Modulators of RAS GTPase
RAS modulating compounds and methods of using the same are provided. The compounds find use in modulating the activity of a target RAS in a sample. The target RAS can be a mutant RAS that is implicated in a disease of interest. In some cases, the subject compounds can inhibit the growth of cancer cells whose progression is driven by kRAS or a mutated kRAS. Methods of treating a subject for a RAS driven disease including administering a therapeutically effective amount of the subject compound are provided. Also provided are pharmaceutical compositions and kits which include the subject compounds.
1 . A RAS modulating compound of formula (I):
wherein:
A is a monocyclic or bicyclic group selected from aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl and substituted cycloalkyl;
Z 0 is N;
Z 1 is CR 1 ;
Z 2 is N or CR 2 ;
Z 3 is N or CR 3 ;
Z 4 is N or CR 4 ;
Z 5 is N or CR 5 ;
L 2 is selected from the group consisting of covalent bond, —NR′—, —(CH 2 ) n —NR′—, —NR′—(CH 2 ) n —, —CO—, —CONR′—, —NR′CO—, —(CH 2 ) m —,
wherein R′ is H, alkyl or substituted alkyl, m is 1-3 and n is 1 or 2
R 1 is selected from alkyl and substituted alkyl;
R 3 and R 4 are independently selected from H, aryl, substituted aryl, heteroaryl and substituted heteroaryl, wherein at least one of R 3 and R 4 is non-hydrogen and
R 2 and R 5 are independently selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, halogen, nitro, cyano, hydroxy, —NH 2 , substituted amino, carboxy, sulfoxy, alkylsulfonyl, substituted alkylsulfonyl, alkanoyl, substituted alkanoyl, alkylsulfonamido, substituted alkylsulfonamido, alkylamido, substituted alkylamido, alkylamino and substituted alkylamino;
or a salt thereof, or a solvate, hydrate or prodrug form thereof.
2 . The compound according to claim 1 , wherein the compound is of one of formulae (IIa)-(IIf):
3 . The compound according to claim 1 , wherein A is
wherein
Z 11 is CR″ or N wherein R″ is H, alkyl or substituted alkyl; and
R 6 is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, halogen, nitro, cyano, hydroxy, —NH 2 , substituted amino, carboxy, sulfoxy, alkylsulfonyl, substituted alkylsulfonyl, alkanoyl and substituted alkanoyl, alkylsulfonamido, substituted alkylsulfonamido, alkylamido, substituted alkylamido, alkylamino and substituted alkylamino.
4 . The compound according to claim 3 , wherein the compound is of formula (IIIa) or (IIIb)
5 . The compound according to claim 3 , wherein R 6 is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, halogen, nitro, cyano, hydroxy, —NH 2 , carboxy, sulfoxy, alkylsulfonyl, substituted alkylsulfonyl, alkanoyl and substituted alkanoyl.
6 . The compound according to claim 5 , wherein the compound is of formula (IVi):
wherein:
Z 11 is CH or N;
q is 0 or 1, wherein when q is 1, Z 11 is N;
R 23 is halogen; and
R 1 , R 3 and R 4 are independently selected from H, (C 1-6 )alkyl and substituted (C 1-6 )alkyl.
7 . The compound according to claim 1 , wherein A is:
wherein:
Z 12 and Z 13 are independently N or CR″ wherein R″ is H, alkyl or substituted alkyl;
R 6 is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, halogen, nitro, cyano, hydroxy, —NH 2 , substituted amino, carboxy, sulfoxy, alkylsulfonyl, substituted alkylsulfonyl, alkanoyl and substituted alkanoyl;
s is 0-4; and
each R 11 is independently selected from alkyl, substituted alkyl and oxo (═O).
8 . The compound according to claim 7 , wherein the compound is of formula (Va)
9 . The compound according to claim 7 , wherein the compound is of one of formulae (Vb)-(Vc):
wherein R 11 is H, C (1-6) alkyl or substituted C (1-6) alkyl.
10 . The compound according to claim 7 , wherein the compound is of formula (Vf) or (Vg):
11 . The compound according to claim 7 , wherein R 6 is selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, halogen, nitro, cyano, hydroxy, —NH 2 , carboxy, sulfoxy, alkylsulfonyl, substituted alkylsulfonyl, alkanoyl and substituted alkanoyl.
12 . The compound according to claim 11 , wherein the compound is of formula (VIa)
wherein:
r is 0 or 1;
R 23 is halogen; and
R 1 is selected from (C 1-6 )alkyl and substituted (C 1-6 )alkyl.
13 . The compound according to claim 11 , wherein the compound is of formula (VIb) or (VIc):
wherein:
R 11 , R 31 and R 32 are independently selected from H, C (1-6) alkyl and substituted C (1-6) alkyl; and
R 21 —R 25 are independently selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, halogen, nitro, cyano, hydroxy, —NH 2 , substituted amino, carboxy, sulfoxy, alkylsulfonyl, substituted alkylsulfonyl, alkanoyl, substituted alkanoyl, alkylsulfonamido, substituted alkylsulfonamido, alkylamido, substituted alkylamido, alkylamino and substituted alkylamino.
14 . The compound according claim 1 , wherein the compound is selected from any one of the compounds of Table 1, or a pharmaceutically acceptable salt or solvate thereof.
15 . A method of modulating the activity of a target RAS in a sample, the method comprising: contacting a sample comprising a target RAS with an effective amount of a compound of claim 1 to modulate the activity of the target RAS.
16 . The method according to claim 15 , wherein the target RAS is a mutant KRAS, a mutant nRAS or a mutant hRAS.
17 . A method of treating a subject for a RAS driven disease, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1 ; wherein the RAS driven disease is cancer.
18 . The method according to claim 17 , further comprising obtaining a sample from the subject and determining whether the sample comprises a mutant RAS.
19 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable vehicle.
20 . The compound of claim 1 , wherein R 3 or R 4 is selected from one of the following structures:
wherein:
n is 1-3;
each R 41 is independently selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, halogen, nitro, cyano, hydroxy, —NH 2 , substituted amino, carboxy, sulfoxy, alkylsulfonyl, substituted alkylsulfonyl, alkanoyl, substituted alkanoyl, alkylsulfonamido, substituted alkylsulfonamido, alkylamido, substituted alkylamido, alkylamino and substituted alkylamino;
R 42 is selected from H, alkyl, substituted alkyl, alkanoyl and substituted alkanoyl;
R 43 and R 44 are independently selected from H, alkyl and substituted alkyl.
21 . The compound of claim 1 , wherein R 3 or R 4 is of the following structure:
wherein:
n is 1-3;
each R 41 is independently selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, halogen, nitro, cyano, hydroxy, —NH 2 , substituted amino, carboxy, sulfoxy, alkylsulfonyl, substituted alkylsulfonyl, alkanoyl, substituted alkanoyl, alkylsulfonamido, substituted alkylsulfonamido, alkylamido, substituted alkylamido, alkylamino and substituted alkylamino;
R 42 is selected from H, alkyl, substituted alkyl, alkanoyl and substituted alkanoyl; and R 43 is selected from H, alkyl and substituted alkyl.
22 . The compound of claim 1 , wherein R 3 or R 4 is of the following structure:
wherein:
n is 1-3;
each R 41 is independently selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, halogen, nitro, cyano, hydroxy, —NH 2 , substituted amino, carboxy, sulfoxy, alkylsulfonyl, substituted alkylsulfonyl, alkanoyl, substituted alkanoyl, alkylsulfonamido, substituted alkylsulfonamido, alkylamido, substituted alkylamido, alkylamino and substituted alkylamino;
R 42 is selected from H, alkyl, substituted alkyl, alkanoyl and substituted alkanoyl; and
R 43 and R 44 are independently selected from H, alkyl and substituted alkyl.
23 . The compound of claim 1 , wherein R 3 or R 4 is of the following structure:
wherein:
n is 1-3; and
each R 41 is independently selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, halogen, nitro, cyano, hydroxy, —NH 2 , substituted amino, carboxy, sulfoxy, alkylsulfonyl, substituted alkylsulfonyl, alkanoyl, substituted alkanoyl, alkylsulfonamido, substituted alkylsulfonamido, alkylamido, substituted alkylamido, alkylamino and substituted alkylamino.