Compounds and methods for kinase modulation, and indications therefor

• US 8,268,858 B2
• Filed: 12/20/2007
• Issued: 09/18/2012
• Est. Priority Date: 12/21/2006
• Status: Active Grant

• Current Assignee: Plexxikon Inc (Daiichi Sankyo Company Limited)
• Original Assignee: Plexxikon Inc (Daiichi Sankyo Company Limited)
• Inventors: Wu, Guoxian, Spevak, Wayne, Shi, Songyuan, Cho, Hanna, Ibrahim, Prabha N., Zhang, Chao, Shi, Shenghua, Zhou, Yong, Artis, Dean, Zhang, Jiazhong
• Primary Examiner(s): BIANCHI, KRISTIN A
• Application Number:
  US11/961,901
• Publication Number:
  US 20080188514A1
• Time in Patent Office: 1,734 Days
• Field of Search: 514/300, 546/113
• US Class Current: 514/300
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

Compounds active on protein kinases are described, as well as methods of using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases.

Claims

1. A compound having the chemical structure of Formula I,

2. The compound of claim 1 having the chemical structure of Formula Ij,

3. The compound of claim 1 having the chemical structure of Formula Ip,

4. The compound of claim 3

wherein:

R⁷ is selected from the group consisting of -Cy₁, -alk-Cy₁, -alk-X-(alk)_b-Cy₁, -alk-NR¹²-(alk)_b-Cy₁, -alk-C(X)-(alk)_b-Cy₁, -alk-S(O)-(alk)_b-Cy₁, -alk-S(O)₂-(alk)_b-Cy₁, -alk-OC(X)-(alk)_b-Cy₁, -alk-C(X)O-(alk)_b-Cy₁, -alk-C(X)NR¹²-(alk)_b-Cy₁, -alk-S(O)₂NR¹²-(alk)_b-Cy₁, -alk-NR¹²C(X)-(alk)_b-Cy₁, -alk-NR¹²S(O)₂-(alk)_b-Cy₁, -alk-NR¹²C(X)O-(alk)_b-Cy₁, -alk-OC(X)NR¹²-(alk)_b-Cy₁, -alk-NR¹²C(X)NR¹²-(alk)_b-Cy₁, and -alk-NR¹²S(O)₂NR¹²-(alk)_b-Cy₁;

R⁸ is selected from the group consisting of —

OR⁹, —

SR⁹, —

CR¹⁰R¹¹R⁹, —

NR¹²R⁹, —

C(O)R⁹, —

C(S)R⁹, —

S(O)R⁹, and —

S(O)₂R⁹; and

R⁹ is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

CN, —

NO₂, —

C(O)OH, —

S(O)₂NH₂, —

C(O)NH₂, —

C(S)NH₂, —

NHC(O)NH₂, —

NHC(S)NH₂, —

NHS(O)₂NH₂, —

OR¹³, —

SR¹³, —

NR¹²R¹³, —

C(O)R¹³, —

C(S)R¹³, —

C(O)OR¹³, —

C(O)NR¹²R¹³, —

C(S)NR¹²R¹³, —

S(O)₂NR¹²R¹³, —

NR¹²C(O)R¹³, —

NR¹²C(S)R¹³, —

NR¹²S(O)₂R¹³, —

NR¹²C(O)NR¹²R¹³, —

NR¹²C(S)NR¹²R¹³, —

NR¹²S(O)₂NR¹²R¹³, —

S(O)R¹³, —

S(O)₂R¹³, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.

5. The compound of claim 4 wherein R⁷ is -Cy, or -alk-Cy₁.

6. The compound of claim 5

wherein:

Cy₁ is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

CN, —

NO₂, —

S(O)₂NH₂, —

C(O)NH₂, —

OR¹³, —

NR¹²R¹³, —

C(O)R¹³, —

C(O)NR¹²R¹³, —

S(O)₂NR¹²R¹³, —

NR¹²C(O)R¹³, —

NR¹²S(O)₂R¹³, —

S(O)₂R¹³, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and

R⁹ is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

CN, —

NO₂, —

S(O)₂NH₂, —

C(O)NH₂, —

NHC(O)NH₂, —

NHS(O)₂NH₂, —

OR¹³, —

SR¹³, —

NR¹²R¹³, —

C(O)R¹³, —

C(O)NR¹²R¹³, —

S(O)₂NR¹²R¹³, —

NR¹²C(O)R¹³, —

NR¹²S(O)₂R¹³, —

NR¹²C(O)NR¹²R¹³, —

NR¹²S(O)₂NR¹²R¹³, —

S(O)₂R¹³, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.

7. A composition comprising:

a pharmaceutically acceptable carrier; and

a compound according to claim 1.

8. A kit comprising a compound according to claim 1.

9. A compound having the chemical structure of Formula I,

10. The compound of claim 9 having the chemical structure of Formula Ip,

11. A composition comprising:

a pharmaceutically acceptable carrier; and

a compound according to claim 9.