# US 10,246,438 B2 · Non-selective kinase inhibitors

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- Number: US 10,246,438 B2
- Document ID: US10246438B2
- Status: Granted
- Kind: B2
- Application number: 15/660,551
- Filed: 2017-07-26
- Published: 2018-06-14
- Granted: 2019-04-02
- Earliest claimed: 2013-01-10
- Assignees: Pulmokine, Inc.
- Applicants: Pulmokine, Inc.; Gilead Sciences, Inc.
- Inventors: Lawrence S Zisman
- Web page: https://patentgrep.com/patent/US10246438B2

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61K 31/4965: Non-condensed pyrazines
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/08: for glucose homeostasis (pancreatic hormones A61P5/48)
- A61P 5/14: of the thyroid hormones, e.g. T3, T4
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 7/06: Antianaemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/12: Antihypertensives
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 33/12: Schistosomicides
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 241/20: Nitrogen atoms (nitro radicals C07D241/16)
- C07D 403/12: linked by a chain containing hetero atoms as chain links
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Disclosed herein are compounds, compositions, and methods for preventing and treating proliferative diseases associated with aberrant receptor tyrosine kinase (RTK) activity. The therapeutic indications described herein more specifically relate to the non-selective inhibition of RTKs associated with vascular and pulmonary disorders.

## Claims

### Claim 1

A method of reducing phosphorylation of an extracellular signal-regulated kinase (ERK), the method comprising administering to a subject a therapeutically-effective amount of a compound of the formula:
or a pharmaceutically-acceptable salt thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the ERK is ERK1.

### Claim 3 (depends on 1)

The method of claim 1, wherein the ERK is ERK2.

### Claim 4 (depends on 1)

The method of claim 1, wherein the phosphorylation is PDGFBB-stimulated phosphorylation.

### Claim 5 (depends on 1)

The method of claim 1, wherein the reduction in phosphorylation is measured in human lung fibroblasts.

### Claim 6 (depends on 1)

The method of claim 1, wherein the reduction is observed at a concentration of 1 μM of the compound.

### Claim 7 (depends on 1)

The method of claim 1, wherein the reduction is observed at a concentration of 10 μM of the compound.

### Claim 8 (depends on 1)

The method of claim 1, wherein the administration is by inhalation.

### Claim 9 (depends on 1)

The method of claim 1, wherein the administration is oral.

### Claim 10 (depends on 1)

The method of claim 1, wherein the method inhibits a kinase receptor.

### Claim 11 (depends on 10)

The method of claim 10, wherein the kinase receptor is a receptor tyrosine kinase.

### Claim 12 (depends on 11)

The method of claim 11, wherein the receptor tyrosine kinase is c-Kit.

### Claim 13 (depends on 11)

The method of claim 11, wherein the receptor tyrosine kinase is PDGFR.

### Claim 14

A method of reducing phosphorylation of a serine/threonine kinase, the method comprising administering to a subject a therapeutically-effective amount of a compound of the formula:
or a pharmaceutically-acceptable salt thereof, wherein the serine/threonine kinase is AKT.

### Claim 15 (depends on 14)

The method of claim 14, wherein the phosphorylation is PDGFBB-stimulated phosphorylation.

### Claim 16 (depends on 14)

The method of claim 14, wherein the reduction in phosphorylation is measured in human lung fibroblasts.

### Claim 17 (depends on 14)

The method of claim 14, wherein the reduction is observed at a concentration of 1 μM of the compound.

### Claim 18 (depends on 14)

The method of claim 14, wherein the reduction is observed at a concentration of 10 μM of the compound.

### Claim 19 (depends on 14)

The method of claim 14, wherein the administration is by inhalation.

### Claim 20 (depends on 14)

The method of claim 14, wherein the administration is oral.