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 A is optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 10-membered heteroarylene;
L 1 is absent or a linker;
W is a cross-linking group comprising a vinyl ketone, vinyl sulfone, ynone, or an alkynyl sulfone;
R 1 is hydrogen, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted C 1 -C 6 heteroalkyl;
R 2 is optionally substituted C 1 -C 6 alkyl; and
R 3 is optionally substituted C 1 -C 6 alkyl or optionally substituted C 1 -C 3 heteroalkyl.
2 . The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein A is optionally substituted thiazole, optionally substituted oxazole, optionally substituted morpholino, optionally substituted pyrrolidinyl, optionally substituted pyridyl, optionally substituted azetidinyl, optionally substituted pyrazinyl, optionally substituted pyrimidine, optionally substituted piperidinyl, optionally substituted oxadiazole, optionally substituted thiadiazole, optionally substituted triazole, optionally substituted thiomorpholino, or optionally substituted phenyl.
3 . The compound of claim 1 or 2 , or pharmaceutically acceptable salt thereof, wherein R 2 is:
4 . The compound of any one of claims 1 to 3 , or pharmaceutically acceptable salt thereof, wherein R 3 is optionally substituted C 1 -C 6 alkyl.
5 . The compound of any one of claims 1 to 3 , or pharmaceutically acceptable salt thereof, wherein R 3 is optionally substituted C 1 -C 3 heteroalkyl.
6 . The compound of any one of claims 1 to 5 , or pharmaceutically acceptable salt thereof, wherein A is optionally substituted 5 to 10-membered heteroarylene.
7 . The compound of any one of claims 1 to 5 , or pharmaceutically acceptable salt thereof, wherein A is optionally substituted phenyl.
8 . The compound of any one of claims 1 to 5 , or pharmaceutically acceptable salt thereof, wherein A is optionally substituted 3 to 6-membered heterocycloalkylene.
9 . The compound of any one of claims 1 to 8 , or pharmaceutically acceptable salt thereof, wherein the linker is the structure of Formula III:
A 1 -(B 1 ) f —(C 1 ) g —(B 2 ) h —(D 1 )—(B 3 ) i —(C 2 ) j —(B 4 ) k -A 2 Formula III,
wherein A 1 is a bond between the linker and CH(R 3 ); 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 ; each R N is, independently, 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 .
10 . The compound of any one of claims 1 to 9 , or pharmaceutically acceptable salt thereof, wherein the linker is or comprises a cyclic moiety.
11 . The compound of claim 10 , or pharmaceutically acceptable salt thereof, wherein the linker has the structure of Formula IIIa:
wherein o is 0 or 1;
R 7 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 1 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 12-membered heterocycloalkylene, optionally substituted 6-10 membered arylene, or optionally substituted 5 to 10-membered heteroarylene; and
L 2 is absent, —SO 2 —, —NH—, optionally substituted C 1 -C 4 alkylene, optionally substituted C 1 -C 4 heteroalkylene, or optionally substituted 3 to 6-membered heterocycloalkylene.
12 . The compound of any one of claims claim 1 to 11 , or pharmaceutically acceptable salt thereof, wherein the compound is not a compound of Table 2.
13 . The compound of any one of claims 1 to 12 , or pharmaceutically acceptable salt thereof, having the structure of Formula II-5:
wherein Cy 1 is optionally substituted spirocyclic 8 to 11-membered heterocycloalkylene or optionally substituted bicyclic 7 to 9-membered heterocycloalkylene; and
wherein W comprises a vinyl ketone or a vinyl sulfone.
14 . The compound of any one of claims 1 to 13 , or pharmaceutically acceptable salt thereof, wherein W is a cross-linking group comprising a vinyl ketone.
15 . The compound of any one of claims 1 to 13 , or pharmaceutically acceptable salt thereof, wherein W is a cross-linking group comprising a vinyl sulfone.
16 . The compound of any one of claims 1 to 13 , or pharmaceutically acceptable salt thereof, wherein W is a cross-linking group comprising an ynone.
17 . The compound of claim 16 , or pharmaceutically acceptable salt thereof, having the structure of Formula II-6:
wherein Q 1 is CH 2 , NR N , or O;
Q 2 is CO, NR N , or O; and
Z is optionally substituted 3 to 6-membered heterocycloalkylene or optionally substituted 5 to 10-membered heteroarylene; or
wherein Q 1 -Q 2 -Z is an optionally substituted 9 to 10-membered spirocyclic heterocycloalkylene.
18 . A compound, or a pharmaceutically acceptable salt thereof, selected from Table 1.
19 . A pharmaceutical composition comprising a compound of any one of claims 1 to 18 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
20 . A conjugate, or salt thereof, comprising the structure of Formula V:
M-L-P Formula V,
wherein L is a linker;
P is a monovalent organic moiety; and
M has the structure of Formula VIa:
wherein A is optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 10-membered heteroarylene;
R 2 is optionally substituted C 1 -C 6 alkyl;
R 3 is optionally substituted C 1 -C 6 alkyl or optionally substituted C 1 -C 3 heteroalkyl;
X 2 is O, C(R 11 ) 2 , NR 12 , S, or SO 2 ;
r is 1 or 2;
each t is, independently, 0, 1, or 2;
R 11 and R 12 are each, independently, hydrogen, optionally substituted C 1 -C 4 alkyl, optionally substituted C 2 -C 4 heteroalkyl, or optionally substituted 3 to 5-membered cycloalkyl;
each R 13 is, independently, —CH 3 ; and
R 4 , R 5 , and R 6 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 heterocycloalkyl; or
R 4 and R 5 combine with the atoms to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or an optionally substituted 3 to 8-membered heterocycloalkyl; or
R 4 and R 6 combine with the atoms to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or an optionally substituted 3 to 8-membered heterocycloalkyl.
21 . A conjugate, or salt thereof, comprising the structure of Formula V:
M-L-P Formula V,
wherein L is a linker;
P is a monovalent organic moiety; and
M has the structure of Formula VIb:
wherein A is optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 10-membered heteroarylene;
R 2 is optionally substituted C 1 -C 6 alkyl;
R 3 is optionally substituted C 1 -C 6 alkyl or optionally substituted C 1 -C 3 heteroalkyl;
R 14 is fluoro, hydrogen, or C 1 -C 3 alkyl;
u is 0 or 1; and
R 4 , R 5 , and R 6 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 heterocycloalkyl; or
R 4 and R 5 combine with the atoms to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or an optionally substituted 3 to 8-membered heterocycloalkyl; or
R 4 and R 6 combine with the atoms to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or an optionally substituted 3 to 8-membered heterocycloalkyl.
22 . A conjugate, or salt thereof, comprising the structure of Formula V:
M-L-P Formula V,
wherein L is a linker;
P is a monovalent organic moiety; and
M has the structure of Formula VIc:
wherein A is optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 10-membered heteroarylene;
R 2 is optionally substituted C 1 -C 6 alkyl;
R 3 is optionally substituted C 1 -C 6 alkyl or optionally substituted C 1 -C 3 heteroalkyl; and
R 4 , R 5 , and R 6 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 heterocycloalkyl; or
R 4 and R 5 combine with the atoms to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or an optionally substituted 3 to 8-membered heterocycloalkyl; or
R 4 and R 6 combine with the atoms to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or an optionally substituted 3 to 8-membered heterocycloalkyl.
23 . A conjugate, or salt thereof, comprising the structure of Formula V:
M-L-P Formula V,
wherein L is a linker;
P is a monovalent organic moiety; and
M has the structure of Formula VId:
wherein A is optionally substituted 3 to 6-membered heterocycloalkylene, optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 10-membered heteroarylene;
R 2 is optionally substituted C 1 -C 6 alkyl;
R 3 is optionally substituted C 1 -C 6 alkyl or optionally substituted C 1 -C 3 heteroalkyl; and
R 4 , R 5 , and R 6 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 heterocycloalkyl; or
R 4 and R 5 combine with the atoms to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or an optionally substituted 3 to 8-membered heterocycloalkyl; or
R 4 and R 6 combine with the atoms to which they are attached to form an optionally substituted 3 to 8-membered cycloalkyl or an optionally substituted 3 to 8-membered heterocycloalkyl.
24 . 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 any one of claims 1 to 18 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 19 .
25 . 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 of any one of claims 1 to 18 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 19 .
26 . A method of inhibiting a Ras protein in a cell, the method comprising contacting the cell with an effective amount of a compound of any one of claims 1 to 18 , or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 19 .