Substituted quinazolines for inhibiting kinase activity

Patent metadata

Field	Value
Publication number	US-9849139-B2
Application number	US-201615359370-A
Country	US
Kind code	B2
Filing date	Nov 22, 2016
Priority date	Aug 23, 2013
Publication date	Dec 26, 2017
Grant date	Dec 26, 2017

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 inhibiting EGFR or an EGFR mutant in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:
X 1 is C—R 2 or N;
X 2 is C—R 11 or N;
X 3 is C—R 12 ;
X 4 is C—R 13 ;
X 5 is C—R 14 ;
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 11 , R 12 , R 13 , and R 14 are independently hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, or optionally substituted carbamimidoyl; and
R 8 , R 9 , and R 10 are independently hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, sulfonyl, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted carbamimidoyl, or E;
wherein E is an electrophilic group capable of forming a covalent bond with a nucleophile; and wherein at least one of R 8 , R 9 , and R 10 is E.

2. The method of claim 1 , further comprising:
a) determining the presence or absence of an EGFR mutation in a biological sample isolated from the subject; and
b) if the EGFR mutation is determined to be present in the subject, administering to the subject a therapeutically effective amount of the compound of Formula Ia.

3. The method of claim 2 , wherein the EGFR mutation is in codon 790.

4. The method of claim 2 , wherein the EGFR mutation is del E746-A750, del E747-E749/A750P, del E747-S752/P753S, del E747-T751/Sins/A750P, del S752-I759, G719S, G719C, L861Q, L858R, T790M, or L858R/T790M.

5. The method of claim 2 , wherein the determining the presence or absence of the EGFR mutation comprises amplifying EGFR nucleic acid from the biological sample and sequencing the amplified nucleic acid.

6. The method of claim 2 , wherein the determining the presence or absence of the EGFR mutation comprises detecting a mutant EGFR polypeptide in the biological sample using a binding agent to a mutant EGFR polypeptide.

7. The method of claim 6 , wherein the binding agent is an antibody.

8. The method of claim 2 , wherein the biological sample is isolated from a tumor of the subject.

9. The method of claim 1 , wherein the subject suffers from skin cancer.

10. The method of claim 1 , wherein the subject suffers from lung cancer.

11. The method of claim 1 , further comprising administering an additional anti-cancer and/or cytotoxic agent.

12. The method of claim 10 , wherein the subject suffers from non-small cell lung cancer.

13. The method of claim 1 , wherein R 1 is hydrogen, cyano, halo, hydroxy, —CONH 2 , optionally substituted alkoxy, or optionally substituted cycloalkyloxy.

14. The method of claim 1 , wherein R 2 , R 3 , and R 4 are independently hydrogen, cyano, halo, hydroxy, carboxy, optionally substituted alkoxy, optionally substituted lower alkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, or optionally substituted aminocarbonyl.

15. The method of claim 14 , wherein R 2 and R 4 are hydrogen, and R 3 is optionally substituted morpholinyl, optionally substituted piperazinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted azetidinyl, or optionally substituted amino.

16. The method of claim 14 , wherein R 2 and R 3 are hydrogen, and R 4 is optionally substituted morpholinyl, optionally substituted piperazinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted azetidinyl, or optionally substituted amino.

17. The method of claim 1 , wherein R 5 is hydrogen, halo, cyano, optionally substituted alkoxy, or optionally substituted alkyl.

18. The method of claim 1 , wherein R 6 is hydrogen or optionally substituted amino.

19. The method of claim 1 , wherein R 7 and R 11 are independently hydrogen, cyano, optionally substituted lower alkyl, halo, or methoxy.

20. The method of claim 1 , wherein R 8 , R 9 , and R 10 are independently hydrogen, cyano, halo, hydroxy, carboxy, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, or E; wherein E is an electrophilic group capable of forming a covalent bond with a nucleophile.

21. The method of claim 20 , wherein at least one of R 8 , R 9 , and R 10 is halo or optionally substituted amino.

22. The method of claim 20 , wherein at least one of R 8 , R 9 , and R 10 is E; and wherein E is selected from

23. The method of claim 22 , wherein E is

24. The method of claim 1 , wherein R 12 is hydrogen, halo, cyano, —CONH 2 , —NHCOCH 3 , or optionally substituted lower alkyl.

25. The method of claim 1 , wherein R 13 and R 14 are independently hydrogen, cyano, optionally substituted lower alkyl, halo, or methoxy.

26. The method of claim 1 , wherein:
X 1 is C—R 2 and X 2 is C—R 11 ;
X 1 is N and X 2 is C—R 11 ; or
X 1 is C—R 2 and X 2 is N.

27. The method of claim 1 , wherein the compound of Formula Ia is a compound of Formula Ib′:

wherein:
X 1 is N or C—R 2 ;
each R 1 , R 2 , R 4 , and R 5 is independently H or halo;
R 3 is optionally substituted heterocycloalkyl; and
E is an electrophilic group capable of forming a covalent bond with a nucleophile.

28. The method of claim 27 , wherein R 1 is hydrogen.

29. The method of claim 27 , wherein X 1 is C—R 2 and R 2 is hydrogen or halo.

30. The method of claim 27 , wher

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