Novel pyrazole compounds as transforming growth factor (tgf) inhibitors

Abstract

Novel pyrazole 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 - 11 . (canceled) 
   
   
       12 . A compound of formula (Ia): 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt, 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 6 )alkylthio, (C 1 -C 6 )alkoxy, (C 5 -C 10 )aryl or (C 5 -C 10 )heteroaryl, (C 5 -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 o )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; 
 R 3  is independently 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 —, 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, alkenyl, 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; 
 R 4  is 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 NH—, alkylNH—, (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 )heterocyclic-(C═O)—, 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, and amino of R 4  is optionally substituted by at least one substituent independently selected from the group consisting of (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—; 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 5 -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  contains at least one heteroatom. 
 
   
   
       13 . A compound of  claim 12 , wherein R 1  is 
     
       
         
         
             
             
         
       
     
   
   
       14 . A compound of claim. 12, wherein R 1  is 
     
       
         
         
             
             
         
       
     
   
   
       15 . A compound of  claim 12 , wherein R 1  is 
     
       
         
         
             
             
         
       
     
   
   
       16 . A compound of  claim 12 , wherein R 1  is 
     
       
         
         
             
             
         
       
     
   
   
       17 . A compound of  claim 12 , wherein R 1  is 
     
       
         
         
             
             
         
       
     
   
   
       18 . A compound of  claim 12 , wherein R 1  is 
     
       
         
         
             
             
         
       
     
   
   
       19 . A compound of  claim 12 , wherein s is one to two R 3  is hydrogen or (C 1 -C 6 )alkyl; R 4  is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 10 )cycloalkyl, amino, (C 1 -C 6 )alkylamino, (C 1 -C 6 )alkyl-(C═O)—, or (C 3 -C 10 )cycloalkyl-(C═O)—; and R 6  is H or (C 1 -C 6 )alkyl, 
   
   
       20 . A pharmaceutical composition comprising a compound of  claim 12  and a pharmaceutically acceptable carrier. 
   
   
       21 . 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. 
   
   
       22 . A method of  claim 21 , 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.