Inhibitors of cyclin-dependent kinases and their use

Abstract

The present invention relates to novel compounds for the inhibition of cyclindependent kinases, and more particularly, to chromenone derivatives of formula (Ia), wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and A have the meanings indicated in the claims. The invention also relates to processes for the preparation of the compounds of formula (Ia), to methods of inhibiting cyclin-dependent kinases and of inhibiting cell proliferation, to the use of the compounds of formula (Ia) in the treatment and prophylaxis of diseases, which can be treated or prevented by the inhibition of cyclindependent kinases such as cancer, to the use of the compounds of formula (Ia) in the preparation of medicaments to be applied in such diseases. The invention further relates to compositions containing a compound of formula (Ia) either alone or in combination with another active agent, in admixture or otherwise in association with an inert carrier, in particular pharmaceutical compositions containing a compound of formula (Ia) either alone or in combination with another active agent, together with pharmaceutically acceptable carrier substances and auxiliary substances.

1 . A method for the treatment of cancer in a mammal in need thereof comprising:
 administering to said mammal an effective amount of a compound of the formula (Ig), or a stereoisomer, optical isomer, a pharmaceutically acceptable salt, or a pharmaceutically acceptable solvate thereof, where the formula (Ig) is represented by:   
       
         
           
           
               
               
           
         
         
           wherein:
 R 1  is phenyl, which is unsubstituted or substituted by 1, 2, or 3 identical or different substituents selected from: halogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, nitro, SR 11 , trifluoromethyl, hydroxyl, cyano, carboxy, C 1 -C 4 alkoxycarbonyl and —C 1 -C 4 -alkylenehydroxyl; 
 R 2  and R 4  are hydrogen; 
 R 3  and R 5  are hydroxy or C 1 -C 4 -alkoxy; 
 Z is O; and 
 A is a saturated 5-membered ring represented by the following formula (I): 
 
         
       
       
         
           
           
               
               
           
         
         
           
             
               wherein: 
                R 6  is —C 1 -C 4 -alkyleneOR 11 ; 
                R 11  is hydrogen, C 1 -C 4 -alkyl, C 1 -C 4 -alkanoyl, or C 1 -C 4 -alkoxycarbonyl; and 
                R 13  is hydrogen or C 1 -C 4 -alkyl; 
             
           
         
         wherein said cancer may be treated with a cyclin dependent kinase 2 inhibitor or cyclin dependent kinase 4 inhibitor. 
       
     
     
         2 . The method of  claim 1 ;
 wherein:
 R 1  is phenyl, which is substituted by 1 or 2 identical or different substituents selected from:
 halogen and C 1 -C 4 -alkoxy; 
 
 R 2  and R 4  are hydrogen; 
 R 3  and R 5  are hydroxy or C 1 -C 4 -alkoxy; 
 R 6  is —C 1 -C 4 -alkylene-OH; and 
 R 13  is C 1 -C 4 -alkyl. 
   
     
     
         3 . The method of  claim 2 ;
 wherein:
 R 1  is phenyl, which is substituted by 1 or 2 identical or different substituents selected from:
 F, Cl, Br and —OCH 3 ; 
 
 R 2  and R 4  are hydrogen; 
 R 3  and R 5  are hydroxy; 
 R 6  is —CH 2 OH; and 
 R 13  is CH 3 . 
   
     
     
         4 . Hie method of  claim 3 ;
 wherein R 1  is phenyl, substituted with Cl in the 2-position.   
     
     
         5 . The method of  claim 3 ;
 wherein R 1  is phenyl, substituted with Br in the 2-position.   
     
     
         6 . Hie method of  claim 3 ;
 wherein R 1  is phenyl, substituted with F in the 2- and 6-positions.   
     
     
         7 . The method of  claim 3 ;
 wherein R 1  is phenyl which is substituted with Br in the 2-position and —OCH 3  in the 5-position.   
     
     
         8 . The method of  claim 1 ;
 wherein the compound of formula (Ig) is selected from the group consisting of:   (+/−)-trans-2-(2-Chloro-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one;   (+)-trans-2-(2-Chloro-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one;   (+)-trans-2-(2-Chloro-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (−)-trans-2-(2-Chloro-phenyl)-8-(2 hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one;   (−)-trans-2-(2-Chloro-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+)-trans-2-(2-Bromo-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one;   (+)-trans-2-(2-Bromo-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+)-trans-2-(4-Bromo-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one;   (+)-trans-2-(4-Bromo-phenyl)-5-hydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-7-methoxy-chromen-4-one;   (+)-trans-2-(4-Bromo-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+)-trans-2-(3-Chloro-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one;   (+)-trans-2-(3-Chloro-phenyl)-5-hydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-7-methoxy-chromen-4-one;   (+)-trans-2-(3-Chloro-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+)-trans-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-2-(2-iodophenyl)-5,7-dimethoxy-chromen-4-one;   (+)-trans-5,7-Dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-2-(2-iodophenyl)-chromen-4-one;   (+)-trans-2-(2-Fluoro-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one;   (+)-trans-2-(2-Fluoro-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one,   (+)-trans-2-(3-Fluoro-phenyl)-5,7-dimethoxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+)-trans-2-(3-Fluoro-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one;   (+)-trans-2-(2,6-Difluoro-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one;   (+)-trans-2-(2,6-Difluoro-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+/−)-trans-4-[8-(2-Hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-4-oxo-4H-chromen-2-yl]-benzonitrile;   (+/−)-trans-4-[5,7-Dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-4-oxo-4H-chromen-2-yl]-benzonitrile;   (+)-trans-4-[8-[2-Hydroxymethyl-1-methyl-pyrrolidin-3-yl]-5,7-dimethoxy-4 oxo-4H-chromen-2-yl]-benzonitrile;   (+)-trans-4-[5,7-Dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin 3 yl)-4-oxo-4H-chromen-2-yl]-benzonitrile;   (+/−)-trans-8-(2-Hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-2-(4-trifluoromethyl-phenyl)-chromen-4-one;   (+/−)-trans 5,7-Dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-2-(4-trifluoromethyl-phenyl)-chromen 4-one;   (+)-trans-8-(2-Hydroxymethyl-1 methyl-pyrrolidin-3-yl)-5,7-dimethoxy-2-(4-trifluoromethyl-phenyl)-chromen-4-one;   (+)-trans-5,7-Dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl-2-(4-trifluoromethyl-phenyl)-chromen-4-one;   (−)-trans-8-(2-Hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-2-(4-trifluoromethyl-phenyl)-chromen-4-one;   (−)-trans-5,7-Dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-2-(4-trifluoromethyl-phenyl)-chromen-4-one;   (+)-trans-8-(2-Hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-2-phenyl-chromen-4-one;   (+)-trans-5,7-Dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-2-phenyl-chromen-4-one;   (+)trans-8-(2-Hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-2-thiophen-2-yl-chromen-4-one;   (+)-trans-5,7-Dihydroxy-8-(2-hydromethyl-1-methyl-pyrrolidin-3-yl)-2-thiophen-2-yl-chromen-4-one;   (+)-trans-4-[5,7-Dihydroxy-8-(2-Hydroxymethyl-1-methyl-pyrrolidine-3-yl)-4-oxo-4H-chromen-2-yl]-3-methyl-benzonitrile;   (+)-trans-4-[8-(2-Hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-4-oxo-4H-chromen-2-yl]-3-methyl-benzonitrile;   (+/−)-trans-2-[2-Bromo-5-methoxy-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl]-5,7-dimethoxy-chromen-4-one;   (+/−)-trans-2-(2-Bromo-5-methoxy-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+)-trans-2-[2-Bromo-5-methoxy-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl]-5,7-dimethoxy-chromen-4-one;   (+)-trans-2-(2-Bromo-5-methoxy-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+/−)-trans-2-(2-bromo-5-hydroxy-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+)-trans-2-(2-bromo-5-hydroxy-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-chromen-4-one;   (+/−)-trans-2-[(3,5-Bis-trifluoromethyl)-phenyl]-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one;   (+/−)-trans-2-[(3,5-Bis-trifluoromethyl)-phenyl]-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+)-trans-2-(2-Chloro-5-methyl-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one;   (+)-trans-2-(2-Chloro-5-methyl-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+)-trans-2-[2-Bromo-5-nitro-phenyl]-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one;   (+/−)-trans-2-(2-Bromo-5 nitro-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dihydroxy-chromen-4-one;   (+/−)-trans-2-(2-Chloro-pyridin-3-yl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one;   (+/−)-trans-2-(2-Chloro-pyridin-3-yl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+/−)-trans-2-(2-Bromo-5-nitrophenyl-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dihydroxy-chromen-4-one;   (+)-trans-2-(2-Chloro-pyridin-3-yl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl-chromen-4-one;   (+/−)-trans-8-(2-Hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-2-(4-nitrophenyl)-4H-chromen-4-one;   (+/−)-trans-5,7-Dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidine-3-yl)-2-(4-nitrophenyl)-chromen-4-one;   (+/−)-trans-2-(4-Aminophenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+/−)-trans-8-(2-Hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-2-(2-methoxy-phenyl)-chromen-4-one;   (+/−)-trans-5,7-Dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-2-(2-hydroxy-1-phenyl)-chromen-4-one;   (+)-trans-3-Chloro-4-[8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-4-oxo-4H-chromen-2-yl]-benzonitrile;   (+)-trans-3-Chloro-4-[5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-4-oxo-4H-chromen-2-yl]-benzonitrile;   (+)-trans-2-(4-Bromo-2-chloro-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-1-chromen-4-one;   (+)-trans-2-(4-Bromo-2-chloro-phenyl)-5,7-dihydroxy-8-(2-hydromethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+/−)-trans-2-(2-Chloro-5-dimethylamino-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one;   (+/−)-trans-2-(2-Chloro-5-methylamino-phenyl)-5,7-dihydroxy-8-(-2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+/−)-trans-2-(2-Chloro-4-methoxy-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl) 5,7-dimethoxy-chromen-4-one;   (+/−)-trans-2-(2-Chloro-4-hydroxy-phenyl)-5,7-dihydroxy-8-[2-hydroxymethyl-1-methyl-pyrrolidin-3-yl]chromen-4-one;   (+/−)-trans 2-(2-Chloro-5-fluoro-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one;   (+/−)-trans-2-(2-Chloro-5-fluoro-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl 1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+/−)-trans-2-(2-Chloro-5-methoxy-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one;   (+/−)-trans-2-(2-Chloro-5-hydroxy-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+/−)-trans-2-(2-Chloro-5-methoxy-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+/−)-trans-2-(2-Chloro-phenyl)-8-[2-hydroxymethyl-1-(4-methoxy-phenyl)-pyrolidin-3-yl]-5,7-dimethoxy-chromen-4-one;   (+/−)-trans-2-(2-Chloro-phenyl)-5,7-dihydroxy-8-[2-hydroxymethyl-1-(4-methoxy-phenyl)-pyrrolidin-3-yl]-chromen-4-one;   (+/−)-trans-2-(2-Chloro-4-nitro-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidin-3-yl)-chromen-4-one;   (+/−)-trans-2-(2-Bromo-4-nitro-phenyl-5,7-dihydroxy-8-(2-hydroxymethyl-1-methylpyrrolidin-3-yl)-chromen-4-one;   (+/−)-trans-3-Chloro-4-[5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-4-oxo-4H-chromen-2-yl]-benzoic acid;   (+/−)-trans-3-Bromo-4-[5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-4-oxo-4H-chromen-2-yl]-benzoic acid;   (+/−)-trans 2-(2-Chloro-4-fluoro-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+/−)-trans-2-(4-Amino-2-chloro-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+/−)-trans-2-(2-Bromo-5-fluoro-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+/−)-trans-2-(4-Amino-2-bromo-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+/−)-trans-4-Chloro-3-[5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-4-oxo-4H-chromen-2-yl]-benzoic acid;   (+/−)-trans-4-Bromo-3-[5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-4-oxo-4H-chromen-2-yl]-benzoic acid;   (+/−)-trans-4-Bromo-3-[5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-4-oxo-4H-chromen-2-yl]-N-hydroxy-benzamide;   (+/−)-trans-4-Chloro-3-[5,7-dihydroxy-8-(2 hydroxylmethyl-1-methyl-pyrrolidin-3-yl)-4-oxo-4H-chromen-2-yl]-N-hydroxy-benzamide;   (+/−)-trans-3-Chloro-4-[5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-4-oxo-4H-chromen-2-yl]-N-hydroxy-benzamide;   (+/−)-trans-3-Bromo-4-[5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-4-oxo-4H-chromen-2-yl]-N-hydroxy-benzamide;   (+/−)-trans-2-(2,4-Difluoro-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+)-trans-2-(2-Chloro-3-fluoro-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one;   (+)-trans-2-(2-Chloro-3-fluoro-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+)-trans-2-(2-Bromo-3-fluoro-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one;   (+)-trans-2-(2-Bromo-3-fluoro-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+)-trans-2-(2-Bromo-5-fluoro-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one;   (+)-trans-2-(2-Bromo-5-fluoro-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+)-trans-2-(2-Chloro-5-iodo-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one;   (+)-trans-2-(2-Chloro-5-iodo-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+)-trans-2-(2-Bromo-5-chloro-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one;   (+)-trans-2-(2-Bromo-5-chloro-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+/−)-trans-2-(2-Chloro-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-1-oxy-pyrrolidin-3-yl)-chromen-4-one;   (+)-trans-2-(2-Bromo-4-nitro-phenyl)-8-(2-hydroxymethyl-1-methylpyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one;   (+)-trans-2-(2-Bromo-4-nitro-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+)-trans-2-(4-Amino-2-bromo-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one;   (+)-trans-2-(4-Amino-2-bromo-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+)-trans-2-(2-Bromo-4-methoxy-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one;   (+)-trans-2-(2-Bromo-4-methoxy-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+)-trans-2-(2-Bromo-4-hydroxy-phenyl) 5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one;   (+)-trans-2-(2,4-Dichloro-5-fluoro-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one; and   (+)-trans-2-(2,4-Dichloro-5-fluoro-phenyl-5,7-dihydroxy-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-chromen-4-one.   
     
     
         9 . The method of  claim 1 ;
 wherein the cancer is selected from the group consisting of:
 bladder cancer, breast cancer, colon cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, stomach cancer, cancer of the cervix, thyroid cancer, prostate cancer, skin cancer, leukemia, acute lymphocytic leukemia, B-cell lymphoma, hystiolytic lymphoma, Burkett's lymphoma, acute and chronic myelogenous leukemia, promyelocyte leukemia, fibrosarcoma, rhabdomyosarcoma, neuroblastoma, glioma, melanoma, seminoma, teratocarcinoma, and osteosarcoma.