Heterocyclic compounds for the inhibition of pask

Abstract

Disclosed herein are new heterocyclic compounds of Formula IIa: and compositions thereof, and their application as pharmaceuticals for the treatment of disease. Methods of inhibiting PAS Kinase (PASK) activity in a human or animal subject are also provided for the treatment of diseases such as diabetes mellitus.

1 - 3 . (canceled) 
     
     
         4 . A compound of structural Formula IIa: 
       
         
           
           
               
               
           
         
         or a salt or ester thereof, wherein: 
         X 5  and X 8  are both N; 
         R 1  is chosen from phenyl, substituted with one or more substituents chosen from heterocyclyl, heteroaryl, heterarylalkyl, CN, alkoxy, alkylamino, dialkylamino, hydroxyalkyl, nitro, COOH, NR 6 SO 2 R 4 , NHSO 2 NHR 4 , NHCOR 4 , NHCONHR 4 , CONHR 4 , CONR 4a R 4b , hydroxy, OCF 3 ; and heteroaryl, optionally substituted with one or more substituents chosen from hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterarylalkyl, CN, alkoxy, alkylamino, dialkylamino, hydroxyalkyl, nitro, COOH, NR 6 SO 2 R 4 , NHSO 2 NHR 4 , NHCOR 4 , NHCONHR 4 , CONHR 4 , CONR 4a R 4b , hydroxy, OCF 3 ; 
         R 2  is chosen from alkyl and phenyl, substituted with one or more substituents chosen from heterocyclyl, heteroaryl, heterarylalkyl, CN, alkoxy, alkylamino, dialkylamino, hydroxyalkyl, nitro, COOH, NR 6 SO 2 R 4 , NHSO 2 NHR 4 , NHCOR 4 , NHCONHR 4 , CONHR 4 , CONR 4a R 4b , hydroxy, OCF 3 ; and heteroaryl, optionally substituted with one or more substituents chosen from hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterarylalkyl, CN, alkoxy, alkylamino, dialkylamino, hydroxyalkyl, nitro, COOH, NR 6 SO 2 R 4 , NHSO 2 NHR 4 , NHCOR 4 , NHCONHR 4 , CONHR 4 , CONR 4a R 4b , hydroxy, OCF 3 ; 
         R 3  is chosen from null, hydrogen, hydroxyl, C 1 -C 5  alkyl, and C 1 -C 5  alkoxy; 
         R 4 , R 4a  and R 4b  are independently chosen from C 1 -C 6  alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted; 
         R 5 , R 5a  and R 5b  are independently chosen from C 1 -C 6  alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted; and 
         R 6  is chosen from hydrogen and C 1 -C 5  alkyl; and 
         wherein R 1  and R 2 , including the optional substitution, are not the same substituent. 
       
     
     
         5 .- 6 . (canceled) 
     
     
         7 . The compound as recited in claim  1  wherein said compound has structural formula IIc: 
       
         
           
           
               
               
           
         
         or a salt or ester thereof, wherein: 
         R 1  is chosen from aryl and heteroaryl, either of which may be optionally substituted with one or more substituents chosen from hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterarylalkyl, CN, alkoxy, alkylamino, dialkylamino, hydroxyalkyl, nitro, COOH, NR 6 SO 2 R 4 , NHSO 2 NHR 4 , NHCOR 4 , NHCONHR 4 , CONHR 4 , CONR 4a R 4b , hydroxy, OCF 3 ; 
         R 2  is chosen from alkyl, aryl and heteroaryl, any of which may be optionally substituted with one or more substituents chosen from hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterarylalkyl, CN, alkoxy, alkylamino, dialkylamino, hydroxyalkyl, nitro, COOH, NR 6 SO 2 R 5 , NHSO 2 NHR 5 , NHCOR 5 , NHCONHR 5 , CONHR 5 , CONR 5   a R 5b , hydroxy, OCF 3 ; 
         R 3  is chosen from null, hydrogen, hydroxyl, C 1 -C 5  alkyl, and C 1 -C 5  alkoxy; 
         R 4 , R 4a  and R 4b  are independently chosen from C 1 -C 6  alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted; 
         R 5 , R 5a  and R 5b  are independently chosen from C 1 -C 6  alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted; and 
         R 6  is chosen from hydrogen and C 1 -C 5  alkyl. 
       
     
     
         8 . The compound as recited in claim  1  wherein said compound has structural formula IId: 
       
         
           
           
               
               
           
         
         or a salt or ester thereof, wherein: 
         X is chosen from NH, S and 0; 
         R 1  is chosen from aryl and heteroaryl, either of which may be optionally substituted with one or more substituents chosen from hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterarylalkyl, CN, alkoxy, alkylamino, dialkylamino, hydroxyalkyl, nitro, COOH, NR 6 SO 2 R 4 , NHSO 2 NHR 4 , NHCOR 4 , NHCONHR 4 , CONHR 4 , CONR 4a R 4b , hydroxy, OCF 3 ; 
         R 2  is chosen from alkyl, aryl and heteroaryl, any of which may be optionally substituted with one or more substituents chosen from hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterarylalkyl, CN, alkoxy, alkylamino, dialkylamino, hydroxyalkyl, nitro, COOH, NR 6 SO 2 R 5 , NHSO 2 NHR 5 , NHCOR 5 , NHCONHR 5 , CONHR 5 , CONR 5   a R 5b , hydroxy, OCF 3 ; 
         R 3  is chosen from null, hydrogen, hydroxyl, C 1 -C 5  alkyl, and C 1 -C 5  alkoxy; 
         R 4 , R 4a  and R 4b  are independently chosen from C 1 -C 6  alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted; 
         R 5 , R 5a  and R 5b  are independently chosen from C 1 -C 6  alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted; and 
         R 6  is chosen from hydrogen and C 1 -C 5  alkyl. 
       
     
     
         9 . The compound as recited in claim  1  wherein said compound has structural formula IIe: 
       
         
           
           
               
               
           
         
         or a salt or ester thereof, wherein: 
         R 1  is chosen from aryl and heteroaryl, either of which may be optionally substituted with one or more substituents chosen from hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterarylalkyl, CN, alkoxy, alkylamino, dialkylamino, hydroxyalkyl, nitro, COOH, NR 6 SO 2 R 4 , NHSO 2 NHR 4 , NHCOR 4 , NHCONHR 4 , CONHR 4 , CONR 4a R 4b , hydroxy, OCF 3 ; 
         R 2  is chosen from alkyl, aryl and heteroaryl, any of which may be optionally substituted with one or more substituents chosen from hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterarylalkyl, CN, alkoxy, alkylamino, dialkylamino, hydroxyalkyl, nitro, COOH, NR 6 SO 2 R 5 , NHSO 2 NHR 5 , NHCOR 5 , NHCONHR 5 , CONHR 5 , CONR 5   a R 5b , hydroxy, OCF 3 ; 
         R 4 , R 4a  and R 4b  are independently chosen from C 1 -C 6  alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted; 
         R 5 , R 5a  and R 5b  are independently chosen from C 1 -C 6  alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted; and 
         R 6  is chosen from hydrogen and C 1 -C 5  alkyl. 
       
     
     
         10 . The compound as recited in claim  1  wherein said compound has structural formula IIf: 
       
         
           
           
               
               
           
         
         or a salt or ester thereof, wherein: 
         R 1  is chosen from aryl and heteroaryl, either of which may be optionally substituted with one or more substituents chosen from hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterarylalkyl, CN, alkoxy, alkylamino, dialkylamino, hydroxyalkyl, nitro, COOH, NR 6 SO 2 R 4 , NHSO 2 NHR 4 , NHCOR 4 , NHCONHR 4 , CONHR 4 , CONR 4a R 4b , hydroxy, OCF 3 ; 
         R 2  is chosen from alkyl, aryl and heteroaryl, any of which may be optionally substituted with one or more substituents chosen from hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterarylalkyl, CN, alkoxy, alkylamino, dialkylamino, hydroxyalkyl, nitro, COOH, NR 6 SO 2 R 5 , NHSO 2 NHR 5 , NHCOR 5 , NHCONHR 5 , CONHR 5 , CONR 5   a R 5b , hydroxy, OCF 3 ; 
         R 4 , R 4a  and R 4b  are independently chosen from C 1 -C 6  alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted; 
         R 5 , R 5a  and R 5b  are independently chosen from C 1 -C 6  alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted; and 
         R 6  is chosen from hydrogen and C 1 -C 5  alkyl. 
       
     
     
         11 - 12 . (canceled) 
     
     
         13 . A method of inhibiting PASK comprising contacting PASK with a compound as recited in claim  1 . 
     
     
         14 . A method of treatment of a PASK-mediated disease comprising the administration of a therapeutically effective amount of a compound as recited in claim  1  to a patient in need thereof. 
     
     
         15 . The method as recited in  claim 14  wherein said disease is chosen from cancers, diabetes, insulin resistance, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH). 
     
     
         16 . A method of treatment of a PASK-mediated disease comprising the administration of:
 a. a therapeutically effective amount of a compound as recited in claim  1 ; and   b. another therapeutic agent.   
     
     
         17 . A compound of structural Formula IIa: 
       
         
           
           
               
               
           
         
         or a salt or ester thereof, wherein: 
         X 5  is N and X 8  is CH; or X 5  is CH and X 8  is N; 
         R 1  is chosen from phenyl, substituted with one or more substituents chosen from heterocyclyl, heteroaryl, heterarylalkyl, CN, alkoxy, alkylamino, dialkylamino, hydroxyalkyl, nitro, COOH, NR 6 SO 2 R 4 , NHSO 2 NHR 4 , NHCOR 4 , NHCONHR 4 , CONHR 4 , CONR 4a R 4b , hydroxy, OCF 3 ; and heteroaryl, optionally substituted with one or more substituents chosen from hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterarylalkyl, CN, alkoxy, alkylamino, dialkylamino, hydroxyalkyl, nitro, COOH, NR 6 SO 2 R 4 , NHSO 2 NHR 4 , NHCOR 4 , NHCONHR 4 , CONHR 4 , CONR 4a R 4b , hydroxy, OCF 3 ; 
         R 2  is chosen from 
         alkyl and phenyl, substituted with one or more substituents chosen from heterocyclyl, heteroaryl, heterarylalkyl, CN, alkoxy, alkylamino, dialkylamino, hydroxyalkyl, nitro, COOH, NR 6 SO 2 R 4 , NHSO 2 NHR 4 , NHCOR 4 , NHCONHR 4 , CONHR 4 , CONR 4a R 4b , hydroxy, OCF 3 ; and heteroaryl, optionally substituted with one or more substituents chosen from hydrogen, halo, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl, heterarylalkyl, CN, alkoxy, alkylamino, dialkylamino, hydroxyalkyl, nitro, COOH, NR 6 SO 2 R 4 , NHSO 2 NHR 4 , NHCOR 4 , NHCONHR 4 , CONHR 4 , CONR 4a R 4b , hydroxy, OCF 3 ; 
         R 3  is chosen from null, hydrogen, hydroxyl, C 1 -C 5  alkyl, and C 1 -C 5  alkoxy; 
         R 4 , R 4a  and R 4b  are independently chosen from C 1 -C 6  alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted; 
         R 5 , R 5a  and R 5b  are independently chosen from C 1 -C 6  alkyl, aryl, heteroaryl, aralkyl and heteroaralkyl, any of which may be optionally substituted; and 
         R 6  is chosen from hydrogen and C 1 -C 5  alkyl; and 
       
       wherein R 1  and R 2 , including the optional substitution, are not the same substituent. 
     
     
         18 . A pharmaceutical composition comprising a compound as recited in  claim 4  or  17 , together with a pharmaceutically acceptable carrier.