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 II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically-acceptable salt or prodrug thereof; 
         wherein:
 Y is N or CR 5 ; 
 Z is NR 3 R 4 , halo, H, OH, alkyl, alkyloxy, or haloalkyl; 
 R 1a  is indolyl, thiazolyl, benzyl, biphenylyl, thiophenyl, pyrrolyl, or phenyl, wherein said phenyl is substituted with at least one of 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, halo, haloalkyl or haloaryl; and wherein said indolyl, thiazolyl, benzyl, biphenylyl, thiophenyl, or pyrrolyl is optionally substituted with OH, —NR 3 R 4 , —C(═O)NR 6 R 7 , —CN, NO 2 , —C(═O)O—R 3 , (C 1 -C 4 )alkyl, halo, haloalkyl or haloaryl; 
 R 1b  is indolyl, thiazolyl, benzyl, biphenylyl, thiophenyl, pyrrolyl, or phenyl wherein said indoyl, thiazolyl, benzyl, biphenylyl, thiophenyl, pyrrolyl, phenyl is optionally substituted with —OH, —NR 3 R 4 , —C(═O)NR 6 R 7 , —CN, NO 2 , —C(═O)O—R 3 , (C 1 -C 4 )alkyl, halo, 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, t-Boc, 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, —CONR 6 R 7 , —SO 2 R 6 R 7 , arylalkoxyalkyl, arylalkylalkoxy, heteroarylalkylalkoxy, aryloxyalkyl, heteroaryloxyalkyl, aryloxyaryl, aryloxyheteroaryl, alkylaryloxyaryl, alkylaryloxyheteroaryl, alkylaryloxyalkyamine, alkoxycarbonyl, aryloxycarbonyl, or heteroaryloxycarbonyl; 
 R 5  is independently H, —OH, halo, optionally monosubstituted (C 1 -C 6 )alkyl, optionally monosubstituted (C 1 -C 4 )alkoxycarbonyl, optionally monosubstituted (C 1 -C 4 )alkanoyl, carbamoyl, optionally monosubstituted (C 1 -C 4 )alkyl carbamoyl, phenyl, halophenyl, optionally monosubstituted (C 1 -C 4 )alkylphenyl, optionally monosubstituted (C 1 -C 4 )alkoxyphenyl, or optionally monosubstituted perhalo(C 1 -C 4 )alkylphenyl, wherein said optional substitution is (C 1 -C 4 )alkyl, OH, or halogen; 
 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 .- 44 . (canceled)