Substituted quinoxalines for inhibiting kinase activity

• US 10,047,059 B2
• Filed: 06/08/2017
• Issued: 08/14/2018
• Est. Priority Date: 11/12/2012
• Status: Active Grant

• Current Assignee: NeuPharma, Inc.
• Original Assignee: NeuPharma, Inc.
• Inventors: Qian, Xiangping, Zhu, Yong-liang
• Primary Examiner(s): Willis, Douglas M
• Application Number:
  US15/617,505
• Publication Number:
  US 20180022714A1
• Time in Patent Office: 432 Days
• Field of Search: 544353
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• 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 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links

Abstract

Described herein are kinase inhibitors represented by Formula I:

pharmaceutical compositions thereof, and uses thereof including but not limited to uses in treatment of cancer.

Claims

1. A method of inhibiting kinase insert domain receptor kinase activity in a subject, comprising administering to the subject a therapeutically effective amount of a compound of Formula I:

2. The method of claim 1, wherein R₁ is hydrogen, cyano, halo, hydroxy, carboxy, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, 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 optionally substituted alkynyl.

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

4. The method of claim 1, wherein R₁ is optionally substituted morpholinyl, optionally substituted piperazinyl, optionally substituted pyrrolidinyl, optionally substituted piperidinyl, optionally substituted imidazolyl, optionally substituted pyrazolyl, or optionally substituted pyridyl.

5. The method of claim 1, wherein R₂, R₃, R₄, and R₅ are independently hydrogen, halo, cyano, optionally substituted alkoxy, or optionally substituted alkyl.

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

7. The method 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.

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

9. The method of claim 1, wherein R₉ is hydrogen, optionally substituted lower alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl.

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

11. The method of claim 1, wherein R₁₁ is —

COR₁₂, —

CO₂R₁₂, —

CONR₁₂R₁₃, —

C(NR₁₄)NR₁₂R₁₃, —

C(NCN)NR₁₂R₁₃, or —

SO₂NR₁₂R₁₃.

12. The method of claim 1, wherein R₁₂ is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;

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

13. The method of claim 1, wherein R₁₂ is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heteroaryl;

and R₁₃ and R₁₄, when present, are independently hydrogen or optionally substituted alkyl.

14. The method of claim 1, wherein R₁₂ is optionally substituted aryl.

15. The method of claim 1, wherein R₁₂ is optionally substituted heteroaryl.

16. The method of claim 1, wherein R₁₂ and R₁₃, when present, are joined together with any intervening atoms to form an optionally substituted 4- to 8-membered heterocycloalkyl ring.

17. 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.

18. The method of claim 1, wherein the subject suffers from a cancer selected from the group consisting of bladder cancer, breast cancer, colorectal cancer, head and neck cancer, liver cancer, lung cancer, skin cancer, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, stomach cancer, and thyroid cancer.

19. The method of claim 1, wherein the subject suffers from a cancer selected from the group consisting of melanoma, non-small cell lung cancer, colon cancer, thyroid cancer, and ovarian cancer.

20. The method of claim 1, wherein the method further comprises administering to the subject an additional anti-cancer agent and/or cytotoxic agent.