Certain chemical entities, compositions, and methods

• US 9,908,866 B2
• Filed: 04/17/2017
• Issued: 03/06/2018
• Est. Priority Date: 01/25/2012
• Status: Active Grant

• Current Assignee: NeuPharma, Inc.
• Original Assignee: NeuPharma, Inc.
• Inventors: Zhu, Yong-Iiang, Qian, Xiangping
• Primary Examiner(s): Anderson, Rebecca L
• Application Number:
  US15/489,679
• Publication Number:
  US 20170283395A1
• Time in Patent Office: 323 Days
• CPC Class Codes: A61K 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07D 241/42 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 241/44 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links

Abstract

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

Claims

1. A method of treating a disorder mediated by Raf in a subject suffering from the disorder, the method comprising administering to the subject a therapeutically effective amount of a compound of Formula II:

2. The method of claim 1, wherein R₁ is optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl.

3. The method of claim 1, wherein R₂, R₃, R₄, and R₅ are hydrogen or halo.

4. The method of claim 1, wherein R₆, R₇, R₈, and R₁₀ are independently hydrogen, cyano, or halo.

5. The method of claim 1, wherein R₉ is hydrogen or optionally substituted lower alkyl.

6. The method of claim 1, wherein R₁₁ is COR₁₂, —

CO₂R₁₂, —

CONR₁₂R₁₃, —

SO₂NR₁₂, or —

SO₂NR₁₂R₁₃.

7. The method of claim 6, wherein R₁₂ is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl;

and R₁₃ is hydrogen or optionally substituted alkyl.

8. The method of claim 6, wherein R₁₂ and R₁₃ are joined together with any intervening atoms to form an optionally substituted 4- to 8-membered heterocycloalkyl ring.

9. The method of claim 1, wherein R₉ and R₁₁ are joined together with any intervening atoms to form an optionally substituted 4- to 8-membered heterocycloalkyl ring.

10. The method of claim 1, wherein the disorder is a cancer mediated by BRAF.

11. The method of claim 10, wherein the cancer is skin cancer, lung cancer, or colon cancer.

12. A method of treating a disorder mediated by Raf in a subject suffering from the disorder, the method comprising:

a. determining the presence or absence of a BRAF mutation in a biological sample isolated from the subject; and

b. if a BRAF mutation is determined to be present in the subject, administering to the subject a therapeutically effective amount of a compound of Formula II;

13. The method of claim 12, wherein the BRAF mutation is V600E.

14. The method of claim 12, wherein R₁ is optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl.

15. The method of claim 12, wherein R₂, R₃, R₄, and R₅ are hydrogen or halo.

16. The method of claim 12, wherein R₆, R₇, R₈, and R₁₀ are independently hydrogen, cyano, or halo.

17. The method of claim 12, wherein R₉ is hydrogen or optionally substituted lower alkyl.

18. The method of claim 12, wherein R₁₁ is COR₁₂, —

CO₂R₁₂, —

CONR₁₂R₁₃, —

SO₂NR₁₂, or —

SO₂NR₁₂R₁₃.

19. The method of claim 18, wherein R₁₂ is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl;

and R₁₃ is hydrogen or optionally substituted alkyl.

20. The method of claim 18, wherein R₁₂ and R₁₃ are joined together with any intervening atoms to form an optionally substituted 4- to 8-membered heterocycloalkyl ring.

21. The method of claim 12, wherein R₉ and R₁₁ are joined together with any intervening atoms to form an optionally substituted 4- to 8-membered heterocycloalkyl ring.

22. The method of claim 12, wherein the disorder is a cancer mediated by BRAF.

23. The method of claim 22, wherein the cancer is skin cancer, lung cancer, or colon cancer.