Substituted quinazolines for inhibiting kinase activity

Patent metadata

Field	Value
Publication number	US-10653701-B2
Application number	US-201816188852-A
Country	US
Kind code	B2
Filing date	Nov 13, 2018
Priority date	Aug 23, 2013
Publication date	May 19, 2020
Grant date	May 19, 2020

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 cancer in a patient, wherein said patient has one or more mutations in the EGFR gene, comprising administering to said patient a therapeutically effective amount of a substituted quinazoline compound comprising an electrophilic group capable of forming a covalent bond with a nucleophile, or a pharmaceutically acceptable salt thereof; wherein the cancer is skin cancer or lung cancer.

2. The method of claim 1 , wherein the cancer is skin cancer.

3. The method of claim 1 , wherein the cancer is lung cancer.

4. The method of claim 3 , wherein the lung cancer is lung carcinoma or small cell lung carcinoma.

5. The method of claim 3 , wherein the lung cancer is non-small cell lung cancer (NSCLC).

6. The method of claim 1 , wherein the mutation is 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 1 , wherein the patient has an exon 19 deletion mutation.

8. The method of claim 1 , wherein the patient has L858R substitution mutation in exon 21.

9. The method of claim 1 , wherein the patient has T790M point mutation.

10. The method of claim 1 , wherein the patient has both the L858R and T790M mutations.

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

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

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

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

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

16. The method of claim 1 , wherein the substituted quinazoline is substituted at the 8 position with a substituted phenyl group and at the 2 position with a —NHR group, wherein R is an aryl or a heteroaryl substituted with an optionally substituted heterocycloalkyl.

17. The method of claim 16 , wherein the substituted phenyl group is substituted with the electrophilic group.

18. The method of claim 1 , wherein the electrophilic group is selected from the group consisting of:

19. The method of claim 18 , wherein the electrophilic group is

20. The method of claim 18 , wherein the electrophilic group is

21. The method of claim 1 , wherein the substituted quinazoline compound is a compound of Formula Ib′:

wherein:
X1 is N or C—R2;
each R1, R2, R4, and R5 is independently H or halo;
R3 is optionally substituted heterocycloalkyl; and
E is an electrophilic group capable of forming a covalent bond with a nucleophile.

22. The method of claim 1 , wherein the substituted quinazoline compound is 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)acryl amide, 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.

Assignees

• Neupharma Inc

Inventors

• Qian Xiangping
• Zhu Yong-Liang

Classifications

• C12Q2600/158

  Expression markers · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/553 Primary

  having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine · CPC title