Method for predicting skin sensitizing activity of compounds

Abstract

Quinoline- and isoquinoline-based compounds exhibiting ATP-utilizing enzyme inhibitory activity, methods of using compounds exhibiting ATP-utilizing enzyme inhibitory activity, and compositions comprising compounds exhibiting ATP-utilizing enzyme inhibitory activity, are disclosed.

1 . A compound of the formula 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof, wherein:
 Ar is chosen from aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 
 A is —N— and B is —CH—, or A is —CH— and B is —N—; 
 L is chosen from NR 1  and 0; 
 R 1  is chosen from H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl; 
 X and Y are independently chosen from CH and N; 
 G is chosen from a covalent bond and NR 6 ; 
 R 6  is chosen from hydrogen and optionally substituted alkyl; and 
 R is chosen from optionally substituted heterocycloalkyl, 
 with the proviso that when Ar is phenyl, A is —N—, B is —CH—, L is NR 1 , R 1  is H, X is CH, Y is CH, and G is a covalent bond, then R is not 4-methylpiperazin-1-yl. 
 
   
   
       2 - 39 . (canceled) 
   
   
       40 . A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient, and a therapeutically effective amount of at least one compound according to  claim 1 . 
   
   
       41 . The pharmaceutical composition of  claim 40 , wherein the at least one chemical entity is present in an amount effective for the treatment in a patient of a disease chosen from Alzheimer's disease, stroke, diabetes, obesity, inflammation, and cancer. 
   
   
       42 . The pharmaceutical composition of  claim 41 , wherein inflammation is chosen from Crohn's disease, rheumatoid arthritis, psoriasis, and inflammatory bowel disease. 
   
   
       43 . A method of treating a disease regulated by at least one ATP-utilizing enzyme in a subject in need of such treatment comprising administering to the patient a therapeutically effective amount of at least one compound according to  claim 1 . 
   
   
       44 . The method according to  claim 43 , wherein the disease is chosen from Alzheimer's disease, stroke, diabetes, obesity, inflammation, and cancer. 
   
   
       45 . The method of  claim 44 , wherein inflammation is chosen from Crohn's disease, rheumatoid arthritis, psoriasis, and inflammatory bowel disease. 
   
   
       46 . A method of inhibiting at least one ATP-utilizing enzyme in a subject comprising administering to the subject at least one compound according to  claim 1 . 
   
   
       47 . The method of  claim 46 , where the ATP-utilizing enzyme is chosen from a human protein kinase. 
   
   
       48 . The method of  claim 47 , wherein the human protein kinase is chosen from ABL1, AKT1, AKT2, AKT3, AURORA-A, BMX, c-TAK1, CDK1, CDK1/cyclinB, CDK2/cyclinA, CDK2/cyclinE, CDK5, CHEK1, CHEK2, CK2, CSK, DAPK1, DYRK2, FLT-3, FYN, GSK3-α, GSK3-β, HCK, INSR, KIT, LCK, LYNA, MAPKAPK2, MAPKAPK3, MSK1, MSK2, NEK2, p38-α, p38-β, p38-δ, p38-γ, P70S6K1, PAK2, PDGFR-α, PAKI, PKA, PRAK, ROCK2, SGK1, SRC, SYK, PIM-1-kinase, PDK1, and RSK2. 
   
   
       49 . The method of  claim 48 , wherein the human protein kinase is chosen from MAPKAPK2. 
   
   
       50 . A method of inhibiting at least one ATP-utilizing enzyme comprising contacting the ATP-utilizing enzyme with at least one compound according to  claim 1 . 
   
   
       51 . The method of  claim 50 , where the ATP-utilizing enzyme is chosen from a human protein kinase. 
   
   
       52 . The method of  claim 51 , wherein human protein kinase is chosen from ABL1, AKT1, AKT2, AKT3, AURORA-A, BMX, c-TAK1, CDK1, CDK1/cyclinB, CDK2/cyclinA, CDK2/cyclinE, CDK5, CHEK1, CHEK2, CK2, CSK, DAPK1, DYRK2, FLT-3, FYN, GSK3-α, GSK3-β, HCK, INSR, KIT, LCK, LYNA, MAPKAPK2, MAPKAPK3, MSK1, MSK2, NEK2, p38-α, p38-β, p38-δ, p38-γ, P70S6K1, PAK2, PDGFR-α, PAKI, PKA, PRAK, ROCK2, SGK1, SRC, SYK, PIM-1-kinase, PDK1, and RSK2. 
   
   
       53 . The method of  claim 52 , wherein the human protein kinase is chosen from MAPKAPK2. 
   
   
       54 - 55 . (canceled)