CERTAIN CHEMICAL ENTITIES, COMPOSITIONS, AND METHODS

• US 20180230128A1
• Filed: 01/19/2018
• Published: 08/16/2018
• Est. Priority Date: 01/25/2012
• Status: Active Grant

• Current Assignee: NeuPharma, Inc.
• Original Assignee: NeuPharma, Inc.
• Inventors: ZHU, Yong-Liang, QIAN, Xiangping
• Granted Patent: US 10,590,106 B2
• Time in Patent Office: 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 compound of Formula II

3. The compound or pharmaceutically acceptable salt of claim 1, wherein R₁ is hydrogen, cyano, optionally substituted alkoxy, optionally substituted cycloalkyloxy, optionally substituted aryloxy, optionally substituted amino, optionally substituted alkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

4. The compound or pharmaceutically acceptable salt of claim 3, wherein R₁ is optionally substituted aryl, optionally substituted heterocycloalkyl, or optionally substituted heteroaryl.

6. The compound or pharmaceutically acceptable salt of claim 1, wherein R₂, R₃, R₄, and R₅ are independently hydrogen, halo, cyano, optionally substituted alkoxy, or optionally substituted alkyl.

7. The compound or pharmaceutically acceptable salt of claim 6, wherein R₂, R₃, R₄, and R₅ are independently hydrogen or halo.

9. The compound or pharmaceutically acceptable salt of claim 1, wherein R₆, R₇, R₈, and R₁₀ are independently hydrogen, cyano, halo, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, or optionally substituted aminosulfonyl.

10. The compound or pharmaceutically acceptable salt of claim 9 wherein R₆, R₇, R₈, and R₁₀ are independently hydrogen, cyano, or halo.

13. The compound or pharmaceutically acceptable salt of claim 1, wherein R₉ is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

14. The compound or pharmaceutically acceptable salt of claim 13, wherein R₉ is hydrogen or optionally substituted lower alkyl.

15. The compound or pharmaceutically acceptable salt of claim 14, wherein R₉ is hydrogen.

16. The compound or pharmaceutically acceptable salt of claim 1, wherein R₁₁ is —

COR₁₂, —

CO₂R₁₂, —

CONR₁₂R₁₃, —

C(NR₁₄)NR₁₂R₁₃, —

C(NCN)NR₁₂R₁₃, —

SO₂NR₁₂, or —

SO₂NR₁₂R₁₃.

17. The compound or pharmaceutically acceptable salt of claim 16, wherein R₁₁ is —

COR₁₂, —

CO₂R₁₂, —

CONR₁₂R₁₃, —

SO₂NR₁₂, or —

SO₂NR₁₂R₁₃.

19. The compound or pharmaceutically acceptable salt of claim 16, wherein R₁₂ is optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

and R₁₃ and R₁₄ are independently hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, or optionally substituted heterocycloalkyl.

21. The compound or pharmaceutically acceptable salt of claim 16, 16, wherein R₁₂ and R₁₃ are joined together with any intervening atoms to form an optionally substituted 4- to 8-membered heterocycloalkyl ring.

22. The compound or pharmaceutically acceptable salt 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.

24. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound or pharmaceutically acceptable salt of claim 1.

25. The pharmaceutical composition of claim 24, wherein the composition is formulated in a form chosen from the group consisting of tablets, capsules, powders, liquids, suspensions, suppositories, and aerosols.

27. A method of treating a cancer in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of the compound or pharmaceutically acceptable salt of claim 1.

29. The method of claim 27, wherein the cancer is melanoma, non-small cell lung cancer, colon cancer, thyroid cancer, or ovarian cancer.

30. A method of treating a disorder mediated by Raf in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound or pharmaceutically acceptable salt of claim 1.

31. A method of treating a disorder in a subject in need thereof, 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 or pharmaceutically acceptable salt of claim 1.

2. (canceled)

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18. (canceled)

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32-41. -41. (canceled)