Biaryl compositions and methods for modulating a kinase cascade

• US 7,968,574 B2
• Filed: 06/29/2006
• Issued: 06/28/2011
• Est. Priority Date: 12/28/2004
• Status: Active Grant

• Current Assignee: ATNX SPV LLC (Athenex, Inc.)
• Original Assignee: Kinex Pharmaceuticals LLC
• Inventors: Hangauer, David G. Jr.
• Primary Examiner(s): Kosack; Joseph R
• Assistant Examiner(s): Coughlin; Matthew P
• Application Number:
  US11/480,174
• Publication Number:
  US 20070015752A1
• Time in Patent Office: 1,825 Days
• Field of Search: 546/323, 546/268.4, 546/337, 514/357, 514/235.5, 514/340, 544/131
• US Class Current: 514/357
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/16 Otologicals
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/20 for DNA viruses
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 233/13 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
• CPC Class Codes: C07C 233/22 having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07D 213/56 : Amides
• CPC Class Codes: C07D 213/64 : attached in position 2 or 6
• CPC Class Codes: C07D 213/74 : Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• CPC Class Codes: C07D 213/89 : with hetero atoms directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 239/26 : with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 239/34 : One oxygen atom
• CPC Class Codes: C07D 401/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond

Abstract

The invention relates to compounds and methods for modulating one or more components of a kinase cascade. The invention relates to compounds of the formula I:

or a pharmaceutically acceptable salt thereof. The compounds of the invention are useful for methods of protecting against or treating hearing loss, osteoporosis, cell proliferative disorders, obesity, diabetes, eye disease, stroke, atherosclerosis, neuropathic pain or hepatitis B.

Claims

1. A compound according to Formula IA

2. The compound of claim 1, wherein X_y is N.

3. The compound of claim 1, wherein Z is

4. The compound of claim 3, wherein at least one of R₇, R₈, R₉, R₁₀, and R₁₁ is halogen, C₁, C₂, C₃, C₄, C₅, or C₆ alkoxy, or O-benzyl.

5. The compound of claim 3, wherein m is 1.

6. The compound of claim 1, wherein R₄ and R₆ are each H.

7. The compound of claim 1, wherein the compound is selected from

8. The compound of claim 2, wherein X_a, X_c, X_d, and X_e are each C—

H.

9. The compound of claim 3, wherein n is 1.

10. The compound of claim 3, wherein R₂ is H.

11. The compound of claim 3, wherein R₁ and R₃ are each H.

12. The compound of claim 1, wherein R₅ is halogen.

13. The compound of claim 12, wherein R₅ is fluorine.

14. The compound of claim 1, wherein P is O-lower (C₁, C₂, C₃, C₄, C₅, or C₆) alkyl-K.

15. The compound of claim 3, wherein P is O-lower (C₁, C₂, C₃, C₄, C₅, or C₆) alkyl-K, X_y is N and X_a, X_c, X_d, and X_e are each C—

H.

16. The compound of claim 14, wherein P is O-lower (C₁, C₂, C₃, C₄, C₅, or C₆) linear alkyl-K.

17. The compound of claim 14, wherein P is O-lower (C₁, C₂, C₃, C₄, C₅, or C₆) branched alkyl-K.

18. The compound of claim 14, wherein P is O-lower (C₂ or C₃) alkyl-K.

19. The compound of claim 14, wherein K is selected from lower C₁, C₂, C₃, C₄, C₅, C₆ alkoxy, COOH, and tetrazole.

20. The compound of claim 15, wherein K is selected from lower C₁, C₂, C₃, C₄, C₅, C₆ alkoxy, COOH, and tetrazole.

21. The compound of claim 20, wherein n and m are each 1;

R₁, R₂, R₃ are each H;

R₈ is halogen, and R₇, R₉, R₁₀ and R₁₁ are hydrogen.

22. The compound of claim 21, wherein R₅ is halogen and R₆ is hydrogen.

23. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

24. A pharmaceutical composition comprising a compound selected from