# US 2025/0145643 A1 · Ras inhibitors

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 2025/0145643 A1
- Document ID: US20250145643A1
- Status: Published application
- Kind: A1
- Application number: 18/762,805
- Filed: 2024-07-03
- Published: 2025-05-08
- Earliest claimed: 2021-05-05
- Assignees: Revolution Medicines, Inc.
- Applicants: Revolution Medicines, Inc.
- Inventors: Elena S. KOLTUN; James CREGG; Adrian L. GILL; John E. KNOX; Yang LIU; G. Leslie BURNETT
- Web page: https://patentgrep.com/patent/US20250145643A1

## CPC

- C07D 487/14: 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
- A61P 35/00: Antineoplastic agents
- C07D 213/55: Acids; Esters
- C07D 213/61: Halogen atoms or nitro radicals
- C07D 421/14: containing three or more hetero rings
- C07D 513/22: in which the condensed system contains four or more hetero rings
- C07F 5/02: Boron compounds
- C07F 5/025: {Boronic and borinic acid compounds}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## Abstract

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.

## Claims

### Claim 1

A compound having the structure of Formula I:
wherein A is optionally substituted 3 to 6-membered cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 10-membered heteroarylene;
L1 is absent or a linker of Formula III:
A1-(B1)f-(C1)g-(B2)h-(D1)-(B3)i-(C2)j-(B4)k-A2 Formula III,
wherein
A1 is a bond between the linker and CH(R3);
A2 is a bond between W and the linker;
B1, B2, B3, and B4 each, independently, is selected from optionally substituted C1-C2 alkylene, optionally substituted C1-C3 heteroalkylene, O, S, and NRN; each RN is independently, hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 alkenyl, optionally substituted C2-C4 alkynyl, optionally substituted 3 to 14-membered heterocycloalkyl, optionally substituted 6 to 10-membered aryl, or optionally substituted C1-C7 heteroalkyl;
C1 and C2 are each, independently, selected from carbonyl, thiocarbonyl, sulphonyl, or phosphoryl; f, q, h, i, j, and k are each, independently, 0 or 1; and
D1 is optionally substituted C1-C10 alkylene, optionally substituted C2-C10 alkenylene, optionally substituted C2-C10 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 C2-C10 polyethylene glycolene, or optionally substituted C1-C10 heteroalkylene, or a chemical bond linking A1-(B1)f—(C1)g—(B2)h-to —(B3)i—(C2)j—(B4)k-A2;
W is a cross-linking group comprising a vinyl ketone, vinyl sulfone, ynone, or an alkynyl sulfone;
R1 is hydrogen, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl;
R2 is optionally substituted C1-C6 alkyl; and
R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl;
or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein A is optionally substituted thiazole, optionally substituted oxazole, optionally substituted pyridyl, optionally substituted pyrazinyl, optionally substituted pyrimidine, optionally substituted oxadiazole, optionally substituted thiadiazole, optionally substituted triazole, or optionally substituted phenyl.

### Claim 3 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R2 is:

### Claim 4 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R3 is optionally substituted C1-C6 alkyl.

### Claim 5 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein R3 is optionally substituted C1-C3 heteroalkyl.

### Claim 6 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein A is optionally substituted 5 to 10-membered heteroarylene.

### Claim 7 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein A is optionally substituted phenyl.

### Claim at position 8

8-9. (canceled)

### Claim 10 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein the linker is or comprises a cyclic moiety.

### Claim 11 (depends on 10)

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;
R7 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted 3 to 8-membered cycloalkylene, or optionally substituted 3 to 8-membered heterocycloalkylene;
X1 is absent, optionally substituted C1-C4 alkylene, O, NCH3, or optionally substituted C1-C4 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
L2 is absent, —SO2—, —NH—, optionally substituted C1-C4 alkylene, optionally substituted C1-C4 heteroalkylene, or optionally substituted 3 to 6-membered heterocycloalkylene.

### Claim 12

(canceled)

### Claim 13 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, having the structure of Formula II-5:
wherein Cy1 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.

### Claim 14 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein W is a cross-linking group comprising a vinyl ketone.

### Claim 15 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein W is a cross-linking group comprising a vinyl sulfone.

### Claim 16 (depends on 1)

The compound of claim 1, or pharmaceutically acceptable salt thereof, wherein W is a cross-linking group comprising an ynone.

### Claim 17 (depends on 16)

The compound of claim 16, or pharmaceutically acceptable salt thereof, having the structure of Formula II-6:
wherein Q1 is CH2, NRN, or O;
Q2 is CO, NRN, or O; and
Z is optionally substituted 3 to 6-membered heterocycloalkylene or optionally substituted 5 to 10-membered heteroarylene; or
wherein Q1-Q2-Z is an optionally substituted 9 to 10-membered spirocyclic heterocycloalkylene.

### Claim 18

A compound, or a pharmaceutically acceptable salt thereof, selected from Table 1.

### Claim 19 (depends on 1)

A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

### Claim 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 cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 10-membered heteroarylene;
R2 is optionally substituted C1-C6 alkyl;
R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl;
X2 is O, C(R11)2, NR12, S, or SO2;
r is 1 or 2;
each t is, independently, 0, 1, or 2;
R11 and R12 are each, independently, hydrogen, optionally substituted C1-C4 alkyl, optionally substituted C2-C4 heteroalkyl, or optionally substituted 3 to 5-membered cycloalkyl;
each R13 is, independently, —CH3; and
R4, R5, and R6 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; or
R4 and R5 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
R4 and R6 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.

### Claim 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 cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 10-membered heteroarylene;
R2 is optionally substituted C1-C6 alkyl;
R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl;
R14 is fluoro, hydrogen, or C1-C3 alkyl;
u is 0 or 1; and
R4, R5, and R6 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; or
R4 and R5 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
R4 and R6 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.

### Claim 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 cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 10-membered heteroarylene;
R2 is optionally substituted C1-C6 alkyl;
R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; and
R4, R5, and R6 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; or
R4 and R5 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
R4 and R6 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.

### Claim 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 cycloalkylene, optionally substituted 6-membered arylene, or optionally substituted 5 to 10-membered heteroarylene;
R2 is optionally substituted C1-C6 alkyl;
R3 is optionally substituted C1-C6 alkyl or optionally substituted C1-C3 heteroalkyl; and
R4, R5, and R6 are each independently selected from hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 heteroalkyl, optionally substituted 3 to 6-membered cycloalkyl, optionally substituted 3 to 6-membered heterocycloalkyl; or
R4 and R5 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
R4 and R6 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.

### Claim 24 (depends on 1)

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 claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 1)

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 claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 26

(canceled)

### Claim 27

A compound of formula:
wherein
R1 is hydrogen, optionally substituted 3 to 10-membered heterocycloalkyl, or optionally substituted C1-C6 heteroalkyl;
R2 is optionally substituted C1-C6 alkyl;
each RINT is independently H, C1-3 alkyl, or TBDPS; and
PNG is H, Boc, or Cbz.

### Claim 28 (depends on 27)

The compound of claim 27, wherein the compound is: