Heterocyclic substituted 1,4-dihydro-4-oxo-1,8-naphthpyridine analogs

Abstract

The present invention relates to 1,4-dihydro-4-oxo-1,8-napthpyridine analogs of the formula and pharmaceutically acceptable salts, esters, and prodrugs thereof, wherein A, X, W and Y are substituents. The present invention also relates to methods for using such compounds.

1 - 27 . (canceled)  
     
     
         28 . A method for identifying a compound that interacts with a quadruplex-forming region of DNA, comprising 
 a) contacting a nucleic acid capable of forming a quadruplex with a primer comprising a label to form a complex;    b) contacting said complex with one or more test compounds and a polymerase to form a reaction mixture, and    c) separating said reaction mixture by capillary electrophoresis to obtain one or more reaction products; and    d) determining the extent of primer extension in said one or more reaction products.    
     
     
         29 . The method of  claim 28 , further comprising the step of determining the binding affinity of said one or more test compounds for said nucleic acid.  
     
     
         30 . The method of  claim 28 , wherein said label is a fluorescent label.  
     
     
         31 - 42 . (canceled)  
     
     
         43 . The method of  claim 28 , wherein the quadruplex-forming DNA is from an oncogene DNA sequence.  
     
     
         44 . The method of  claim 43 , wherein the oncogene is the MYC, HIF, VEGF, ABL, TGF, PDGFA, MYB, SPARC, HUMTEL, HER, VAV, RET, H-RAS, EGF, SRC, BCL1, or BCL2 oncogene.  
     
     
         45 . The method of  claim 28 , wherein the quadruplex forming DNA is from a viral DNA sequence.  
     
     
         46 . The method of  claim 45 , wherein the virus is HIV.  
     
     
         47 . The method of  claim 28 , wherein the primer is covalently linked to the label.  
     
     
         48 . The method of  claim 28 , wherein the label is a radioactive isotope, an enzyme, a protein, or a chromagenic label.  
     
     
         49 . The method of  claim 28 , wherein the polymerase is Taq polymerase.  
     
     
         50 . The method of  claim 28 , wherein the reaction mixture further comprises an ion.  
     
     
         51 . The method of  claim 50 , wherein the ion is potassium.  
     
     
         52 . The method of  claim 28 , further comprising the step of denaturing the primer/template complex mixture and then renaturing the complex prior to adding the test compound.  
     
     
         53 . A method for treating a cell proliferative disorder in a subject or system, comprising administering to said subject or system, an effective amount of the compound of formula (1) or a pharmaceutical composition thereof, thereby treating said cell-proliferative disorder, said compound having formula (1)  
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof; wherein:  
         W is NR 1 R 2  or NR 1 —(CR 1   2 ) n —NR 3 R 4 ;  
         Z is OR 2 , NH 2 , NR 1 R 2  or NR 1 —(CR 1   2 ) n —NR 3 R 4 ;  
         wherein in NR 1 R 2  and NR 3 R 4 , R 1  and R 2  together with N and R 3  and R 4  together with N may form an optionally substituted 5-6 membered ring containing N, O, or S;  
         A is H, halo or NR 1   2 ;  
         R 1  and R 3  are independently H or a C 1-6  alkyl;  
         R 2  is a C 1-10  alkyl or C 2-10  alkenyl optionally containing one or more non-adjacent heteroatoms selected from N, O, and S, and optionally substituted with a C 3-6  cycloalkyl, aryl, or a 5-14 membered heterocyclic ring containing N, O, or S; or R 2  is an aryl, heteroaryl, or an optionally substituted 5-14 membered heterocyclic ring containing N, O, or S;  
         R 4  is H or a C 1-10  alkyl or C 2-10  alkenyl optionally containing one or more non-adjacent heteroatoms selected from N, O, and S, and optionally substituted with a carbocyclic or a 5-6 membered heterocyclic ring;  
         m is 1-2;  
         n is 1-6;  
         Y is selected from the group consisting of  
         
           
             
             
                 
                 
             
           
         
         where R 6  is a substituent at any position on the ring or fused ring; and is H, OR 1 , C 1-6  alkyl, C 2-6  alkenyl, each optionally substituted by halo, C═O or one or more heteroatoms; or two adjacent R 6  is linked to obtain a 5-6 membered substituted or unsubstituted carbocyclic or heterocyclic ring, optionally fused to an additional substituted or unsubstituted carbocyclic or heterocyclic ring;  
         Q is CH or N;  
         and X is O, NH, or S.  
       
     
     
         54 . The method of  claim 53 , wherein said cell proliferative disorder is cancer.  
     
     
         55 . The method of  claim 53 , wherein cell proliferation is reduced, or cell death is induced.  
     
     
         56 . The method of  claim 53 , wherein said subject is human or an animal; and said system is a cell or tissue.  
     
     
         57 . The method of  claim 53 , wherein said compound is selected from the group consisting of: