# US 11,993,597 B2 · Inhibitors of KRAS G12C and methods of using the same

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- Number: US 11,993,597 B2
- Document ID: US11993597B2
- Status: Granted
- Kind: B2
- Application number: 17/692,026
- Filed: 2022-03-10
- Published: 2022-07-07
- Granted: 2024-05-28
- 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/US11993597B2

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

## Claims

### Claim 1

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—C6 alkyl, wherein the —C1-C6 alkyl is substituted with one or more of independently selected from halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, nitro, cyano, alkylamino, —C1—C8 alkyl, —C2—C8 alkenyl, —C2—C8 alkynyl, —NC, amino, —CO2H, —CO2C1—C8_alkyl, —OOOC1—C8_alkyl, cycloalkyl, —C3—C10 heterocycloalkyl, —C5—C10 aryl, and —C5—C10 heteroaryl;
R3is 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.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

The compound or salt of claim 1, wherein A is N.

### Claim 4 (depends on 2)

The compound or salt of claim 2, wherein A is N.

### Claim 5 (depends on 1)

The compound or salt of claim 1, wherein W is N.

### Claim 6 (depends on 2)

The compound or salt of claim 2, wherein W is N.

### Claim 7 (depends on 1)

The compound or salt of claim 1, wherein both of A and W are N.

### Claim 8 (depends on 2)

The compound or salt of claim 2, wherein both of A and W are N.

### Claim 9 (depends on 1)

The compound or salt of claim 1, wherein R1 and R2 are CH3 substituted with one or more of independently selected from halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, nitro, cyano, alkylamino, —C1—C8 alkyl, —C2—C8 [[—C2-8]]alkenyl, —C2—C8 alkynyl, —NC, amino, —CO2H, —CO2C1—Csalkyl, -OOOC1—Csalkyl, —C3—C10 cycloalkyl, —C3—C10 heterocycloalkyl, —C5—C10 aryl, and —C5—C10 heteroaryl.

### Claim 10 (depends on 2)

The compound or salt of claim 2, wherein R1 and R2 are CH3 substituted with one or more of independently selected from halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, nitro, cyano, alkylamino, —C1—C8 alkyl, —C2—C8 [[—C2-8]]alkenyl, —C2—C8 alkynyl, —NC, amino, —CO2H, —CO2C1—C8_alkyl, —OOOC1—C8_alkyl, —C3—C10 cycloalkyl, —C3—C10 heterocycloalkyl, —C5—C10 aryl, and —C5—C10 heteroaryl.

### Claim 11 (depends on 7)

The compound or salt of claim 7, wherein R1 and R2 are CH3 substituted with one or more of independently selected from halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, nitro, cyano, alkylamino, —C1—C8 alkyl, —C2—C8 [[—C2-8]]alkenyl, —C2—C8 alkynyl, —NC, amino, —CO2H, —CO2C1—Csalkyl, —OOOC1—Csalkyl, —C3—C10 cycloalkyl, —C3—C10 heterocycloalkyl, —C5—C10 aryl, and —C5—C10 heteroaryl.

### Claim 12 (depends on 8)

The compound or salt of claim 8, wherein R1 and R2 are CH3 substituted with one or more of independently selected from halo, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, nitro, cyano, alkylamino, —C1—C8 alkyl, —C2—C8 alkenyl, —C2—C8 alkynyl, —NC, amino, —CO2H, —CO2C1—C8_alkyl, —OOOC1—C8_alkyl, —C3—C10 cycloalkyl, —C3—C10 heterocycloalkyl, —C5—C10 aryl, and —C5—C10 heteroaryl.

### Claim 13 (depends on 1)

The compound or salt of claim 1, wherein R1 and R2 are CH3 substituted with one or more of independently selected —C1—C8 [[—C1-8 —C2—C8 alkenyl, and —C3—C10 cycloalkyl.

### Claim 14 (depends on 2)

The compound or salt of claim 2, wherein R1 and R2 are CH3 substituted with one or more of independently selected —C1—C8 [[—C1-8 —C2—C8 alkenyl, and —C3—C10 cycloalkyl.

### Claim 15 (depends on 7)

The compound or salt of claim 7, wherein R1 and R2 are CH3 substituted with one or more of independently selected —C1—C8 [[—C1-8 —C2—C8 alkenyl, and —C3—C10 cycloalkyl.

### Claim 16 (depends on 8)

The compound or salt of claim 8, wherein R1 and R2 are CH3 substituted with one or more of independently selected —C1—C8 [[—C1-8 —C2—C8 alkenyl, and —C3—C10 cycloalkyl.

### Claim 17 (depends on 1)

The compound or salt of claim 1, wherein R3 is

### Claim 18 (depends on 2)

The compound or salt of claim 2, wherein R3 is

### Claim 19 (depends on 2)

The compound or salt of claim 2, wherein R3 is

### Claim 20 (depends on 8)

The compound or salt of claim 8, wherein R3 is

### Claim 21 (depends on 15)

The compound or salt of claim 15, wherein R3 is

### Claim 22 (depends on 16)

The compound or salt of claim 16, wherein R3 is

### Claim 23 (depends on 1)

The compound or salt of claim 1, wherein R4 is Cl.

### Claim 24 (depends on 1)

The compound or salt of claim 1, wherein R4 is F.

### Claim 25 (depends on 2)

The compound or salt of claim 2, wherein R4 is Cl.

### Claim 26 (depends on 2)

The compound or salt of claim 2, wherein R4 is F.

### Claim 27 (depends on 7)

The compound or salt of claim 7, wherein R4 is Cl.

### Claim 28 (depends on 7)

The compound or salt of claim 7, wherein R4 is F.

### Claim 29 (depends on 8)

The compound or salt of claim 8, wherein R4 is Cl.

### Claim 30 (depends on 8)

The compound or salt of claim 8, wherein R4 is F.

### Claim 31 (depends on 21)

The compound or salt of claim 21, wherein R4 is Cl.

### Claim 32 (depends on 21)

The compound or salt of claim 21, wherein R4 is F.

### Claim 33 (depends on 22)

The compound or salt of claim 22, wherein R4 is Cl.

### Claim 34 (depends on 22)

The compound or salt of claim 22, wherein R4 is F.

### Claim 35 (depends on 1)

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

### Claim 36 (depends on 2)

A pharmaceutical composition comprising the compound or salt of claim 2 and a pharmaceutically acceptable excipient.

### Claim 37 (depends on 7)

A pharmaceutical composition comprising the compound or salt of claim 7 and a pharmaceutically acceptable excipient.

### Claim 38 (depends on 8)

A pharmaceutical composition comprising the compound or salt of claim 8 and a pharmaceutically acceptable excipient.

### Claim 39 (depends on 31)

A pharmaceutical composition comprising the compound or salt of claim 31 and a pharmaceutically acceptable excipient.

### Claim 40 (depends on 32)

A pharmaceutical composition comprising the compound or salt of claim 32 and a pharmaceutically acceptable excipient.

### Claim 41 (depends on 33)

A pharmaceutical composition comprising the compound or salt of claim 33 and a pharmaceutically acceptable excipient.

### Claim 42 (depends on 34)

A pharmaceutical composition comprising the compound or salt of claim 34 and a pharmaceutically acceptable excipient.

### Claim 43 (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 or salt of claim 1, wherein the cancer is non-small cell lung cancer, colorectal cancer, or pancreatic cancer and wherein the cancer is mediated by a KRAS G12C mutation.

### Claim 44 (depends on 2)

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 or salt of claim 2, wherein the cancer is non-small cell lung cancer, colorectal cancer, or pancreatic cancer and wherein the cancer is mediated by a KRAS G12C mutation.

### Claim 45 (depends on 7)

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 or salt of claim 7, wherein the cancer is non-small cell lung cancer, colorectal cancer, or pancreatic cancer and wherein the cancer is mediated by a KRAS G12C mutation.

### Claim 46 (depends on 8)

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 or salt of claim 8, wherein the cancer is non-small cell lung cancer, colorectal cancer, or pancreatic cancer and wherein the cancer is mediated by a KRAS G12C mutation.

### Claim 47 (depends on 31)

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 or salt of claim 31, wherein the cancer is non-small cell lung cancer, colorectal cancer, or pancreatic cancer and wherein the cancer is mediated by a KRAS G12C mutation.

### Claim 48 (depends on 32)

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 or salt of claim 32, wherein the cancer is non-small cell lung cancer, colorectal cancer, or pancreatic cancer and wherein the cancer is mediated by a KRAS G12C mutation.

### Claim 49 (depends on 33)

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 or salt of claim 33, wherein the cancer is non-small cell lung cancer, colorectal cancer, or pancreatic cancer and wherein the cancer is mediated by a KRAS G12C mutation.

### Claim 50 (depends on 34)

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 or salt of claim 34, wherein the cancer is non-small cell lung cancer, colorectal cancer, or pancreatic cancer and wherein the cancer is mediated by a KRAS G12C mutation.