Pyrazolo pyrimidine derivatives and methods of use thereof

Abstract

This invention generally relates to pyrazolo pyrimidine derivatives useful as, inter alia, inhibitors of short chain dehydrogenase/reductase (SDR) family of NAD(P)(H) dependent oxido-reductases. More specifically, the invention relates to pyrazolo pyrimidine derivatives, including derivatives and analogs of SDR inhibitors, pharmaceutical compositions containing derivatives and analogs of SDR inhibitors, methods of making derivatives and analogs of SDR inhibitors and methods of use thereof.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically-acceptable salt thereof; 
         wherein:
 Y is N; 
 Z is NR 3 R 4 , halo, H, OH, alkyl, alkyloxy, or haloalkyl; 
 R 1a  is benzyl or phenyl, wherein said benzyl or phenyl is optionally substituted with one or two OH, —NR 3 R 4 , —C(═O)NR 6 R 7 , —CN, NO 2 —C(═O)OH, —C(═O)O-alkyl, (C 1 -C 4 )alkyl, haloalkyl or haloaryl; 
 R 2  is C 1 -C 6  alkyl or C 4 -C 7  cycloalkyl, wherein said alkyl or said cycloalkyl is optionally substituted with mono- or di-alkoxy, mono- or di-halophenyl, mono- or di-(C 1-4 )alkoxy phenyl, mono- or di-(C 1-4 )alkyl phenyl, perhalo(C 1-4 )alkyl phenyl, carboxyl, tert-butyl carboxyl, phosphoryl, (C 1-6 )alkyl, (C 4-7 )cycloalkyl, indolyl, isoindolyl, pyridyl, naphthyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, or alkylmorpholino; 
 R 3  and R 4  are independently H, C 1 -C 6  alkyl, tert-butyloxycarbonyl, morpholino(C 1 -C 4 )alkyl, carboxy(C 1 -C 3 )alkyl, (C 1 -C 4 )alkoxycarbonyl(C 1 -C 3 )alkyl, aryl, heteroaryl, aryloxy, heterocycle, cycloalkyl, alkenyl with the proviso that the double bond of the alkenyl is not present at the carbon atom that is directly linked to N, alkynyl with the proviso that the triple bond of the alkynyl is not present at the carbon atom that is directly linked to N, perfluoroalkyl, —S(O) 2 alkyl, —S(O) 2 aryl, —(C═O)heteroaryl, —(C═O)aryl, —(C═O)(C 1 -C 6 ) alkyl, —(C═O)cycloalkyl, —(C═O)heterocycle, alkyl-heterocycle, aralkyl, arylalkenyl, —CON R 6 R 7 , —SO 2 R 6 R 7 , arylalkoxyalkyl, arylalkylalkoxy, heteroarylalkylalkoxy, aryloxyalkyl, heteroaryloxyalkyl, aryloxyaryl, aryloxyheteroaryl, alkylaryloxyaryl, alkylaryloxyheteroaryl, alkylaryloxyalkyamine, alkoxycarbonyl, aryloxycarbonyl, or heteroaryloxycarbonyl; 
 R 6  and R 7  are independently H, alkyl, aryl, heteroaryl, alkylaryl, arylalkyl, heteroarylalkyl, or alkylheteroaryl; 
 provided the compound is not 1-tert-butyl-3-p-tolyl-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine. 
 
       
     
     
         2 . A compound according to  claim 1 , wherein R 1a  is benzyl optionally substituted with mono, di or tri —OH. 
     
     
         3 . A compound according to  claim 1 , wherein R 1a  is phenyl optionally substituted with mono, di or tri-OH. 
     
     
         4 . (canceled) 
     
     
         5 . (canceled) 
     
     
         6 . A compound according to  claim 1 , wherein R 2  is C 1 -C 6  alkyl. 
     
     
         7 . A compound according to  claim 1 , wherein Z is NR 3 R 4 ; and R 3  and R 4  are H. 
     
     
         8 . A compound according to  claim 1 , wherein R 2  is C 1 -C 6  alkyl optionally substituted with alkoxy. 
     
     
         9 . A compound according to  claim 1 , wherein R 6  is H and R 7  is methyl. 
     
     
         10 . A compound according to  claim 1 , wherein, R 1a  is phenyl optionally substituted with —CH 3 . 
     
     
         11 . A compound according to  claim 1 , wherein R 1a  is phenyl substituted with —NH 2 . 
     
     
         12 .- 14 . (canceled) 
     
     
         15 . A compound or pharmaceutically-acceptable salt according to  claim 1 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 2  is isopropyl, tert-butyl, or ethoxyethyl. 
     
     
         16 . A compound or pharmaceutically-acceptable salt according to  claim 15 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         17 . (canceled) 
     
     
         18 .- 19 . (canceled) 
     
     
         20 . A pharmaceutical composition, comprising:
 a pharmaceutically acceptable carrier; and   a compound or pharmaceutically-acceptable salt according to  claim 1 .   
     
     
         21 .- 44 . (canceled) 
     
     
         45 . A compound or pharmaceutically-acceptable salt according to  claim 1 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 2  is isopropyl, tert-butyl, or ethoxyethyl. 
     
     
         46 . A compound or pharmaceutically-acceptable salt according to  claim 45 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         47 . A compound or pharmaceutically-acceptable salt according to  claim 1 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
       wherein R 2  is isopropyl, tert-butyl, or ethoxyethyl. 
     
     
         48 . A compound or pharmaceutically-acceptable salt according to  claim 47 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         49 . A compound or pharmaceutically-acceptable salt according to  claim 1 , wherein said compound has the formula: