# US 12,180,220 B2 · Heteroaryl modulators of RAS GTPase

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- Number: US 12,180,220 B2
- Document ID: US12180220B2
- Status: Granted
- Kind: B2
- Application number: 17/484,739
- Filed: 2021-09-24
- Published: 2022-04-14
- Granted: 2024-12-31
- Earliest claimed: 2020-10-14
- Assignees: Tosk, Inc.
- Applicants: Tosk, Inc.
- Inventors: Solomon B. Ungashe; Stephen D. Yanofsky
- Web page: https://patentgrep.com/patent/US12180220B2

## CPC

- C07D 491/056: with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
- C07D 239/84: Nitrogen atoms
- C07D 401/04: directly linked by a ring-member-to-ring-member bond
- C07D 401/12: linked by a chain containing hetero atoms as chain links
- C07D 401/14: containing three or more hetero rings
- C07D 405/04: directly linked by a ring-member-to-ring-member bond
- C07D 405/10: linked by a carbon chain containing aromatic rings
- C07D 405/14: containing three or more hetero rings
- C07D 413/04: directly linked by a ring-member-to-ring-member bond
- C07D 471/04: Ortho-condensed systems
- C07D 519/00: Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
- C12N 9/99: Enzyme inactivation by chemical treatment
- C12Y 306/05002: Small monomeric GTPase (3.6.5.2)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES

## 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.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the sample is a cellular sample.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the sample is in vitro.

### Claim 4 (depends on 1)

The method according to claim 1, wherein the sample is in vivo.

### Claim 5

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.

### Claim 6 (depends on 1)

The method of claim 1, wherein A is a substituted heterocycle that is substituted with one or more groups selected from aryl, substituted aryl, carboxy, substituted carboxy, alkylsulfonyl, substituted alkylsulfonyl, alkanoyl, and substituted alkanoyl.

### Claim 7 (depends on 6)

The method of claim 6, wherein A is a substituted heterocycle that is substituted with a substituted carboxy group.

### Claim 8 (depends on 7)

The method of claim 7, wherein A has the formula:
wherein:
each Ra is independently selected from H, alkyl and substituted alkyl;
X2 is selected from alkyl, substituted alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, cycloalkyl, and substituted cycloalkyl;
q is 1-6.

### Claim 9 (depends on 5)

The method of claim 5, wherein A is a substituted heterocycle that is substituted with one or more groups selected from aryl, substituted aryl, carboxy, substituted carboxy, alkylsulfonyl, substituted alkylsulfonyl, alkanoyl, and substituted alkanoyl.

### Claim 10 (depends on 9)

The method of claim 9, wherein A is a substituted heterocycle that is substituted with a substituted carboxy group.

### Claim 11 (depends on 10)

The method of claim 10, wherein A has the formula:
wherein:
each Ra is independently selected from H, alkyl and substituted alkyl;
X2 is selected from alkyl, substituted alkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl, substituted heteroaryl, cycloalkyl, and substituted cycloalkyl;
q is 1-6.

### Claim 12 (depends on 1)

The method of claim 1, wherein Z1 is C (CH3).

### Claim 13 (depends on 5)

The method of claim 5, wherein Z1 is C (CH3).