SUBSTITUTED PYRAZOLO[1,5-a] PYRIDINE COMPOUNDS AND THEIR METHODS OF USE

Abstract

The present invention is directed to substituted pyrazolo[1,5-a]pyridines and related methods for their synthesis and use.

1 . A substituted pyrazolo[1,5-c]pyridine compound having the following structure: 
     
       
         
         
             
             
         
       
       where, 
       R 2  is independently H or an organic radical selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, hydroxy, sulfhydryl, alkoxy, substituted alkoxy, aryloxy, substituted aryloxy, carbamoyloxy, thioalkyl, substituted thioalkyl, carbamoylthio, thioaryl, substituted thioaryl, amino, and carbamoylamino; 
       R 3  is independently H or an organic radical selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl; and 
       R 6  is independently H or an organic radical selected from the group consisting of hydroxy, sulfhydryl, alkoxy, aryloxy, thioalkyl, thioaryl, amino, halogen, alkyl, alkenyl, alkynyl, aryl, cyano, carboxyl, and carboxamido, 
       where at least one of R 2 , R 3 , and R 6  is other than a hydrogen, and in the event that R 2  is isopropyl and R 3  is 2-methylpropan-1-one, then R 6  is an organic radical other than hydrogen. 
     
   
   
       2 . A compound in accordance with structure I that is di-substituted at ring positions 2 and 3. 
   
   
       3 . A compound of  claim 1 , wherein R 2  is selected from the group consisting of lower alkyl, substituted lower alkyl, amino, aryl, or substituted aryl. 
   
   
       4 . A compound of  claim 3 , wherein R 2  is lower alkyl or mono-substituted lower alkyl. 
   
   
       5 . A compound of  claim 3 , wherein R 2  is selected from isopropyl, 2-hydroxypropan-2-yl, phenyl and mono-substituted phenyl. 
   
   
       6 . A compound of  claim 1 , wherein R 6  is H and R 2  is isopropyl. 
   
   
       7 . A compound of  claim 5 , wherein R 2  is a phenyl ring possessing either a single halogen or an alkoxy substituent. 
   
   
       8 . A compound of  claim 7 , wherein R 2  is 4-halo phenyl. 
   
   
       9 . A compound of  claim 8 , wherein R 2  is 4-fluorophenyl and R 3  is 2-methylpropan-1-one oxime. 
   
   
       10 . A compound of  claim 1 , wherein R 3  possesses the structure: 
     
       
         
         
             
             
         
       
     
     where 
     
       
         
         
             
             
         
       
     
     represents the pyrazolo[1,5-a]pyridine ring system, the carbon atom in structure II is covalently attached to ring carbon 3, and C is saturated or unsaturated, where the following apply.
 (i) when C in structure II is saturated, X and Y are each independently selected from the group consisting of —H or an organic radical selected from the group consisting of hydroxyl, amino, alkoxy, cyano, halo, sulfhydryl, thioalkyl, lower alkyl, and substituted lower alkyl, 
 (ii) when C in structure II is unsaturated, X and Y, when taken together form a double bond attached to a functional group, Z, selected from O, S, and N—R 11 , where R 11  is selected from —OH, —O—C(O)—NR 12 R 13 , —O—C(O)—R 14 , and CR 15 R 16 , and R 12 , R 13 , R 14  and R 15  are each independently selected from —H, lower alkyl, and aryl, and 
 R 10  is independently H or an organic radical selected from alkyl, substituted alkyl, aryl, substituted aryl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, and ester. 
 
   
   
       11 . The compound of  claim 10 , where R 10  is selected from lower alkyl, substituted lower alkyl, and ester. 
   
   
       12 . The compound of  claim 11 , where R 10  is isopropyl or 2-hydroxyisopropyl. 
   
   
       13 . A compound of  claim 10 , where C is unsaturated, and X and Y, when taken together with C, form a moiety selected from: ˜C═O, ˜C═S, ˜C═N—OH, ˜C═N—O—C(O)—NR 12 R 13 , ˜C═N—O—C(O)—R 14 , and ˜C═CR 15 R 16 . 
   
   
       14 . The compound of  claim 13 , where R 12  and R 13  are both hydrogen. 
   
   
       15 . A compound of  claim 1 , wherein R 3  possesses the structure: 
     
       
         
         
             
             
         
       
       where 
     
     
       
         
         
             
             
         
       
        represents the pyrazolo[1,5-a]pyridine ring system, C is covalently attached to ring carbon 3, and is unsaturated, where X and Y, when taken together with C, form a double bond to C that, when taken together with R 10 , forms pant of an aromatic heterocycle. 
     
   
   
       16 . The compound of  claim 15 , where C, together with X, Y, and R 10  forms part of an aromatic heterocycle selected from a pyridine, a pyrazole, a pyrimidine, a pyridazine, an imidazole, a 1H-imidazole-2(3H)-thione, a thiazole, and a thiazol-2(5H)-imine, each of which may optionally be mono- or di-substituted. 
   
   
       17 . The compound of  claim 16 , where C is unsaturated, and C, taken together with X, Y, and R 10 , forms a 3-pyridin-4-yl substituent, and R 2  is isopropyl. 
   
   
       18 . The compound of  claim 16 , where C is unsaturated, and C, taken together with X, Y, and R 10  forms a substituted pyrimidine ring having a substituent at the 2-position, and R 2  is isopropyl. 
   
   
       19 . The compound of  claim 18 , wherein the substituent at the 2-position of the pyrimidine ring is isopropylamino, and the pyrimidine ring is attached to the core pyrazolo[1,5-a]pyridine ring at its 4 position. 
   
   
       20 . A compound of  claim 1 , having the structure: 
     
       
         
         
             
             
         
       
       where 7 is O, N—OH, or N—O—C(O)NH 2 ; 
       W is lower alkyl or amino; and 
       V is lower alkyl or substituted phenyl. 
     
   
   
       21 . The compound of  claim 20 , where W is —CH 3  or —NH 2 , and V is isopropyl or 4-fluorophenyl. 
   
   
       22 . The compound of  claim 20 , where Z is O, W is —NH 2 , and V is isopropyl. 
   
   
       23 . The compound of  claim 20 , where Z is N—O—C(O)NH 2 , W is methyl, and V is isopropyl. 
   
   
       24 . The compound of  claim 20 , where Z is N—OH, W is methyl, and V is 4-fluorophenyl. 
   
   
       25 . A compound of  claim 1 , having the structure: 
     
       
         
         
             
             
         
       
       where R 3  is selected from: 
     
     
       
         
         
             
             
         
       
     
   
   
       26 . A compound of  claim 1 , where R 3  is selected from alkyl, substituted alkyl, alkanoyl and substituted alkanoyl. 
   
   
       27 . A compound of  claim 26 , where R 3  is selected from lower alkyl, substituted lower alkyl, lower alkanoyl, and substituted alkanoyl. 
   
   
       28 . A compound of  claim 1 , where R 3  is selected from 2-aminoethanone, 2-amino-propan-1-one, 2-methylpropan-1-one oxime, and 2-methylpropan-1-one-O-carbamoyl oxime. 
   
   
       29 . A compound of  claim 1 , where R 2  is isopropyl, R 3  is selected from 2-aminoethanone, 2-amino-propan-1-one, 2-methylpropan-1-one oxime, and 2-methylpropan-1-one-O-carbamoyl oxime, and R 6  is H. 
   
   
       30 . A compound of  claim 1 , selected from the group consisting of compound 1013 (2-amino-1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)propan-1-one), 1014 (1-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one O-carbamoyl oxime), 1019 (1-(2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-3-yl)-2-methylpropan-1-one oxime), 1103 (2-Isopropyl-3-pyridin-4-yl-pyrazolo[1,5-a]pyridine), 1137 (isopropyl-[4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]-amine, 1085 (4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-1H-imidazole-2(3H)-thione), and 1087 (4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)thiazol-2(5H)-imine). 
   
   
       31 . A pharmaceutical composition comprising a 2,3,6-substituted pyrazolo[1,5-]pyridine compound of  claim 1  and a pharmaceutically acceptable excipient.