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.

What is claimed is: 
     
         1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         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 heteroaryl, or R 1a  is aryl substituted with at least one of OH, 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; 
 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 . A compound according to  claim 1 , wherein Y is N. 
     
     
         3 . A compound according to  claim 2 , wherein R 1a  is heteroaryl. 
     
     
         4 . A compound according to  claim 3 , wherein R 1a  is pyrryl, furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, thiophenyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl, or isoxazolyl. 
     
     
         5 . A compound according to  claim 4 , wherein R 1a  is benzimidazolyl. 
     
     
         6 . A compound according to  claim 1 , wherein R 2  is 2-methyl-propane. 
     
     
         7 . A compound according to  claim 1 , wherein R 3  and R 4  are H. 
     
     
         8 . A pharmaceutical composition, comprising:
 a pharmaceutically acceptable carrier; and   a compound according to  claim 1 .   
     
     
         9 . A pharmaceutical composition according to  claim 8 , further comprising at least one anthracycline compound. 
     
     
         10 . A pharmaceutical composition according to  claim 9 , wherein said anthracycline compound is daunorubicin, doxorubicin, epirubicin, idarubicin, or a mixture thereof. 
     
     
         11 . A method for treating a disease in a mammal in need thereof, comprising the steps of:
 administering to the mammal a composition comprising an effective amount of a compound according to  claim 1 .   
     
     
         12 . The method of  claim 11 , wherein Y is N. 
     
     
         13 . The method of  claim 12 , wherein R 1a  is heteroaryl. 
     
     
         14 . The method of  claim 13 , wherein pyrryl, furyl, pyridyl, 1,2,4-thiadiazolyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, thiophenyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, purinyl, carbazolyl, benzimidazolyl, or isoxazolyl. 
     
     
         15 . The method of  claim 14 , wherein R 1a  is benzimidazolyl. 
     
     
         16 . The method of  claim 11 , wherein the disease is cancer, inflammation, or metabolic disease. 
     
     
         17 . The method of  claim 16 , wherein the disease is colon cancer, ovarian cancer, leukemia, lymphoma, myeloma, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, neuroblastoma, breast cancer, acquired immunodeficiency syndrome (AIDS)-associated Kaposi's sarcoma (KS), or lung cancer. 
     
     
         18 . The method of  claim 16 , wherein the disease is diffuse inflammation, focal inflammation, croupous inflammation, interstitial inflammation, obliterative inflammation, parenchymatous inflammation, reactive inflammation, specific inflammation, toxic inflammation or traumatic inflammation. 
     
     
         19 . The method of  claim 16 , wherein the disease is obesity or diabetes. 
     
     
         20 . A method for identifying a therapeutic cancer treatment, comprising the steps of:
 (i) contacting a tumor cell culture with an effective amount of a compound according to  claim 1 ;   (ii) measuring growth inhibition of the tumor cells in culture; and   (iii) identifying a therapeutic cancer treatment for a mammalian subject by inhibition of the tumor cell growth in culture.