Novel fused heteroaromatic compounds as transforming growth factor (tgf) inhibitors

Abstract

Novel fused heteroaromatic compounds, including derivatives thereof, to intermediates for their preparation, to pharmaceutical compositions containing them and to their medicinal use are described. The compounds of the present invention are potent inhibitors of transforming growth factor (“TGF”)- signaling pathway. They are useful in the treatment of various TGF-related disease states including, for example, cancer and fibrotic diseases.

1 . A compound of the formula (Ia) or (Ib): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, tautomer, prodrug, hydrate, or solvate thereof, wherein:
 R 1  is an optionally substituted benzotriazole; 
 each R 3  is independently selected from the group consisting of: hydrogen, halo, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, perhalo(C 1 -C 6 )alkyl, (C 5 -C 10 )heteroaryl, (C 5 -C 10 )heterocycle, (C 3 -C 10 )cycloalkyl, hydroxy, (C 1 -C 6 )alkoxy, perhalo(C 1 -C 6 )alkoxy, phenoxy, (C 5 -C 10 )heteroaryl-O—, C 5 -C 10 )heterocycle-O—, (C 3 -C 10 )cycloalkyl-O—, (C 1 -C 6 )alkyl-S—, (C 1 -C 6 )alkyl-SO 2 —, (C 1 -C 6 )alkyl-NH—SO 2 —, nitro, cyano, amino, PH(CH 2 ) 1-6 NH—, (C 1 -C 6 )alkylamino, [(C 1 -C 6 )alkyl] 2 -amino, (C 1 -C 6 )alkyl-SO 2 —NH—, amino(C═O)—, aminoSO 2 —, (C 1 -C 6 )alkyl-(C═O)—NH—, (C 1 -C 6 )alkyl-(C═O)—[((C 1 -C 6 )alkyl-N]—, phenyl-(C═O)—NH—, phenyl-(C═O)—[((C 1 -C 6 )alkyl)-N]—, (C 1 -C 6 )alkyl-(C═O)—, phenyl-(C═O)—, (C 5 -C 10 )heteroaryl-(C═O)—, (C 5 -C 10 )heterocycle-(C═O)—, (C 3 -C 10 )cycloalkyl-(C═O)—, HO—(C═O)—, (C 1 -C 6 )alkyl-O—(C═O)—, H 2 N(C═O)—(C 1 -C 6 )alkyl-NH—(C═O)—, [(C 1 -C 6 )alkyl] 2 -N—(C═O)—, phenyl-NH—(C═O)—, phenyl-[((C 1 -C 6 )alkyl)-N]—(C═O)—, (C 5 -C 10 )heteroaryl-NH—(C═O)—, (C 3 -C 10 )cycloalkyl-NH—(C═O)— and (C 1 -C 6 )alkyl-(C═O)—O—, where R 3  is optionally substituted by at least one substituent independently selected from (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkyl, halo, H 2 N—, Ph(CH 2 ) 1-6 NH—, and (C 1 -C 6 )alkylNH—; 
 s is an integer from one to four; and 
 R 4  and R 6  taken together with the atoms to which they are attached form a core fused heteroaromatic. 
 
     
     
         2 . A compound of  claim 1 , wherein R 3  is a (C 1 -C 6 )alkyl or a (C 3 -C 10 )cycloalkyl group. 
     
     
         3 . A compound of  claim 2 , wherein R 3  is a methyl or a cyclopropyl group; 
     
     
         4 . A compound of  claim 1 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
       wherein R 2a  is independently selected from the group consisting of: hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 10 )cycloalkyl, (C 5 -C 10 )aryl, (C 1 -C 6 )alkyl(C 5 -C 10 )aryl, amino, carbonyl, carboxyl, (C 5 -C 10 )heteroaryl, (C 5 -C 10 )heterocyclyl, (C 1 -C 6 )alkoxy, nitro, halo, and hydroxyl; and where alkyl, alkenyl, alkynyl, cycloalkyl, aryl, amino, heteroaryl, heterocyclyl, and alkoxy of R 2a  is optionally substituted by at least one moiety independently selected from the group consisting of hydrogen, halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, perhalo(C 1 -C 6 )alkyl phenyl, (C 3 -C 10 )cycloalkyl, (C 5 -C 10 )heteroaryl, (C 5 -C 10 )heterocycle, formyl, —CN, (C 1 -C 6 )alkyl-(C═O)—, phenyl-(C═O)—, HO—(C═O)—, (C 1 -C 6 )alkyl-O—(C═O)—, (C 1 -C 6 )alkyl-NH—(C═O)—, ((C 1 -C 6 )alkyl) 2 -N—(C═O)—, phenyl-NH—(C═O)—, phenyl-[((C 1 -C 6 )alkyl)-N]—(C═O)—, nitro, amino, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 -amino, (C 1 -C 6 )alkyl-(C═O)—NH—, (C 1 -C 6 )alkyl-(C═O)—[((C 1 -C 6 )alkyl)-N]—, phenyl-(C═O)—NH—, phenyl-(C═O)—[((C 1 -C 6 )alkyl)-N]—, H 2 N—(C═O)—NH—, (C 1 -C 6 )alkyl-HN—(C═O)—NH—, ((C 1 -C 6 )alkyl) 2 N—(C═O)—NH—, (C 1 -C 6 )alkyl-HN—(C═O)-[((C 1 -C 6 )alkyl)-N]—, ((C 1 -C 6 )alkyl) 2 N—(C═O)—[(C 1 -C 6 )alkyl-N]—, phenyl-HN—(C═O)—NH—, (phenyl) 2 N—(C═O)—NH—, phenyl-HN—(C═O)—[((C 1 -C 6 )alkyl)-N]—, (phenyl-) 2 N—(C═O)—[((C 1 -C 6 )alkyl)-N]—, (C 1 -C 6 )alkyl-O—(C═O)—NH—, (C 1 -C 6 )alkyl-O—(C═O)—[((C 1 -C 6 )alkyl)-N]—, phenyl-O—(C═O)—NH—, phenyl-O—(C═O)—[((C 1 -C 6 )alkyl)-N]—, (C 1 -C 6 )alkyl-SO 2 NH—, phenyl-SO 2 NH—, (C 1 -C 6 )alkyl-SO 2 —, phenyl-SO 2 —, hydroxy, (C 1 -C 6 )alkoxy, perhalo(C 1 -C 6 )alkoxy, phenoxy, (C 1 -C 6 )alkyl-(C═O)—O—, phenyl-(C═O)—O—, H 2 N—(C═O)—O—, (C 1 -C 6 )alkyl-HN—(C═O)—O—, ((C 1 -C 6 )alkyl) 2 N—(C═O)—O—, phenyl-HN—(C═O)—O—, and (phenyl) 2 N—(C═O)—O—. 
     
     
         5 . (canceled) 
     
     
         6 . A compound of  claim 4 , wherein said core fused heteroaromatic is: 
       
         
           
           
               
               
           
         
       
     
     
         7 . A compound of  claim 4 , wherein said core fused heteroaromatic is: 
       
         
           
           
               
               
           
         
       
     
     
         8 . A compound of  claim 4 , wherein said core fused heteroaromatic is: 
       
         
           
           
               
               
           
         
       
     
     
         9 . A compound of  claim 4 , wherein said core fused heteroaromatic is: 
       
         
           
           
               
               
           
         
       
     
     
         10 . A compound of  claim 4 , wherein said core fused heteroaromatic is: 
       
         
           
           
               
               
           
         
       
     
     
         11 . A compound of  claim 4 , wherein said core fused heteroaromatic is: 
       
         
           
           
               
               
           
         
       
     
     
         12 . A compound of  claim 4 , wherein said core fused heteroaromatic is: 
       
         
           
           
               
               
           
         
       
     
     
         13 . A compound selected from the group consisting of: 
       1-Methyl-6-[3-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyrimidin-2-yl]-1H-benzotriazole; 
       1-Methyl-6-[2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyridin-3-yl]-1H-benzotriazole; 
       1-Methyl-6-[2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyrimidin-3-yl]-1H-benzotriazole; 
       1-Methyl-6-[6-(6-methyl-pyridin-2-yl)-imidazo[2,1-b]thiazol-5-yl]-1-benzotriazole; 
       1-Methyl-6-[6-(6-methyl-pyridin-2-yl)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-1H-benzotriazole; 
       2-Methyl-5-[2-(6-methyl-pyridin-2-yl)-imidazo[1,2-a]pyrimidin-3-yl]-2H-benzotriazole; 
       2-Methyl-5-[6-(6-methyl-pyridin-2-yl)-imidazo[2,1-b]thiazol-5-yl]-2H-benzotriazole; 
       2-Methyl-5-[6-(6-methyl-pyridin-2-yl)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-2H-benzotriazole; 
       1-Methyl-6-[6-(6-methyl-pyridin-2-yl)-2 ethylsulfanyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-1H-benzotriazole; 
       2-Methyl-5-[3-methyl-6-(6-methyl-pyridin-2-yl)-imidazo[2,1-b]thiazol-5-yl]-2H-benzotriazole; 
       2-Methyl-5-[2-methyl-6-(6-methyl-pyridin-2-yl)-imidazo[2,1-b]thiazol-5-yl]-2H-benzotriazole; 
       1-Methyl-6-[6-(6-cyclopropyl-pyridin-2-yl)-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]-1H-benzotriazole; 
       2-Methyl-5-[2-(6-methyl-pyridin-2-yl)-7H-imidazo[1,2-a]imidazol-3-yl]-2H-benzotriazole. 
     
     
         14 . (canceled) 
     
     
         15 . (canceled)