Imidazolyl tricyclic enones as antioxidant inflammation modulators

Patent metadata

Field	Value
Publication number	US-11059792-B2
Application number	US-201615548909-A
Country	US
Kind code	B2
Filing date	Feb 12, 2016
Priority date	Feb 12, 2015
Publication date	Jul 13, 2021
Grant date	Jul 13, 2021

Abstract

Disclosed herein are compounds of the formula: (I), wherein the variables are defined herein. Also provided are pharmaceutical compositions thereof. In some aspects, the compounds and compositions provided herein may be used as antioxidant inflammation modulators. In some aspects, the present disclosure provides methods wherein the compounds and composition described herein are used for the treatment of diseases and disorders associated with inflammation and cancer.

First claim

What is claimed is:

1. A compound of the formula:

wherein:
X is —CN or —C(O)R a , wherein R a is —NH 2 ;
R 1 and R 2 are each independently hydrogen, alkyl (C≤12) , or substituted alkyl (C≤12) ;
R 3 is:
absent or hydrogen, provided that R 3 is absent when the atom to which it is bound forms part of a double bond;

R 4 is:
hydrogen, hydroxy, amino, halo, or cyano; or
alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; or
-alkanediyl (C≤6) -Y 1 wherein Y 1 is:
hydroxy, amino, halo, or cyano; or
acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , arylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups;

R 5 is:
absent, hydrogen, or hydroxy; or
alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; or
-alkanediyl (C≤6) -Y 2 ,
-arenediyl (C≤8) -Y 3 , or
-arenediyl (C≤8) -alkanediyl (C≤6) -Y 4 ,
wherein Y 2 , Y 3 , and Y 4 are each independently:
hydroxy, amino, halo, or cyano; or
alkyl (C≤12) , aryl (C≤12) , heteroaryl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups;

provided that R 5 is absent when the atom to which it is bound forms part of a double bond; and

R 6 is alkyl (C≤12) or aryl (C≤12) , or a substituted version of any of these groups;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , further defined by the formula:

wherein:
X is —CN or —C(O)R a , wherein R a is —NH 2 ;
R 1 and R 2 are each independently hydrogen, alkyl (C≤12) , or substituted alkyl (C≤12) ;
R 3 is:
absent or hydrogen, provided that R 3 is absent when the atom to which it is bound forms part of a double bond;

R 4 is:
hydrogen, hydroxy, amino, halo, or cyano; or
alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; or
-alkanediyl (C≤6) -Y 1 , wherein Y 1 is:
hydroxy, amino, halo, or cyano; or
acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; and

R 5 is:
absent, hydrogen, or hydroxy; or
alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; or
-alkanediyl (C≤6) -Y 2 ,
-arenediyl (C≤8) -Y 3 , or
-arenediyl (C≤8) -alkanediyl (C≤6) -Y 4 ,
wherein Y 2 , Y 3 , and Y 4 are each independently:
hydroxy, amino, halo, or cyano; or
alkyl (C≤12) , aryl (C≤12) , heteroaryl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups;

provided that R 5 is absent when the atom to which it is bound forms part of a double bond;

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 2 , further defined by the formula:

wherein:
R 1 and R 2 are each independently hydrogen, alkyl (C≤12) , or substituted alkyl (C≤12) ;
R 3 is:
absent or hydrogen, provided that R 3 is absent when the atom to which it is bound forms part of a double bond;

R 4 is:
hydrogen, hydroxy, amino, halo, or cyano; or
alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; or
-alkanediyl (C≤6) -Y 1 , wherein Y 1 is:
hydroxy, amino, halo, or cyano; or
acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; and

R 5 is:
absent, hydrogen, or hydroxy; or
alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups; or
-alkanediyl (C≤6) -Y 2 ,
-arenediyl (C≤8) -Y 3 , or
-arenediyl (C≤8) -alkanediyl (C≤6) -Y 4 ,
wherein Y 2, Y 3, and Y 4 are each independently:
hydroxy, amino, halo, or cyano; or
alkyl (C≤12) , aryl (C≤12) , heteroaryl (C≤12) , acyl (C≤12) , alkoxy (C≤12) , aryloxy (C≤12) , aralkoxy (C≤12) , heteroaryloxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , arylamino (C≤12) , aralkylamino (C≤12) , heteroarylamino (C≤12) , amido (C≤12) , or a substituted version of any of these groups;

provided that R 5 is absent when the atom to which it is bound forms part of a double bond;

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 3 , further defined by the formula:

wherein:
R 3 is:
absent or hydrogen, provided that R 3 is absent when the atom to which it is bound forms part of a double bond;

R 4 is:
hydrogen, hydroxy, amino, halo, or cyano; or
alkyl (C≤12) , cycloalkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , aryl (C≤12) , aralkyl (C≤12) , heteroaryl (C≤12) , heterocycloalkyl (C≤12) , acyl (C≤12) , alkoxy (C≤12

Assignees

• Reata Pharmaceuticals Inc

Inventors

• Jiang Xin
• Caprathe Bradley William
• Lee Chitase
• Bolton Gary
• Bender Christopher F
• Visnick Melean

Classifications

• C07D401/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D403/10

  linked by a carbon chain containing aromatic rings · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D235/10

  Radicals substituted by halogen atoms or nitro radicals · CPC title

• C07D403/14

  containing three or more hetero rings · CPC title