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, —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 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 1 , wherein R 1a  or R 1b  is phenyl substituted with mono, di or tri-OH. 
     
     
         4 . A compound according to  claim 3 , wherein said phenyl is further substituted with a halo. 
     
     
         5 . A compound according to  claim 4 , wherein said halo is F. 
     
     
         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 compound according to  claim 1 , wherein R 5  is H. 
     
     
         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, independently, R 1a  is phenyl substituted at a meta position with —CH 3 , tert-butyl, —CF 3  or halo. 
     
     
         11 . A compound according to  claim 1 , wherein, independently, R 1a  is phenyl substituted at a meta position with halo, alkyl, haloalkyl, haloaryl, aryl, O-alkyl, CN, NO 2 , CO—O-R 3 , CO—N(R 3 ) 2 . 
     
     
         12 . A compound according to  claim 1 , wherein Z is F, Br Cl, or I. 
     
     
         13 . A compound according to  claim 10 , wherein Z is F, Br Cl, or I. 
     
     
         14 . A compound according to  claim 1 , selected from the group consisting of: 
       3-(4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-phenol; 
       3-(7-isopropyl-4-methylamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-phenol; 
       [5-(3-amino-phenyl)-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-methyl-amine; 
       3-(4-benzylamino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-phenol; 
       3-(4-dibenzylamino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-phenol; 
       3-[5-(3-hydroxy-phenyl)-4-methylamino-pyrrolo[2,3-d]pyrimidin-7-yl]-propionic acid tert-butyl ester; 
       3-[5-(3-hydroxy-phenyl)-4-methylamino-pyrrolo[2,3-d]pyrimidin-7-yl]-propionic acid; 
       3-bromo-5-(7-isopropyl-4-methylamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-phenol; 
       3-(7-isopropyl-4-methylamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-methyl-phenol; 
       3-tert-Butyl-5-(7-isopropyl-4-methylamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-phenol; 
       3-(7-Isopropyl-4-methylamino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-trifluoromethyl-phenol; 
       3-bromo-5-(4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-phenol; 
       3-(4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-methyl-phenol; 
       3-tert-butyl-5-(4-chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-phenol; and 
       3-(4-Chloro-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-5-trifluoromethyl-phenol 
       or a pharmaceutically-acceptable salt or prodrug thereof. 
     
     
         15 . A compound according to  claim 1 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         16 . A compound according to  claim 15 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         17 . A compound according to  claim 1 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         18 . A compound according to  claim 1 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         19 . A compound according to  claim 18 , wherein said compound has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         20 . A pharmaceutical composition, comprising:
 a pharmaceutically acceptable carrier; and   a compound according to  claim 1 .   
     
     
         21 . A pharmaceutical composition according to  claim 20 , further comprising at least one anthracycline compound. 
     
     
         22 . A pharmaceutical composition according to  claim 21 , wherein said anthracycline compound is daunorubicin, doxorubicin, epirubicin, idarubicin, or a mixture thereof. 
     
     
         23 . A method for preventing or treating a disease or condition associated with carbonyl reductase 1 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 .   
     
     
         24 . The method of  claims 23 , wherein said composition further comprises an effective amount of an anthracycline compound. 
     
     
         25 . The method of  claim 23 , wherein the anthracycline compound is daunorubicin, doxorubicin, epirubicin, idarubicin or a mixture thereof. 
     
     
         26 . The method of  claim 23 , wherein the potency of the anthracycline compound is maintained in the absence of a cardiotoxic side effect. 
     
     
         27 . The method of  claim 23 , wherein the disease or condition is cancer, metastatic cancer, colon cancer, ovarian cancer, leukemia, lymphoma, myeloma, acute myeloid leukemia, acute lymphocytic leukemia, chronic myelogenous leukemia, neuroblastoma, lung cancer, breast cancer, acquired immunodeficiency syndrome (AIDS)-associated Kaposi's sarcoma (KS), inflammation, obesity, or diabetes. 
     
     
         28 . The method of  claim 23 , wherein the disease state or condition is acquired immunodeficiency syndrome (AIDS)-associated Kaposi's sarcoma (KS). 
     
     
         29 . A method of preventing or treating a disease or condition associated with the synthesis of prostaglandin E 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  and inhibiting synthesis of prostaglandin E2.   
     
     
         30 . The method of  claim 29 , wherein the disease or condition is metastatic cancer. 
     
     
         31 . The method of  claim 29 , wherein the disease or condition is colon cancer. 
     
     
         32 . A method for preventing or treating a disease or condition associated with short chain dehydrogenase/reductase (SDR) family of NAD(P)(H) dependent oxido-reductases in a mammal in need thereof, comprising the step of:
 administering to the mammal an effective amount of a compound according to  claim 1 .   
     
     
         33 . The method of  claim 32 , wherein the short chain dehydrogenase/reductase (SDR) family of NAD(P)(H) dependent oxido-reductase is an 11β-hydroxysteroid dehydrogenase I. 
     
     
         34 . The method of  claim 32 , wherein the short chain dehydrogenase/reductase (SDR) family of NAD(P)(H) dependent oxido-reductase is an 11β-hydroxysteroid dehydrogenase II. 
     
     
         35 . The method of  claim 32 , wherein the compound stimulates synthesis of cortisol. 
     
     
         36 . The method of  claim 35  wherein the disease state is inflammation. 
     
     
         37 . The method of  claim 32 , wherein the compound stimulates degradation of cortisone. 
     
     
         38 . The method of  claim 37 , wherein the disease is obesity, diabetes, or a combination thereof. 
     
     
         39 . The method of  claim 32 , wherein the short chain dehydrogenase/reductase (SDR) family of NAD(P)(H) dependent oxido-reductase is an 17β-hydroxysteroid dehydrogenase. 
     
     
         40 . The method of  claim 39 , wherein the disease is inflammation, ovarian cancer, breast cancer, or a combination thereof. 
     
     
         41 . A method for identifying a therapeutic cancer treatment, comprising the steps of:
 contacting a tumor cell culture with an effective amount of a according to  claim 1 ;   measuring growth inhibition of the tumor cells in culture; and   identifying a therapeutic cancer treatment for a mammalian subject by inhibition of the tumor cell growth in culture.   
     
     
         42 . A method for preventing or treating cancer in a mammal, comprising the step of:
 administering to the mammal an effective amount of a compound according to  claim 1 .   
     
     
         43 . The method of  claim 42 , wherein said cancer is lung cancer. 
     
     
         44 . The method of  claim 42 , wherein the cancer is metastatic cancer, 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).