkyl;
R 5a , R 6a and R 7a are each independently hydrogen, halo or C 1 -C 6 alkyl;
or R 5 and R 6 taken together with the atoms to which they are attached form optionally substituted 3- to 7-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;
or R 6 and R 7 taken together with the atoms to which they are attached form optionally substituted 3- to 7-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;
or R 5 and R 5a taken together with the atom to which they are attached form optionally substituted 3- to 7-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;
or R 6 and R 6a taken together with the atom to which they are attached form optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;
or R 7 and R 7a taken together with the atom to which they are attached form an optionally 3- to 7-membered substituted cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;
or R 5 and R 6 taken together form a bond;
R 10 is H, —OR 11 or —NR 12 R 13 ;
R 11 , R 12 , and R 13 are each, independently, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 4-14 membered heterocycloalkyl, optionally substituted C 3 -C 10 cycloalkyl or R 12 and R 13 combine to form an optionally substituted 3- to 10-membered heterocycloalkyl;
and
when R 10 is H, then ring A is optionally substituted 2,4-oxazol-diyl or optionally substituted 2,5-oxazol-diyl and R 2 is hydrogen, substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5 or 6-membered heteroaryl;
or a pharmaceutically acceptable salt thereof.
3 . The compound of claim 1 or 2 , wherein the moiety:
in Formula I′ is selected from:
wherein:
R 5a is H, halogen or C 1-6 alkyl;
R 6a is H, halogen or C 1-6 alkyl;
each R 23 is independently halogen or C 1-6 alkyl; and
each p is independently an integer of 0, 1 or 2.
4 . The compound of claim 1 or 2 , having the structure of Formula I′-a:
wherein:
A is optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5 to 6-membered heteroarylene, optionally substituted C 2 -C 4 alkylene, or optionally substituted C 2 -C 4 alkenylene;
L is a bond or —CH(R 20 )—N(R 21 )—C(O)—, wherein R 20 and R 21 are each independently an optionally substituted C 1-6 alkyl; or R 20 and R 21 taken together with the atoms to which they are attached form 4-10 membered heterocycloalkyl;
W is optionally substituted 3 to 10-membered heterocycloalkyl or optionally substituted 3 to 10-membered cycloalkyl;
X 4 is CH 2 or NH;
R 1 is 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 15-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 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5 or 6-membered heteroaryl; and R 3 is hydrogen;
or R 2 and R 3 combine, together with the atoms to which they are attached, to form an optionally substituted 8- to 14-membered heterocycloalkyl;
each of R 4 , R 5 , R 6 , and R 7 are hydrogen; or R 4 and R 6 are hydrogen and R 5 and R 7 combine, together with the atoms to which they are attached, to form an optionally substituted four-membered cycloalkyl; or R 5 and R 7 are hydrogen and R 4 and R 6 combine, together with the atoms to which they are attached, to form an optionally substituted four-membered cycloalkyl;
R 5a , R 6a and R 7a are each independently hydrogen, halo or C 1 -C 6 alkyl;
R 10 is H, —OR 11 or —NR 12 R 13 ;
R 11 , R 12 , and R 13 are each, independently, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 4-14 membered heterocycloalkyl, optionally substituted C 3 -C 10 cycloalkyl or R 12 and R 13 combine to form an optionally substituted 3- to 10-membered heterocycloalkyl;
and
when R 10 is H, then ring A is optionally substituted 2,4-oxazol-diyl or optionally substituted 2,5-oxazol-diyl and R 2 is hydrogen, substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5 or 6-membered heteroaryl;
or a pharmaceutically acceptable salt thereof.
5 . The compound of any one of claims 1, 2 and 4 or a pharmaceutically acceptable salt thereof, having the structure of Formula I:
wherein:
A is optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5 to 6-membered heteroarylene, optionally substituted C 2 -C 4 alkylene, or optionally substituted C 2 -C 4 alkenylene;
W is optionally substituted 3 to 10-membered heterocycloalkyl or optionally substituted 3 to 10-membered cycloalkyl;
X 4 is CH 2 or NH;
R 1 is 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 15-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 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5 or 6-membered heteroaryl; and R 3 is hydrogen;
or R 2 and R 3 combine, together with the atoms to which they are attached, to form an optionally substituted 8- to 14-membered heterocycloalkyl;
each of R 4 , R 5 , R 6 , and R 7 are hydrogen; or R 4 and R 6 are hydrogen and R 5 and R 7 combine, together with the atoms to which they are attached, to form an optionally substituted four-membered cycloalkyl; or R 5 and R 7 are hydrogen and R 4 and R 6 combine, together with the atoms to which they are attached, to form an optionally substituted four-membered cycloalkyl;
R 10 is H, —OR 11 or —NR 12 R 13 ;
R 11 , R 12 , and R 13 are each, independently, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 4-14 membered heterocycloalkyl, optionally substituted C 3 -C 10 cycloalkyl or R 12 and R 13 combine to form an optionally substituted 3- to 10-membered heterocycloalkyl; and
when R 10 is H, then ring A is optionally substituted 2,4-oxazol-diyl or optionally substituted 2,5-oxazol-diyl and R 2 is hydrogen, substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5 or 6-membered heteroaryl;
or a pharmaceutically acceptable salt thereof.
6 . The compound of any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein:
ring A is optionally substituted 2,4-oxazol-diyl or optionally substituted 2,5-oxazol-diyl;
R 2 is hydrogen, substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, optionally substituted 5 or 6-membered heteroaryl; and
R 10 is H.
7 . The compound of any one of claims 1 to 2 and 4 to 6 , having the structure of Formula I′-b:
or a pharmaceutically acceptable salt thereof,
wherein R 22 is H, CN, OH, optionally substituted C 1-6 alkyl, optionally substituted C 1-6 alkoxy, optionally substituted C 36 cycloalkyl or optionally substituted 4- to 6-membered heterocycloalkyl; and
R 2 is substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5 or 6-membered heteroaryl.
8 . The compound of any one of claims 1 to 7 , or a pharmaceutically acceptable salt thereof, wherein R 2 is optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted 6-membered aryl, or optionally substituted 5 or 6-membered heteroaryl
9 . The compound of any one of claims 1 to 2 and 4 to 8 , having the structure of Formula I:
wherein A is optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 6-membered arylene, optionally substituted 5 to 6-membered heteroarylene, optionally substituted C 2 -C 4 alkylene, or optionally substituted C 2 -C 4 alkenylene;
W is optionally substituted 3 to 10-membered heterocycloalkyl or optionally substituted 3 to 10-membered cycloalkyl;
X 4 is CH 2 or NH;
R 1 is 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 15-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 1 -C 6 heteroalkyl, 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; and R 3 is hydrogen;
or R 2 and R 3 combine, together with the atoms to which they are attached, to form an optionally substituted 8- to 14-membered heterocycloalkyl;
each of R 4 , R 5 , R 6 , and R 7 are hydrogen; or R 4 and R 6 are hydrogen and R 5 and R 7 combine, together with the atoms to which they are attached, to form an optionally substituted four-membered cycloalkyl; or R 5 and R 7 are hydrogen and R 4 and R 6 combine, together with the atoms to which they are attached, to form an optionally substituted four-membered cycloalkyl;
R 10 is —OR 11 or —NR 12 R 13 ; and
R 11 , R 12 , and R 13 are each, independently, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or R 12 and R 13 combine to form an optionally substituted 3- to 10-membered heterocycloalkyl;
or a pharmaceutically acceptable salt thereof,
10 . The compound of any one of claims 1 to 9 , or a pharmaceutically acceptable salt thereof, wherein X 4 is NH.
11 . The compound of any one of claims 1 to 9 , or a pharmaceutically acceptable salt thereof, wherein X 4 is CH 2 .
12 . The compound of any one of claims 1 to 9 , or a pharmaceutically acceptable salt thereof, having the structure of Formula Ia:
13 . The compound of any one of claims 1 to 9 , or pharmaceutically acceptable salt thereof, having the structure of Formula Ib:
14 . The compound of any one of claims 1 to 13 , or a pharmaceutically acceptable salt thereof, wherein each of R 4 , R 5 , R 6 , and R 7 are hydrogen.
15 . The compound of any one of claims 1 to 9 , or pharmaceutically acceptable salt thereof, having the structure of Formula Ic:
16 . The compound of any one of claims 1 to 9 , or pharmaceutically acceptable salt thereof, having the structure of Formula Id:
17 . The compound of any one of claims 1 to 9 , or pharmaceutically acceptable salt thereof, having the structure of Formula Ie:
18 . The compound of any one of claims 1 to 17 , or a pharmaceutically acceptable salt thereof, wherein A is optionally substituted 5 to 6-membered heteroarylene.
19 . The compound of claim 18 , or a pharmaceutically acceptable salt thereof, wherein A is oxazole-diyl or thiazole-diyl.
20 . The compound of any one of claims 1 to 9 , or pharmaceutically acceptable salt thereof, having the structure of Formula Ic-1:
21 . The compound of any one of claims 1 to 9 , or pharmaceutically acceptable salt thereof, having the structure of Formula Id-1:
22 . The compound of any one of claims 1 to 9 , or pharmaceutically acceptable salt thereof, having the structure of Formula Ie-1:
23 . The compound of any one of claims 1 to 9 , or pharmaceutically acceptable salt thereof, having the structure of Formula Ic-2:
24 . The compound of any one of claims 1 to 9 , or pharmaceutically acceptable salt thereof, having the structure of Formula Id-2:
25 . The compound of any one of claims 1 to 9 , or pharmaceutically acceptable salt thereof, having the structure of Formula Ie-2:
26 . The compound of any one of claims 1 to 25 , or pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.
27 . The compound of any one of claims 1 to 25 , or pharmaceutically acceptable salt thereof, wherein R 2 and R 3 combine to form an optionally substituted 8- to 14-membered heterocycloalkyl.
28 . The compound of any one of claims 1 to 26 , or pharmaceutically acceptable salt thereof, wherein R 2 is optionally substituted C 1 -C 6 heteroalkyl or optionally substituted 3 to 7-membered heterocycloalkyl.
29 . The compound of claim 28 , or pharmaceutically acceptable salt thereof, wherein R 2 is optionally substituted C 1 -C 6 heteroalkyl.
30 . The compound of claim 28 , or pharmaceutically acceptable salt thereof, wherein R 2 is optionally substituted 3 to 7-membered heterocycloalkyl.
31 . The compound of any one of claims 1 to 9 , or a pharmaceutically acceptable salt thereof, having the structure of Formula Ic-3:
wherein each R 14 is independently C 1 -C 3 alkyl; and
n is 0, 1, 2, or 3.
32 . The compound of any one of claims 1 to 9 , or pharmaceutically acceptable salt thereof, having the structure of Formula Id-3:
wherein each R 14 is independently C 1 -C 3 alkyl; and
n is 0, 1, 2, or 3.
33 . The compound of any one of claims 1 to 9 , or pharmaceutically acceptable salt thereof, having the structure of Formula Ie-3:
wherein each R 14 is independently C 1 -C 3 alkyl; and
n is 0, 1, 2, or 3.
34 . The compound of any one of claims 1 to 9 , or pharmaceutically acceptable salt thereof, having the structure of Formula Ic-4:
wherein each R 14 is independently C 1 -C 3 alkyl; and
n is 0, 1, 2, or 3.
35 . The compound of any one of claims 1 to 9 , or pharmaceutically acceptable salt thereof, having the structure of Formula Id-4:
wherein each R 14 is independently C 1 -C 3 alkyl; and
n is 0, 1, 2, or 3.
36 . The compound of any one of claims 1 to 9 , or pharmaceutically acceptable salt thereof, having the structure of Formula Ie-4:
wherein each R 14 is independently C 1 -C 3 alkyl; and
n is 0, 1, 2, or 3.
37 . The compound of any one of claims 31 to 36 , or pharmaceutically acceptable salt thereof, wherein each R 14 is methyl.
38 . The compound of any one of claims 31 to 37 , or pharmaceutically acceptable salt thereof, wherein n is 1.
39 . The compound of any one of claims 31 to 37 , or pharmaceutically acceptable salt thereof, wherein n is 2.
40 . The compound of any one of claims 31 to 36 , or pharmaceutically acceptable salt thereof, wherein n is 0.
41 . The compound of any one of claims 1 to 9 , or a pharmaceutically acceptable salt thereof, having the structure of Formula Ic-5:
wherein R 16 is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl.
42 . The compound of any one of claims 1 to 9 , or pharmaceutically acceptable salt thereof, having the structure of Formula Id-5:
wherein R 15 is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl.
43 . The compound of any one of claims 1 to 9 , or pharmaceutically acceptable salt thereof, having the structure of Formula Ie-5:
wherein R 15 is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl.
44 . The compound of any one of claims 1 to 9 , or pharmaceutically acceptable salt thereof, having the structure of Formula Ic-6:
wherein R 15 is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl.
45 . The compound of any one of claims 1 to 9 , or pharmaceutically acceptable salt thereof, having the structure of Formula Id-6:
wherein R 16 is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl.
46 . The compound of any one of claims 1 to 9 , or pharmaceutically acceptable salt thereof, having the structure of Formula Ie-6:
wherein R 15 is C 1 -C 3 alkyl or C 3 -C 6 cycloalkyl.
47 . The compound of any one of claims 41 to 46 , or a pharmaceutically acceptable salt thereof, wherein R 15 is C 3 -C 6 cycloalkyl.
48 . The compound of claim 47 , wherein R 15 is cyclopropyl.
49 . The compound of any one of claims 1 to 48 , or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen.
50 . The compound of any one of claims 1 to 48 , or a pharmaceutically acceptable salt thereof, wherein R 1 is
wherein X 3 is N or CH;
m is 1 or 2;
R 15 , R 16 , R 17 , and R 18 are each independently selected from hydrogen, 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 16 and R 17 combine with the atoms to which they are attached to form an optionally substituted 3 to 8-membered heterocycloalkyl; or
R 17 and R 18 combine with the atoms to which they are attached to form an optionally substituted 3 to 8-membered heterocycloalkyl; or
R 17 and R 15 combine with the atoms to which they are attached to form an optionally substituted 4 to 8-membered heterocycloalkyl.
51 . The compound of claim 50 , or a pharmaceutically acceptable salt thereof, wherein R 1 is
52 . The compound of claim 50 , or a pharmaceutically acceptable salt thereof, wherein R 1 is
53 . The compound of any one of claims 50 to 52 , or a pharmaceutically acceptable salt thereof, wherein R 16 is methyl.
54 . The compound of any one of claims 50 to 52 , or a pharmaceutically acceptable salt thereof, wherein R 16 is cyclopropyl.
55 . The compound of any one of claims 1 to 54 , or a pharmaceutically acceptable salt thereof, wherein W is optionally substituted 3 to 10-membered heterocycloalkyl.
56 . The compound of claim 55 , or a pharmaceutically acceptable salt thereof, wherein W is optionally substituted 4- to 6-membered optionally substituted heterocycloalkyl.
57 . The compound of claim 55 or 56 , or a pharmaceutically acceptable salt thereof, wherein the heterocycloalkyl comprises one oxygen atom.
58 . The compound of claim 55 or 56 , or a pharmaceutically acceptable salt thereof, wherein the heterocycloalkyl comprises one nitrogen atom.
59 . The compound of any one of claims 1 to 54 , or a pharmaceutically acceptable salt thereof, wherein W is optionally substituted 3 to 10-membered heterocycloalkyl.
60 . The compound of claim 59 , or a pharmaceutically acceptable salt thereof, wherein W is optionally substituted 3- to 6-membered optionally substituted heterocycloalkyl
61 . The compound of claim 60 , or a pharmaceutically acceptable salt thereof, wherein W is optionally substituted cyclopropyl.
62 . The compound of any one of claims 1 to 61 , or a pharmaceutically acceptable salt thereof, wherein R 10 is —OR 11 .
63 . The compound of claim 62 , or a pharmaceutically acceptable salt thereof, wherein R 11 is optionally substituted C 1 -C 6 alkyl.
64 . The compound of claim 62 , or a pharmaceutically acceptable salt thereof, wherein R 11 is optionally substituted C 1 -C 6 heteroalkyl.
65 . The compound of claim 62 , or a pharmaceutically acceptable salt thereof, wherein R 10 is —OCH 2 CH 3 .
66 . The compound of any one of claims 1 to 61 , or a pharmaceutically acceptable salt thereof, wherein R 10 is —NR 12 R 13 .
67 . The compound of claim 66 , or a pharmaceutically acceptable salt thereof, wherein R 12 and R 13 combine to form an optionally substituted 3- to 10-membered heterocycloalkyl.
68 . The compound of claim 67 , or a pharmaceutically acceptable salt thereof, wherein R 12 and R 13 combine to form an optionally substituted pyrrolidine.
69 . The compound of claim 67 , or a pharmaceutically acceptable salt thereof, wherein R 12 and R 13 combine to form an optionally substituted azetidine.
70 . The compound of claim any one of claims 1 to 61 , or a pharmaceutically acceptable salt thereof, wherein R 10 is
—OCH 3 , —N(CH 3 ) 2 , —OCH 2 CH(CH 3 ) 2 , or —OCH 2 SO 2 CH 3 , each of which is optionally substituted.
71 . A compound of Table 1, or a pharmaceutically acceptable salt thereof.
72 . A compound of Table 2, or a pharmaceutically acceptable salt thereof.
73 . A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1 to 72 and a pharmaceutically acceptable excipient
74 . 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, or a pharmaceutically acceptable salt thereof, of any one of claims 1 to 72 or a pharmaceutical composition of claim 73 .
75 . The method of claim 74 , wherein the cancer is pancreatic cancer, colorectal cancer, non-small cell lung cancer, gastric cancer, esophageal cancer, ovarian cancer or uterine cancer.
76 . The method of claim 75 , wherein the cancer comprises a Ras mutation.
77 . The method of claim 76 , wherein the Ras mutation is K-Ras G12V.
78 . A method of treating a Ras protein-related disorder in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, of any one of claims 1 to 72 or a pharmaceutical composition of claim 73 .
79 . The method of any one of claims 74 to 78 , wherein the method further comprises administering to the subject an additional anticancer agent or therapy.
80 . The method of claim 79 , wherein the additional anticancer agent or 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.
81 . A compound of Formula V:
wherein:
R 4 , R 5 , R 6 , R 7 , R 5a , R 6a and R 7a are each independently hydrogen, halo or C 1 -C 6 alkyl;
or R 5 and R 7 are taken together to form a methylene or ethylene bridge between the carbon atoms to which they are attached, and R 4 , R 5a , R 6 , R 6a , and R 7a are each independently hydrogen, halogen, or C 1-6 alkyl;
or R 4 and R 6 are taken together to form a methylene or ethylene bridge between the carbon atoms to which they are attached, and R 5 , R 5a , R 6a , R 7 and R 7a are each independently hydrogen, halogen, or C 1-6 alkyl;
or R 5 and R 6 taken together with the atoms to which they are attached form optionally substituted 3- to 7-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;
or R 6 and R 7 taken together with the atoms to which they are attached form optionally substituted 3- to 7-membered cycloalkyl or optionally substituted 3- to 7-membered heterocycloalkyl;
or R 5 and R 5a taken together with the atom to which they are attached form optionally substituted 3- to 7-membered cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;
or R 6 and R 6a taken together with the atom to which they are attached form optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;
or R 7 and R 7a taken together with the atom to which they are attached form an optionally 3- to 7-membered substituted cycloalkyl or an optionally substituted 3- to 7-membered heterocycloalkyl;
or R 5 and R 6 taken together form a bond;
X 4 is NH or CH 2 ;
Z 1 is O or S;
PG is an amino protecting group;
R 24 is H or C 1-6 alkyl;
R 25 is halogen; and
R 12 , and R 13 are each, independently, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, or R 12 and R 13 taken together with the nitrogen atom to which they are attached form optionally substituted 3- to 11-membered heterocycloalkyl.
82 . The compound of claim 81 , wherein X 4 is NH.
83 . The compound of claim 81 or 82 , wherein R 24 is C 1-6 alkyl.
84 . The compound of any one of claims 81 to 83 , wherein PG is Boc or Cbz.
85 . The compound of any one of claims 81 to 84 , wherein R 25 is Br or I.
86 . The compound of any one of claims 81 to 85 , wherein R 12 and R 13 taken together with the nitrogen atom to which they are attached form optionally substituted 7- to 11-membered sprio heterocycloalkyl.
87 . The compound of any one of claims 81 to 86 , wherein R 5 and R 7 are taken together to form a methylene bridge between the carbon atoms to which they are attached, and R 4 , R 5a , R 6 , R 6a , and R 7a are each independently hydrogen, halogen, or C 1-6 alkyl.
88 . The compound of any one of claims 81 to 87 , wherein the moiety:
in Formula (V) is
R 5 and R 7 are taken together to form a methylene or ethylene bridge between the carbon atoms to which they are attached, and R 4 , R 5 , R 5a , R 6 , R 6a , R 7 and R 7a are each independently hydrogen, halogen, or C 1-6 alkyl.
89 . The compound of any one of claims 81 to 88 , wherein Z 1 is O.
90 . The compound of any one of claims 81 to 88 , wherein Z 1 is S.
91 . A compound of Formula (VI):
wherein:
Z 1 is O or S;
PG is an amino protecting group;
R 24 is H or C 1-6 alkyl; and
R 25 is halogen.
92 . The compound of claim 91 , wherein Z 1 is O.
93 . The compound of claim 91 , wherein Z 1 is S.
94 . The compound of any one of claims 91 to 93 , wherein PG is Boc or Cbz.
95 . The compound of any one of claims 91 to 94 , wherein R 24 is C 1-6 alkyl.
96 . The compound of any one of claims 91 to 95 , wherein R 25 is Br or I.
97 . The compound of claim 91 , wherein Z 1 is O, R 25 is I, PG is Boc and R 14 is Et.
98 . A compound of Formula VII:
wherein:
R 1 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-membered heterocycloalkyl, optionally substituted 6 to 10-membered aryl, optionally substituted 5 to 10-membered heteroaryl, —B(OH) 2 or 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl;
R 2 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 5- to 10-membered heteroaryl;
R 26 is halogen, toluenesulfonyloxy, CH 3 SO 3 —, CF 3 SO 3 — or —B(OH) 2 ; and
R 27 is —CH 2 —OH, —CH 2 O-PG 1 , —COOH or —COOR 28 ;
R 28 is C 1-6 alkyl or NR 29 R 29 ;
R 29 is H or independently C 1-6 alkyl; and
PG 1 is a hydroxy protecting group.
99 . The compound of claim 98 , wherein R 1 is H, 4-methylpiperazin-1-yl, 4-cyclopropylpiperazin-1-yl, —B(OH) 2 or 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl.
100 . The compound of claim 98 or 99 , wherein R 2 is H, C 1-6 alkyl, 2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl, or 3-cyanocyclobutyl.
101 . The compound of any one of claims 98 to 100 , wherein R 26 is Br or I.
102 . The compound of any one of claims 98 to 101 , wherein PG 1 is TBDPS.
103 . The compound of any one of claims 98 to 102 , wherein R 27 is —CH 2 OH.
104 . The compound of claim 98 , wherein the compound is selected from:
105 . A compound of Formula (VIII):
wherein:
Z 1 is O or S;
PG is H or an amino protecting group;
R 30 and R 31 are each H; or R 30 and R 31 taken together with the nitrogen atom to which they are attached form optionally substituted 7- to 11-membered spiro heterocycloalkyl;
R 24 is H or C 1-6 alkyl; and
R 25 is Br or I.
106 . The compound of claim 105 , wherein R 24 is H.
107 . The compound of claim 105 or 106 , wherein PG is Boc.
108 . The compound of any one of claims 105 to 107 , wherein R 30 and R 31 are each H.
109 . The compound of any one of claims 105 to 107 , wherein R 30 and R 31 taken together with the nitrogen atom to which they are attached form optionally substituted 7- to 11-membered spiro heterocycloalkyl.
110 . The compound of any one of claims 105 to 109 , wherein Z 1 is O.
111 . The compound of any one of claims 105 to 109 , wherein Z 1 is S.
112 . The compound of claim 105 , wherein the compound is:
113 . A compound of Formula (IX):
wherein:
Z 1 is O or S;
PG is an amino protecting group;
PG 2 is a hydroxy protecting group; and
R 25 is Br or I.
114 . The compound of claim 113 , wherein PG is Boc.
115 . The compound of claim 113 or 114 , wherein PG 2 is —C(O) CHs.
116 . The compound of any one of claims 113 to 115 , wherein Z 1 is O.
117 . The compound of any one of claims 113 to 115 , wherein Z 1 is S.
118 . The compound of any one of claims 113 to 117 , wherein R 25 is Br.
119 . A compound of Formula (X):
wherein:
PG is H or an amino protecting group;
Z 1 is O or S;
R 2 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 5- to 10-membered heteroaryl;
R 32 is halogen, —B(OH) 2 or 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl;
R 4 , R 5 , R 6 , R 7 , R 5a , R 6a and R 7a are each independently hydrogen, halo or C 1 -C 6 alkyl;
or R 5 and R 7 are taken together to form a methylene or ethylene bridge between the carbon atoms to which they are attached, and R 4 , R 5a , R 6 , R 6a , and R 7a are each independently hydrogen, halogen, or C 1-6 alkyl;
or R 4 and R 6 are taken together to form a methylene or ethylene bridge between the carbon atoms to which they are attached, and R 5 , R 5a , R 6a , R 7 and R 7a are each independently hydrogen, halogen, or C 1-6 alkyl;
or R 5 and R 6 taken together with the atoms to which they are attached form optionally substituted 3- to 7-membered cycloalkyl or optionally substituted 4- to 7-membered heterocycloalkyl;
or R 6 and R 7 taken together with the atoms to which they are attached form optionally substituted 3- to 7-membered cycloalkyl or optionally substituted 4- to 7-membered heterocycloalkyl;
or R 5 and R 5a taken together with the atom to which they are attached form optionally substituted 3- to 7-membered cycloalkyl or an optionally substituted 4- to 7-membered heterocycloalkyl;
or R 6 and R 6a taken together with the atom to which they are attached form optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;
or R 7 and R 7a taken together with the atom to which they are attached form an optionally 3- to 7-membered substituted cycloalkyl or an optionally substituted 4- to 7-membered heterocycloalkyl;
or R 5 and R 6 taken together form a bond.
120 . The compound of claim 119 , wherein PG is Boc.
121 . The compound of claim 119 or 120 , wherein R 2 is H or optionally substituted C 1-6 alkyl.
122 . The compound of any one of claims 119 to 121 , wherein R 32 is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, Br or I.
123 . The compound of any one of claims 119 to 122 , wherein Z 1 is O.
124 . The compound of any one of claims 119 to 122 , wherein Z 1 is S.
125 . The compound of any one of claims 119 to 124 , wherein R 4 , R 5 , R 6 , R 7 , R 5a , R 6a and R 7a are each hydrogen.
126 . The compound of any one of claims 119 to 124 , wherein R 5 and R 7 are taken together to form a methylene bridge between the carbon atoms to which they are attached, and R 4 , R 5a , R 6 , R 6a , and R 7a are each hydrogen.
127 . A compound of Formula (XI):
wherein:
PG is H or an amino protecting group;
Z 1 is O or S;
R 1 is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 2-6 alkenyl, optionally substituted C 2-6 alkynyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted 3- to 10-membered cycloalkyl, optionally substituted 3- to 6-membered cycloalkenyl, optionally substituted 3- to 15-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 1 -C 6 heteroalkyl, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted 4 to 10-membered heterocycloalkyl, optionally substituted 6- to 10-membered aryl, optionally substituted 5- to 10-membered heteroaryl;
R 4 , R 5 , R 6 , R 7 , R 5a , R 6a and R 7a are each independently hydrogen, halo or C 1 -C 6 alkyl;
or R 5 and R 7 are taken together to form a methylene or ethylene bridge between the carbon atoms to which they are attached, and R 4 , R 5a , R 6 , R 6a , and R 7a are each independently hydrogen, halogen, or C 1-6 alkyl;
or R 4 and R 6 are taken together to form a methylene or ethylene bridge between the carbon atoms to which they are attached, and R 5 , R 5a , R 6a , R 7 and R 7a are each independently hydrogen, halogen, or C 1-6 alkyl;
or R 5 and R 6 taken together with the atoms to which they are attached form optionally substituted 3- to 7-membered cycloalkyl or optionally substituted 4- to 7-membered heterocycloalkyl;
or R 6 and R 7 taken together with the atoms to which they are attached form optionally substituted 3- to 7-membered cycloalkyl or optionally substituted 4- to 7-membered heterocycloalkyl;
or R 5 and R 5a taken together with the atom to which they are attached form optionally substituted 3- to 7-membered cycloalkyl or an optionally substituted 4- to 7-membered heterocycloalkyl;
or R 6 and R 6a taken together with the atom to which they are attached form optionally substituted cycloalkyl or optionally substituted heterocycloalkyl;
or R 7 and R 7a taken together with the atom to which they are attached form an optionally 3- to 7-membered substituted cycloalkyl or an optionally substituted 4- to 7-membered heterocycloalkyl;
or R 5 and R 6 taken together form a bond.
128 . The compound of claim 127 , wherein PG is H or Boc.
129 . The compound of claim 127 or 128 , wherein R 1 is H or optionally substituted heterocycloalkyl.
130 . The compound of any one of claims 127 to 129 , wherein R 2 is H or optionally substituted C 1-6 alkyl.
131 . The compound of any one of claims 127 to 130 , wherein Z 1 is O.
132 . The compound of any one of claims 127 to 130 , wherein Z 1 is S.
133 . The compound of any one of claims 127 to 132 , wherein R 4 , R 5 , R 6 , R 7 , R 5a , R 6a and R 7a are each hydrogen.
134 . The compound of any one of claims 128 to 132 , wherein R 5 and R 7 are taken together to form a methylene bridge between the carbon atoms to which they are attached, and R 4 , R 5a , R 6 , R 6a , and R 7a are each hydrogen.