Substituted quinazolines for inhibiting kinase activity

Patent metadata

Field	Value
Publication number	US-10172868-B2
Application number	US-201715806165-A
Country	US
Kind code	B2
Filing date	Nov 7, 2017
Priority date	Aug 23, 2013
Publication date	Jan 8, 2019
Grant date	Jan 8, 2019

Abstract

Chemical entities that are kinase inhibitors, pharmaceutical compositions and methods of treatment of cancer are described.

First claim

What is claimed is:

1. A method of treating a patient diagnosed with non-small cell lung cancer (NSCLC) comprising administering to the patient in need thereof a therapeutically effective amount of a compound selected from the group consisting of N-(3-(2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide, N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide, N-(3-(2-((2,3-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide, N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide, N-(3-(2-((2,3-difluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide, N-(3-(2-((4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide, N-(3-(2-((3-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide, N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide, N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)phenyl)acrylamide, N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide and pharmaceutically acceptable salts thereof.

2. The method of claim 1 , wherein the patient is diagnosed with metastatic NSCLC.

3. The method of claim 1 , wherein the patient is treatment naïve.

4. The method of claim 1 , wherein the patient has progressed on or after epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy.

5. The method of claim 1 , wherein the patient has one or more mutations in the EGFR gene.

6. The method of claim 5 , wherein the one or more mutations are selected from the group consisting of EGFR del E746-A750, EGFR del E747-E749/A750P, EGFR del E747-S752/P753S, EGFR del E747-T751/Sins/A750P, EGFR del S752-1759, EGFR G719S, EGFR G719C, EGFR L861Q, EGFR L858R, EGFR T790M, and EGFR L858R/T790M.

7. The method of claim 5 , wherein the patient has an exon 19 deletion mutation.

8. The method of claim 5 , wherein the patient has L858R substitution mutation in exon 21.

9. The method of claim 5 , wherein the patient has T790M point mutation.

10. The method of claim 5 , wherein the patient has both the L858R and T790M mutations.

11. The method of claim 1 , wherein the compound is administered in a unit dose ranging from about 1 mg to about 1000 mg.

12. The method of claim 1 , wherein the compound is administered in a unit dose ranging from about 1 mg to about 300 mg.

13. The method of claim 1 , wherein the compound is administered in a unit dose ranging from about 10 mg to about 200 mg.

14. The method of claim 1 , wherein the compound is administered in a dosage form comprising one or more unit doses.

15. The method of claim 1 , wherein the compound is administered in a dosage range of about 0.01 mg/kg body weight of the patient to about 100 mg/kg body weight of the patient per day.

16. The method of claim 1 , wherein the compound is N-(3-(2-((4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide.

17. The method of claim 1 , wherein the compound is N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide.

18. The method of claim 1 , wherein the compound is N-(3-(2-((2,3-difluoro-4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide.

19. The method of claim 1 , wherein the compound is N-(3-(2-((2,3-difluoro-4-(4-(2-hydroxy-2-methylpropyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide.

20. The method of claim 1 , wherein the compound is N-(3-(2-((2,3-difluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide.

21. The method of claim 1 , wherein the compound is N-(3-(2-((4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide.

22. The method of claim 1 , wherein the compound is N-(3-(2-((3-fluoro-4-(4-(2-methoxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide.

23. The method of claim 1 , wherein the compound is N-(3-(2-((2-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide.

24. The method of claim 1 , wherein the compound is N-(3-(2-((6-(4-methylpiperazin-1-yl)pyridin-3-yl)amino)quinazolin-8-yl)phenyl)acrylamide.

25. The method of claim 1 , wherein the compound is N-(3-(2-((4-(4-methylpiperazin-1-yl)phenyl)amino)quinazolin-8-yl)phenyl)acrylamide.

Assignees

• Neupharma Inc

Inventors

• Qian Xiangping
• Zhu Yong-Liang

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• A61P35/00

  Antineoplastic agents · CPC title