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US 12,180,220 B2Granted
Heteroaryl modulators of RAS GTPase
AssigneeTosk, Inc.
InventorsSolomon B. Ungashe, Stephen D. Yanofsky
Life of this patent
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Abstract
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.
Claims13
A method of modulating the activity of a target RAS in a sample, the method comprising:
- contacting the sample comprising a target RAS with an effective amount of a RAS modulating compound to modulate the activity of the target RAS, wherein the RAS modulating compound is a compound of formula (I):
- wherein:
- A is a monocyclic or bicyclic group selected from heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl and substituted cycloalkyl;
- wherein if A is a substituted heterocycle then A is substituted with one or more groups selected from aryl, substituted aryl, carboxy, substituted carboxy, alkylsulfonyl, substituted alkylsulfonyl, alkanoyl, and substituted alkanoyl;
- ring B is a cyclic group selected from aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle;
- Z0 is N or CR0;
- Z1 is N or CR1;
- Z2 is N or CR2;
- Z4 is N or CR4;
- Z5 is N or CR5;
- L2 is a covalent bond, a linker having a backbone of 1-4 atoms in length, or an optionally substituted non-aromatic heterocycle;
- R0-R2 and R4-R5 are independently selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, halogen, nitro, cyano, hydroxy, —NH2, substituted amino, carboxy, sulfoxy, alkylsulfonyl, substituted alkylsulfonyl, alkanoyl, substituted alkanoyl, alkylsulfonamido, substituted alkylsulfonamido, alkylamido, substituted alkylamido, alkylamino and substituted alkylamino;
- each R41 is independently selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, halogen, nitro, cyano, hydroxy, —NH2, substituted amino, carboxy, sulfoxy, alkylsulfonyl, substituted alkylsulfonyl, alkanoyl, substituted alkanoyl, alkylsulfonamido, substituted alkylsulfonamido, alkylamido, substituted alkylamido, alkylamino and substituted alkylamino;
- and
- n is 1-2;
- or a salt thereof, or a solvate, hydrate or prodrug form thereof.
13 more elements
A method of treating a subject for a RAS driven disease, the method comprising:
- administering to the subject a therapeutically effective amount of a RAS modulating compound is a compound of formula (I):
- wherein:
- A is a monocyclic or bicyclic group selected from heteroaryl, substituted heteroaryl, heterocycle, substituted heterocycle, cycloalkyl and substituted cycloalkyl;
- wherein if A is a substituted heterocycle then A is substituted with one or more groups selected from aryl, substituted aryl, carboxy, substituted carboxy, alkylsulfonyl, substituted alkylsulfonyl, alkanoyl, and substituted alkanoyl;
- ring B is a cyclic group selected from aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocycle, and substituted heterocycle;
- Z0 is N or CR0;
- Z1 is N or CR1;
- Z2 is N or CR2;
- Z4 is N or CR4;
- Z5 is N or CR5;
- L2 is a covalent bond, a linker having a backbone of 1-4 atoms in length, or an optionally substituted non-aromatic heterocycle;
- R0, R2, and R4-R5 are independently selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, halogen, nitro, cyano, hydroxy, —NH2, substituted amino, carboxy, sulfoxy, alkylsulfonyl, substituted alkylsulfonyl, alkanoyl, substituted alkanoyl, alkylsulfonamido, substituted alkylsulfonamido, alkylamido, substituted alkylamido, alkylamino and substituted alkylamino;
- R1 is selected from alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, halogen, nitro, cyano, hydroxy, —NH2, substituted amino, carboxy, sulfoxy, alkylsulfonyl, substituted alkylsulfonyl, alkanoyl, substituted alkanoyl, alkylsulfonamido, substituted alkylsulfonamido, alkylamido, substituted alkylamido, alkylamino and substituted alkylamino;
- each R41 is independently selected from H, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, substituted alkoxy, halogen, nitro, cyano, hydroxy, —NH2, substituted amino, carboxy, sulfoxy, alkylsulfonyl, substituted alkylsulfonyl, alkanoyl, substituted alkanoyl, alkylsulfonamido, substituted alkylsulfonamido, alkylamido, substituted alkylamido, alkylamino and substituted alkylamino;
- and
- n is 1-2;
- or a salt thereof, or a solvate, hydrate or prodrug form thereof.
14 more elements
Dependencies are inferred from the claim text.