# US 12,599,672 B2 · KRAS proteolysis targeting chimeras

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- Number: US 12,599,672 B2
- Document ID: US12599672B2
- Status: Granted
- Kind: B2
- Application number: 18/904,330
- Filed: 2024-10-02
- Published: 2025-05-08
- Granted: 2026-04-14
- Earliest claimed: 2023-10-03
- Assignees: PAQ Therapeutics Inc.
- Applicants: PAQ Therapeutics Inc.
- Inventors: Nan Ji; Hui Qiu; Ruoxi Lan
- Web page: https://patentgrep.com/patent/US12599672B2

## CPC

- A61K 47/55: the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
- 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
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/545: {Heterocyclic compounds (A61K47/558 takes precedence)}
- A61P 35/00: Antineoplastic agents
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided herein are KRAS proteolysis targeting chimeras (PROTACs), compositions comprising the KRAS PROTACs, and methods of making and using the KRAS PROTACs, e.g., to promote degradation of KRAS and/or treat KRAS-associated cancers. In an embodiment, the KRAS PROTAC has the following structural formula: or a pharmaceutically acceptable salt thereof, wherein values for the variables are as described herein.

## Claims

### Claim 1

A compound of the following formula:
or a pharmaceutically acceptable salt thereof, wherein:
R1 is
X1 is N or C(R10);
R10 is hydrogen, halogen, (C1-C6)alkyl, (C1-C6)haloalkyl, (C1-C6)haloalkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, —CN, (C1-C6)alkoxy, —S—(C1-C6)alkyl or —S—(C1-C6)haloalkyl;
R3 is
R4 is hydrogen or fluoro;
L′ is
wherein * indicates point of attachment of L′ to Degron;
and
Degron is
wherein one or more of the hydrogen atoms on the benzene ring of the Degron is optionally replaced with a fluorine atom,
provided the compound is not
or a salt thereof.

### Claim 2 (depends on 1)

The compound of claim 1, wherein X1 is N.

### Claim 3 (depends on 1)

The compound of claim 1, wherein X1 is C(R10), and R10 is hydrogen, fluoro, chloro, methyl, —CF3, —OCF3, —CN, —OCH3, —SCH3, or —SCF3.

### Claim 4 (depends on 1)

The compound of claim 1, wherein R4 is fluoro.

### Claim 5 (depends on 1)

The compound of claim 1, wherein Degron is
wherein one or more of the hydrogen atoms on the benzene ring of the Degron is optionally replaced with a fluorine atom.

### Claim 6

A compound of the following structure:
or a pharmaceutically acceptable salt thereof.

### Claim 7

A compound selected from:
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

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

### Claim 9 (depends on 6)

A pharmaceutical composition comprising a compound of claim 6, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 10 (depends on 7)

A pharmaceutical composition comprising a compound of claim 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 11 (depends on 1)

The compound of claim 1, of the following formula:
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

The compound of claim 1, wherein R3 is

### Claim 13 (depends on 1)

The compound of claim 1, wherein R3 is

### Claim 14 (depends on 5)

The compound of claim 5, wherein Degron is
wherein one or more of the hydrogen atoms on the benzene ring of the Degron is optionally replaced with a fluorine atom.

### Claim 15 (depends on 5)

The compound of claim 5, wherein Degron is
wherein one or more of the hydrogen atoms on the benzene ring of the Degron is optionally replaced with a fluorine atom.

### Claim 16 (depends on 7)

The compound of claim 7, of the following structure:
or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 7)

The compound of claim 7, of the following structure:
or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 7)

The compound of claim 7, of the following structure:
or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 7)

The compound of claim 7, of the following structure:
or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 7)

The compound of claim 7, of the following structure:
or a pharmaceutically acceptable salt thereof.

### Claim 21 (depends on 7)

The compound of claim 7, of the following structure:
or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 7)

The compound of claim 7, of the following structure:
or a pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 7)

The compound of claim 7, of the following structure:
or a pharmaceutically acceptable salt thereof.

### Claim 24 (depends on 7)

The compound of claim 7, of the following structure:
or a pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 7)

The compound of claim 7, of the following structure:
or a pharmaceutically acceptable salt thereof.