# US 11,306,087 B2 · Inhibitors of KRAS G12C and methods of using the same

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- Number: US 11,306,087 B2
- Document ID: US11306087B2
- Status: Granted
- Kind: B2
- Application number: 16/817,109
- Filed: 2020-03-12
- Published: 2020-07-02
- Granted: 2022-04-19
- Earliest claimed: 2017-09-08
- Assignees: Amgen Inc.
- Applicants: Amgen Inc.
- Inventors: Brian Alan Lanman; Shon Booker; Clifford Goodman; Anthony B. Reed; Jonathan D. Low; Hui-Ling Wang; Ning Chen; Ana Elena Minatti; Ryan Wurz; Victor J. Cee
- Web page: https://patentgrep.com/patent/US11306087B2

## CPC

- C07D 471/04: Ortho-condensed systems
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61P 35/00: Antineoplastic agents
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 38/07: Tetrapeptides
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided herein are methods of using KRAS G12C inhibitors. These methods of using the inhibitors are useful for treating a number of disorders, including pancreatic, colorectal, and lung cancers.

## Claims

### Claim 1

A method of treating cancer having a KRAS G12C mutation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having a structure of formula (I)
wherein
A is independently N or CH;
W is independently N or CH;
wherein one or both of A and W is N;
R1 and R2 are independently a branched or a linear C1-6alkyl;
R3 is phenyl substituted by 1 or 2 R5 substituents;
R5 is independently selected from one or more halo, —OH, or NH2;
R4 is halo; or
a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof, wherein the cancer having a KRAS G12C mutation is non-small cell lung cancer, pancreatic cancer, colorectal cancer, appendix cancer, endometrial cancer, esophageal cancer, gastric cancer, small intestine cancer, nasal cavity cancer, paranasal sinus cancer, bile duct cancer, skin cancer, or intraocular melanoma.

### Claim 2 (depends on 1)

The method of claim 1, wherein the compound is a compound having a structure of formula (Ia)
or
a pharmaceutically acceptable salt thereof.

### Claim 3 (depends on 1)

The method of claim 1, wherein A is N.

### Claim 4 (depends on 1)

The method of claim 1, wherein A is CH.

### Claim 5 (depends on 1)

The method of claim 1, wherein W is N.

### Claim 6 (depends on 1)

The method of claim 1, wherein W is CH.

### Claim 7 (depends on 1)

The method of claim 1, wherein R1 is CH3.

### Claim 8 (depends on 1)

The method of claim 1, wherein R1 is CH(CH3)2.

### Claim 9 (depends on 1)

The method of claim 1, wherein R2 is CH3.

### Claim 10 (depends on 1)

The method of claim 1, wherein R2 is CH(CH3)2.

### Claim 11 (depends on 1)

The method of claim 1, wherein R5 is halo.

### Claim 12 (depends on 11)

The method of claim 11, wherein R5 is F.

### Claim 13 (depends on 1)

The method of claim 1, wherein R5 is —OH.

### Claim 14 (depends on 1)

The method of claim 1, wherein R5 is —NH2.

### Claim 15 (depends on 1)

The method of claim 1, wherein R3 is

### Claim 16 (depends on 15)

The method of claim 15, wherein R3 is

### Claim 17 (depends on 15)

The method of claim 15, wherein R3 is

### Claim 18 (depends on 15)

The method of claim 15, wherein R3 is

### Claim 19 (depends on 1)

The method of claim 1, wherein R4 is halo.

### Claim 20 (depends on 19)

The method of claim 19, wherein R4 is Cl.

### Claim 21 (depends on 19)

The method of claim 19, wherein R4 is F.

### Claim 22

A method of treating cancer having a KRAS G12C mutation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having a structure of formula (II)
wherein
A is independently N or CH;
W is independently N or CH;
wherein one or both A and W is N;
R1 and R2 are independently a branched or a linear C1-6alkyl;
R3 is phenyl substituted by one or two R5 substituents;
R5 is independently selected from one or more halo, —OH, or NH2; and
R4 is halo; or
a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof, wherein the cancer having a KRAS G12C mutation is non-small cell lung cancer, pancreatic cancer, colorectal cancer, appendix cancer, endometrial cancer, esophageal cancer, gastric cancer, small intestine cancer, nasal cavity cancer, paranasal sinus cancer, bile duct cancer, skin cancer, or intraocular melanoma.

### Claim 23 (depends on 22)

The method of claim 22, wherein the compound is a compound having a structure of formula (IIa)
or
a pharmaceutically acceptable salt thereof.

### Claim 24 (depends on 22)

The method of claim 22, wherein A is N.

### Claim 25 (depends on 22)

The method of claim 22, wherein A is CH.

### Claim 26 (depends on 22)

The method of claim 22, wherein W is N.

### Claim 27 (depends on 22)

The method of claim 22, wherein W is CH.

### Claim 28 (depends on 22)

The method of claim 22, wherein R1 is CH3.

### Claim 29 (depends on 22)

The method of claim 22, wherein R1 is CH(CH3)2.

### Claim 30 (depends on 22)

The method of claim 22, wherein R2 is CH3.

### Claim 31 (depends on 22)

The method of claim 22, wherein R2 is CH(CH3)2.

### Claim 32 (depends on 22)

The method of claim 22, wherein R5 is halo.

### Claim 33 (depends on 32)

The method of claim 32, wherein R5 is F.

### Claim 34 (depends on 22)

The method of claim 22, wherein R5 is —OH.

### Claim 35 (depends on 22)

The method of claim 22, wherein R5 is —NH2.

### Claim 36 (depends on 22)

The method of claim 22, wherein R3 is

### Claim 37 (depends on 36)

The method of claim 36, wherein R3 is

### Claim 38 (depends on 36)

The method of claim 36, wherein R3 is

### Claim 39 (depends on 36)

The method of claim 36, wherein R3 is

### Claim 40 (depends on 22)

The method of claim 22, wherein R4 is halo.

### Claim 41 (depends on 40)

The method of claim 40, wherein R4 is Cl.

### Claim 42 (depends on 40)

The method of claim 40, wherein R4 is F.

### Claim 43

A method of treating cancer having a KRAS G12C mutation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having a structure selected from:
or a stereoisomer thereof, an atropisomer thereof, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt of the stereoisomer thereof, or a pharmaceutically acceptable salt of the atropisomer thereof, wherein the cancer having a KRAS G12C mutation is non-small cell lung cancer, pancreatic cancer, colorectal cancer, appendix cancer, endometrial cancer, esophageal cancer, gastric cancer, small intestine cancer, nasal cavity cancer, paranasal sinus cancer, bile duct cancer, skin cancer, or intraocular melanoma.

### Claim 44

A method of treating cancer having a KRAS G12C mutation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound having a structure selected from:
or a pharmaceutically acceptable salt thereof, wherein the cancer having a KRAS G12C mutation is non-small cell lung cancer, pancreatic cancer, colorectal cancer, appendix cancer, endometrial cancer, esophageal cancer, gastric cancer, small intestine cancer, nasal cavity cancer, paranasal sinus cancer, bile duct cancer, skin cancer, or intraocular melanoma.

### Claim 45 (depends on 44)

The method of claim 44, wherein the compound is a compound having a structure
or the pharmaceutically acceptable salt thereof.

### Claim 46 (depends on 1)

The method of claim 1, wherein the cancer having a KRAS G12C mutation is non-small cell lung cancer.

### Claim 47 (depends on 1)

The method of claim 1, wherein the cancer having a KRAS G12C mutation is colorectal cancer.

### Claim 48 (depends on 22)

The method of claim 22, wherein the cancer having a KRAS G12C mutation is non-small cell lung cancer.

### Claim 49 (depends on 22)

The method of claim 22, wherein the cancer having a KRAS G12C mutation is colorectal cancer.

### Claim 50 (depends on 43)

The method of claim 43, wherein the cancer having a KRAS G12C mutation is non-small cell lung cancer.

### Claim 51 (depends on 43)

The method of claim 43, wherein the cancer having a KRAS G12C mutation is colorectal cancer.

### Claim 52 (depends on 44)

The method of claim 44, wherein the cancer having a KRAS G12C mutation is non-small cell lung cancer.

### Claim 53 (depends on 44)

The method of claim 44, wherein the cancer having a KRAS G12C mutation is colorectal cancer.

### Claim 54 (depends on 45)

The method of claim 45, wherein the cancer having a KRAS G12C mutation is non-small cell lung cancer.

### Claim 55 (depends on 45)

The method of claim 45, wherein the cancer having a KRAS G12C mutation is colorectal cancer.