2,5-aryl-thiazole analogs for the treatment of neurodegenerative diseases

Abstract

The present disclosure is concerned with 2,5-amino-thiazole compounds that are capable of activating NF-κB signaling. The present disclosure is also concerned with methods of using these compounds for the treatment of neurological disorders such as, for example, amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, spinal muscular atrophy, traumatic brain injury, vascular dementia, Huntington's disease, mental retardation, and attention deficit and hyperactivity disorder (ADHD), and neuromuscular disorders such as, for example, Duchenne muscular dystrophy (DMD). This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

1 - 20 . (canceled) 
     
     
         21 . A compound having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from hydrogen and C1-C4 alkyl; 
         wherein R 2  is selected from —C(F)═CHCH 3 , —C(CN)═NOCH 3 , —CO 2 R 21 , —CH 2 NR 22a R 22b , —CH 2 OR 21 , —NR 23a R 23b , —C(O)NR 23a R 23b , —CH(CF 3 )NR 22a R 22b , —NR 24 SO 2 R 25 , and Cy 1 ;
 wherein each of R 21  is selected from halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and Cy 1 ; 
 wherein each of R 22a , R 22b , R 24 , and R 25  is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and Cy 1 ; 
 wherein each of R 23a  and R 23b  is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and Cy 1 , provided that each of R 23a  and R 23b , when present, is not simultaneously hydrogen; 
 wherein Cy 1  is a structure having a formula selected from: 
 
       
       
         
           
           
               
               
           
         
         wherein Ar 1  is selected from monocyclic aryl and pyridinyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, —CN, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and 
         wherein Ar 2  is selected from monocyclic aryl and pyridinyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, —CN, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         22 . The compound of  claim 21 , wherein R 2  is selected from —CO 2 R 21 , —CH 2 NR 22a R 22b , and —CH 2 OR 21 . 
     
     
         23 . The compound of  claim 21 , wherein Ar 1  is monocyclic aryl substituted with 0 groups independently selected from halogen, —CN, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. 
     
     
         24 . The compound of  claim 21 , wherein Ar 1  is pyridinyl substituted with 0 groups independently selected from halogen, —CN, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. 
     
     
         25 . The compound of  claim 21 , wherein Ar 2  is monocyclic aryl substituted with 0 groups selected from halogen, —CN, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. 
     
     
         26 . The compound of  claim 21 , wherein Ar 2  is pyridinyl substituted with 0 groups selected from halogen, —CN, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. 
     
     
         27 . The compound of  claim 21 , wherein the compound has a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         28 . The compound of  claim 21 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         29 . A compound having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from hydrogen and C1-C4 alkyl; 
         wherein R 2  is selected from —C(F)═CHCH 3 , —C(CN)═NOCH 3 , —CO 2 R 21 , —CH 2 NR 22a R 22b , —CH 2 OR 21 , —NR 23a R 23b , —C(O)NR 23a R 23b , —CH(CF 3 )NR 22a R 22b , —NR 24 SO 2 R 25 , and Cy 1 ;
 wherein each of R 21 , R 22a , R 22b , R 24 , and R 25  is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and Cy 1 ; 
 wherein each of R 23a  and R 23b  is independently selected from hydrogen, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, and Cy 1 , provided that each of R 23a  and R 23b , when present, is not simultaneously hydrogen; 
 wherein Cy 1  is a structure having a formula selected from: 
 
       
       
         
           
           
               
               
           
         
         wherein Ar 1  is selected from monocyclic aryl and pyridinyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, —CN, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and 
         wherein Ar 2  is monocyclic aryl substituted with 0, 1, or 2 groups independently selected from halogen, —CN, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         30 . The compound of  claim 29 , wherein R 2  is —CO 2 H. 
     
     
         31 . The compound of  claim 29 , wherein Ar 1  is monocyclic aryl substituted with 0 groups independently selected from halogen, —CN, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. 
     
     
         32 . The compound of  claim 29 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         33 . A compound having a structure represented by a formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is selected from hydrogen and C1-C4 alkyl; 
         wherein R 3  is selected from halogen and C1-C4 alkyl; 
         wherein Ar 1  is selected from monocyclic aryl and pyridinyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, —CN, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino; and 
         wherein each of Ar 2  and Ar 3 , when present, is selected from monocyclic aryl and pyridinyl, and is substituted with 0, 1, or 2 groups independently selected from halogen, —CN, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino, 
         provided that either Ar 3  is monocyclic aryl or R 3  is C1-C4 alkyl, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         34 . The compound of  claim 33 , wherein R 3  is halogen. 
     
     
         35 . The compound of  claim 33 , wherein R 3  is C1-C4 alkyl. 
     
     
         36 . The compound of  claim 33 , wherein Ar 1  is monocyclic aryl substituted with 0 groups independently selected from halogen, —CN, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. 
     
     
         37 . The compound of  claim 33 , wherein Ar 3  is monocyclic aryl substituted with 0, 1, or 2 groups independently selected from halogen, —CN, —NH 2 , —OH, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 alkylamino, and (C1-C4)(C1-C4) dialkylamino. 
     
     
         38 . The compound of  claim 33 , wherein the compound has a structure represented by a formula: 
       
         
           
           
               
               
           
         
       
     
     
         39 . The compound of  claim 33 , wherein the compound has a structure represented by a formula selected from: 
       
         
           
           
               
               
           
         
       
     
     
         40 . The compound of  claim 33 , wherein the compound is: