Substituted pyrroline kinase inhibitors

Abstract

The present invention is directed to novel substituted pyrroline compounds useful as kinase or dual-kinase inhibitors and methods for treating or ameliorating a kinase or dual-kinase mediated disorder.

1 . A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       wherein
 R is selected from the group consisting of R a , -C 1-8 alkyl-R a , -C 2-8 alkenyl-R a , -C 2-8 alkynyl-R a  and cyano; 
 R a  is selected from the group consisting of cycloalkyl, heterocyclyl, aryl and heteroaryl; 
 R 1  is selected from the group consisting of -heterocyclyl-R 6  and -heteroaryl-R 6 ; wherein heterocyclyl and heteroaryl are attached to the azaindole nitrogen atom in the one position via a heterocyclyl or heteroaryl ring carbon atom; 
 R 5  is 1 to 2 substituents independently selected from the group consisting of -heterocyclyl-R 6  and -heteroaryl-R 6 ; 
 R 6  is 1 to 4-(C 1-8 )alkyl-heteroaryl-R 8  attached to a carbon or nitrogen atom; with the proviso that, when R 6  is attached to a carbon atom, R 6  is -heteroaryl-R 8 ; 
 R 7  is 2 substituents independently selected from the group consisting of, -(C 1-8 )alkyl-heterocyclyl-R 8  and -(C 1-8 )alkyl-heteroaryl-R 8 ; 
 R 8  is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from the group consisting of hydrogen, -C 1-8 alkyl, -(C 1-8 )alkyl-(halo) 1-3  and -(C 1-8 )alkyl-OH; 
 with the proviso that, when R 8  is attached to a carbon atom, R 8  is further selected from the group consisting of -C 1-8 alkoxy, —NH 2 , —NH(C 1-8 alkyl), —N(C 1-8 alkyl) 2 , cyano, halo, -(C 1-8 )alkoxy-(halo) 1-3 , hydroxy and nitro; 
 R 9  is 1 to 2 substituents independently selected from the group consisting of hydrogen, -C 1-8 alkoxy, —NH 2 , —NH(C 1-8 alkyl), —N(C 1-8 alkyl) 2 , cyano, (halo) 1-3 , hydroxy and nitro; 
 R 2  is one substituent attached to a carbon or nitrogen atom selected from the group consisting of —C(O)-heterocyclyl-R 8  and —C(O)-heteroaryl-R 8 ; 
 with the proviso that, when R 2  is attached to a carbon atom, R 2  is further selected from the group consisting of -heterocyclyl-R 6  and -heteroaryl-R 6 ; 
 R 3  is 1 to 3 substituents attached to a carbon atom independently selected from the group consisting of —C(O)-heterocyclyl-R 8 , —C(O)-heteroaryl-R 8 , -heterocyclyl-R 8  and -heteroaryl-R 8 ; 
 R 4  is 1 to 4 substituents attached to a carbon atom independently selected from the group consisting of —C(O)-heterocyclyl-R 8 , —C(O)-heteroaryl-R 8 , -heterocyclyl-R 8  and -heteroaryl-R 8 ; 
 R 10  is 1 to 2 substituents independently selected from the group consisting of hydrogen, —NH 2 , —NH(C 1-8 alkyl), —N(C 1-8 alkyl) 2 , cyano, (halo) 1-3 , hydroxy, nitro and oxo; and, 
 Y and Z are independently selected from the group consisting of O, S, (H,OH) and (H,H); with the proviso that one of Y and Z is O and the other is selected from the group consisting of O, S, (H,OH) and (H,H); 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The compound of  claim 1  wherein R is selected from the group consisting of R a , -C 1-4 alkyl-R a , -C 2-4 alkenyl-R a , -C 2-4 alkynyl-R a  and cyano. 
     
     
         3 . The compound of  claim 1  wherein R a  is selected from the group consisting of heterocyclyl, aryl and heteroaryl. 
     
     
         4 . The compound of  claim 1  wherein R a  is selected from the group consisting of dihydro-pyranyl, phenyl, naphthyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridinyl, azaindolyl, indazolyl, benzofuryl, benzothienyl, dibenzofuryl and dibenzothienyl. 
     
     
         5 . The compound of  claim 1  wherein R 1  is -heteroaryl-R 6 ; wherein heteroaryl is attached to the azaindole nitrogen atom in the one position via a heteroaryl ring carbon atom. 
     
     
         6 . The compound of  claim 1  wherein R 5  is 1 to 2-heteroaryl-R 6 . 
     
     
         7 . The compound of  claim 1  wherein R 5  is 1 to 2 substituents independently selected from the group consisting of -imidazolyl-R 6 , -triazolyl-R 6  and -tetrazolyl-R 6 . 
     
     
         8 . The compound of  claim 1  wherein R 6  is 1 to 4-(C 1-4 )alkyl-heteroaryl-R 8 ;
 with the proviso that, when R 6  is attached to a carbon atom, R 6  is -heteroaryl-R 8 .   
     
     
         9 . The compound of  claim 1  wherein R 7  is 2 substituents independently selected from the group consisting of -(C 1-4 )alkyl-heterocyclyl-R 8  and -(C 1-4 )alkyl-heteroaryl-R 8 . 
     
     
         10 . The compound of  claim 1  wherein R 8  is 1 to 4 substituents attached to a carbon or nitrogen atom independently selected from the group consisting of hydrogen, -C 1-4 alkyl, -(C 1-4 )alkyl-(halo) 1-3  and -(C 1-4 )alkyl-OH;
 with the proviso that, when R 8  is attached to a carbon atom, R 8  is further selected from the group consisting of -C 1-4 alkoxy, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , cyano, halo, -(C 1-4 )alkoxy-(halo) 1-3 , hydroxy and nitro.   
     
     
         11 . The compound of  claim 1  wherein R 9  is 1 to 2 substituents independently selected from the group consisting of hydrogen, -C 1-4 alkoxy, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , cyano, (halo) 1-3 , hydroxy and nitro. 
     
     
         12 . The compound of  claim 1  wherein R 2  is -heteroaryl-R 6 . 
     
     
         13 . The compound of  claim 1  wherein R 4  is 1 to 4 substituents attached to a carbon atom independently selected from the group consisting of -heterocyclyl and -heteroaryl. 
     
     
         14 . The compound of  claim 1  wherein R 10  is 1 to 2 substituents independently selected from the group consisting of hydrogen, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , cyano, (halo) 1-3 , hydroxy, nitro and oxo. 
     
     
         15 . The compound of  claim 1  wherein R 10  is 1 to 2 substituents independently selected from the group consisting of hydrogen and (halo) 1-3 . 
     
     
         16 . The compound of  claim 1  wherein R 10  is 1 to 2 substituents independently selected from the group consisting of hydrogen and (fluoro) 3 . 
     
     
         17 . The compound of  claim 1  wherein Y and Z are independently selected from the group consisting of O, S, (H,OH) and (H,H); with the proviso that one of Y and Z is O and the other is selected from the group consisting of O, S, (H,OH) and (H,H). 
     
     
         18 . The compound of  claim 1  wherein Y and Z are independently selected from the group consisting of O and (H,H); with the proviso that one of Y and Z is O, and the other is selected from the group consisting of O and (H,H). 
     
     
         19 . The compound of  claim 1  wherein Y and Z are independently selected from O.