Novel triazole compounds as transforming growth factor (TGF) inhibitors

Abstract

Novel triazole 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”)-β 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 formula (Ia), (Ib), or (Ic):  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, prodrug, tautomer, hydrate or solvate thereof, wherein: 
 R 1  is a saturated, unsaturated, or aromatic C 3 -C 20  mono-, bi- or polycyclic ring optionally containing at least one heteroatom selected from the group consisting of N, O and S, wherein R 1  can optionally be further independently substituted with at least one moiety independently selected from the group consisting of: carbonyl, halo, halo(C 1 -C 6 )alkyl, perhalo(C 1 -C 6 )alkyl, perhalo(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy, oxo, mercapto, (C 1 -C 6 )alkylthio, (C 1 -C 6 )alkoxy, (C 5 -C 10 )aryl or (C 5 -C 10 )heteroaryl, (C 1 -C 10 )aryloxy or (C 5 -C 10 )heteroaryloxy, (C 5 -C 10 )ar(C 1 -C 6 )alkyl or (C 5 -C 10 )heteroar(C 1 -C 6 )alkyl, (C 5 -C 10 )ar(C 1 -C 6 )alkoxy or (C 5 -C 10 )heteroar(C 1 -C 6 )alkoxy, HO—(C═O)—, ester, amido, ether, amino, amino(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, di(C 1 -C 6 )alkylamino(C 1 -C 6 )alkyl, (C 5 -C 10 )heterocyclyl(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl- and di(C 1 -C 6 )alkylamino, cyano, nitro, carbamoyl, (C 1 -C 6 )alkylcarbonyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylaminocarbonyl, di(C 1 -C 6 )alkylaminocarbonyl, (C 5 -C 10 )arylcarbonyl, (C 5 -C 10 )aryloxycarbonyl, (C 1 -C 6 )alkylsulfonyl, and (C 5 -C 10 )arylsulfonyl;  
 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, phenyl, (C 5 -C 10 )heteroaryl, (C 5 -C 10 )heterocyclic, (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 )heterocyclic-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 —, O 2 N—, NC—, amino, Ph(CH 2 ) 1-6 HN—, (C 1 -C 6 )alkyl HN—, (C 1 -C 6 )alkylamino, [(C 1 -C 6 )alkyl] 2 -amino, (C 1 -C 6 )alkyl-SO 2 —NH—, amino(C═O)—, aminoO 2 S—, (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 )heterocyclic-(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 5 -C 10 )heterocyclic-NH—(C═O)—, (C 3 -C 10 )cycloalkyl-NH—(C═O)— and (C 1 -C 6 )alkyl-(C═O)—O—;  
 where alkyl, alkenyl, alkynyl, phenyl, heteroaryl, heterocyclic, cycloalkyl, alkoxy, phenoxy, amino of 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 HN—, and (C 1 -C 6 )alkylHN—;  
 s is an integer from one to five; and  
 R 6  is selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, phenyl, (C 5 -C 10 )heteroaryl, (C 5 -C 10 )heterocyclic, (C 3 -C 10 )cycloalkyl, (C 1 -C 6 )alkyl-(SO 2 )—, phenyl-(SO 2 )—, H 2 N—(SO 2 )—, (C 1 -C 6 )alkyl-NH—(SO 2 )—, ((C 1 -C 6 )alkyl) 2 N—(SO 2 )—, phenyl-NH—(SO 2 )—, (phenyl) 2 N—(SO 2 )—, (C 1 -C 6 )alkyl-(C═O)—, phenyl-(C═O)—, (C 5 -C 10 )heteroaryl-(C═O)—, (C 5 -C 10 )heterocyclic-(C═O)—, (C 3 -C 10 )cycloalkyl-(C═O)—, (C 1 -C 6 )alkyl-O—(C═O)—, (C 5 -C 10 )heterocyclic-O—(C═O)—, (C 3 -C 10 )cycloalkyl-O—(C═O)—, H 2 N—(C═O)—, (C 1 -C 6 )alkyl-NH—(C═O)—, phenyl-NH—(C═O)—, (C 5 -C 10 )heteroaryl-NH—(C═O)—, (C 5 -C 10 )heterocyclic-NH—(C═O)—, (C 3 -C 10 )cycloalkyl-NH—(C═O)—, ((C 1 -C 6 )alkyl) 2 N—(C═O)—, (phenyl) 2 N—(C═O)—, phenyl-[((C 1 -C 6 )alkyl)-N]—(C═O)—, (C 5 -C 10 )heteroaryl-[((C 1 -C 6 )alkyl)-N]—(C═O)—, (C 5 -C 10 )heterocyclic-[((C 1 -C 6 )alkyl)-N]—(C═O)—, and (C 3 -C 10 )cycloalkyl-[((C 1 -C 6 )alkyl)-N]—(C═O)—;  
 where alkyl, alkenyl, alkynyl, phenyl, benzyl, heteroaryl, heterocyclic, cycloalkyl, alkoxy, phenoxy, amino of R 6  is optionally substituted with at least one moiety independently selected from the group consisting of halo, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, perhalo(C 1 -C 6 )alkyl, (C 3 -C 10 )cycloalkyl, phenyl, benzyl, (C 5 -C 10 )heterocyclic, (C 5 -C 10 )heteroaryl, (C 1 -C 6 )alkyl-SO 2 —, formyl, NC—, (C 1 -C 6 )alkyl-(C═O)—, (C 3 C 10 )cycloalkyl-(C═O)—, phenyl-(C═O)—, (C 5 -C 10 )heterocyclic-(C═O)—, (C 1 -C 10 )heteroaryl-(C═O)—, HO—(C═O)—, (C 1 -C 6 )alkyl-O—(C═O)—, (C 3 -C 10 )cycloalkyl-O—(C═O)—, (C 5 -C 10 )heterocyclic-O—(C═O)—, (C 1 -C 6 )alkyl-NH—(C═O)—, (C 3 -C 10 )cycloalkyl-NH—(C═O)—, phenyl-NH—(C═O)—, (C 5 -C 10 )heterocyclic-NH—(C═O)—, (C 5 -C 10 )heteroaryl-NH—(C═O)—, ((C 1 -C 6 )alkyl) 2 —N—(C═O)—, phenyl-[((C 1 -C 6 )alkyl)-N]—(C═O)—, hydroxy, (C 1 -C 6 )alkoxy, perhalo(C 1 -C 6 )alkoxy, (C 3 -C 10 )cycloalkyl-O—, phenoxy, (C 5 -C 10 )heterocyclic-O—, (C 5 -C 10 )heteroaryl-O—, (C 1 -C 6 )alkyl-(C═O)—O—, (C 3 -C 10 )cycloalkyl-(C═O)—O—, phenyl-(C═O)—O—, (C 5 -C 10 )heterocyclic-(C═O)—O—, (C 5 -C 10 )heteroaryl-(C═O)—O—, O 2 N—, amino, (C 1 -C 6 )alkylamino, ((C 1 -C 6 )alkyl) 2 -amino, formamidyl, (C 1 -C 6 )alkyl-(C═O)—NH—, (C 3 -C 10 )cycloalkyl-(C═O)—NH—, phenyl-(C═O)—NH—, (C 5 -C 10 )heterocyclic-(C═O)—NH—, (C 5 -C 10 )heteroaryl-(C═O)—NH—, (C 1 -C 6 )alkyl-(C═O)—[((C 1 -C 6 )alkyl)-N]—, phenyl-(C═O)—[(C 1 -C 6 )alkyl-N]—, (C 1 -C 6 )alkyl-SO 2 NH—, (C 3 -C 10 )cycloalkyl-SO 2 NH—, phenyl-SO 2 NH—, (C 5 -C 10 )heterocyclic-SO 2 NH— and (C 5 -C 10 )heteroaryl-SO 2 NH—;  
 wherein the phenyl or heteroaryl moiety of a R 6  substituent is optionally further substituted with at least one radical independently selected from the group consisting of halo, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, perfluoro(C 1 -C 6 )alkyl and perfluoro(C 1 -C 6 )alkoxy,  
 with the proviso that R 1  is not a naphthyl or phenyl; and  
 with the proviso that when R 1  is a phenyl fused with an aromatic or non-aromatic cyclic ring of 5-7 members containing up to three N atoms, said N is other than —NH or —NC 1-6 alkyl or if said N is —NH or —NC 1-6 alkyl, then R 1  must be further substituted; and  
 with the proviso that when R 1  is a phenyl fused with an aromatic or non-aromatic cyclic ring of 5-7 members containing 1-3 heteroatoms independently selected from O and S, then R 1  must be further substituted.  
 
   
   
       2 . A compound of  claim 1 , wherein R 1  is  
     
       
         
         
             
             
         
       
     
   
   
       3 . A compound of  claim 1 , wherein R 1  is  
     
       
         
         
             
             
         
       
     
   
   
       4 . A compound of  claim 1 , wherein R 1  is  
     
       
         
         
             
             
         
       
     
   
   
       5 . A compound of  claim 1 , wherein R 1  is  
     
       
         
         
             
             
         
       
     
   
   
       6 . A compound of  claim 1 , wherein R 1  is  
     
       
         
         
             
             
         
       
     
   
   
       7 . A compound of  claim 1 , wherein R 1  is  
     
       
         
         
             
             
         
       
     
   
   
       8 . A compound of  claim 1 , wherein R 1  is  
     
       
         
         
             
             
         
       
     
   
   
       9 . A compound of  claim 1 , wherein s is one to two; R 3  is hydrogen or (C 1 -C 6 )alkyl; and R 6  is H, (C 1 -C 6 )alkyl, or (C 3 -C 10 )cycloalkyl.  
   
   
       10 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier.  
   
   
       11 . A method of preventing or treating a TGF-related disease state in an animal or human comprising the step of administering a therapeutically effective amount of a compound of  claim 1  to the animal or human suffering from the TGF-related disease state.  
   
   
       12 . A method of  claim 11 , wherein said TGF-related disease state is selected from the group consisting of cancer, glomerulonephritis, diabetic nephropathy, hepatic fibrosis, pulmonary fibrosis, intimal hyperplasia and restenosis, scleroderma, and dermal scarring.