Compounds which inhibit rna polymerase, compositions including such compounds, and their use

Abstract

RNA polymerase I (Pol I) is a dedicated polymerase for the transcription of the 47S ribosomal RNA precursor subsequently processed into the mature 5.8S, 18S and 28S ribosomal RNAs and assembled into ribosomes in the nucleolus. Pol I activity is commonly deregulated in human cancers. Based on the discovery of lead molecule BMH-21, a series of pyridoquinazolinecarboxamides were synthesized as inhibitors of Pol I and activators of the destruction of RPA194, the Pol I large catalytic subunit protein. The present invention identifies a set of bioactive compounds, including purified stereoisomers, that potently cause RPA194 degradation that function in a tightly constrained chemical space. Pharmaceutical compositions comprising these compounds and their uses in cancer and other Pol I related diseases is also provided.

1 . A method for modulating RNA Pol I activity in a mammalian cell or a population of mammalian cells, the method comprising contacting the cell or the population of cells with a compound of formula I: 
       
         
           
           
               
               
           
         
         wherein X is NR 2 ; 
         wherein L is R 3  or an optionally substituted cycloamine 
       
       
         
           
           
               
               
           
         
         wherein R 1  is a straight-chained or branched C 1 -C 6  hydrocarbon group (e.g., an alkyl group, an alkenyl group, an alkynyl group, alkylol group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, cyclic groups, whether substituted or unsubstituted, such as cyclopentyl, cyclohexyl, pyramido, phenyl, or benzyl, cycloalkyl, heterocyclyl, indole, wherein each of alkyl, aryl, or heterocyclyl moiety may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, hydroxy, carboxy, phosphoryl, phosphonyl, phosphono C 1 -C 6  alkyl, carboxy C 1 -C 6  alkyl, dicarboxy C 1 -C 6  alkyl, dicarboxy halo C 1 -C 6  alkyl, sulfonyl, cyano, nitro, alkoxy, alkylthio, acyl, acyloxy, thioacyl, acylthio, aryloxy, amino, alkylamino, dialkylamino, trialkylamino, arylalkylamino, guanidino, aldehydo, ureido, and aminocarbonyl, a branched or straight-chain alkylamino, dialkylamino, or alkyl or dialkylaminoalkyl, or thioalkyl, thioalkenyl, thioalkynyl, aryloxy, acyloxy, thioacyl, amido, sulphonamido, etc.), or the like; 
         when X is NR 2 , R 2  is H or a straight-chained C 1 -C 6  alkyl group; 
         when L is R 3 , R 3  is a straight-chained or branched C 2 -C 6  alkyl group; 
       
       when L is 
       
         
           
           
               
               
           
         
       
       m=1-8 and each Y is independently selected from (CH 2 ) n Y 1   p  wherein n=1-8, p=0-4 and the sum of n and p is at least 2, and each Y 1  is independently selected from NR 4 , O, S, or P, wherein R 4  is as hereinbefore defined for R 3 , and X≠O; or a pharmaceutically acceptable salt, solvate, stereoisomer, or a prodrug thereof. 
     
     
         2 . The method of  claim 1 , wherein L is R 3  and R 3  is a straight-chained or branched C 2 -C 6  alkyl group having at least one chiral carbon. 
     
     
         3 . The method of  claim 1 , wherein the compound has formula II, 
       
         
           
           
               
               
           
         
         wherein R 1 =H and R 2 =C 1 -C 6  alkyl, substituted with one or more C 1 -C 4  alkyl, OH, NH 2 , NR 3 R 4 , cyano, SO 2 R 3 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl (including but not limited to imidazolyl, imidazolidinonyl, pyridyl, indolyl, oxazolyl, thiazolyl, oxadiazolyl), substituted or unsubstituted cycloalkyl or substituted or unsubstituted nitrogen-containing heterocycles including, but not limited to azetidine, pyrrolidine, piperidine, piperazine, azapine, morpholino; wherein R 3  and R 4 , are independently selected from the group including H, C 1 -C 6  alkyl, and C 1 -C 4  alkoxyl alkyl, having at least one chiral carbon, when R 2  is substituted with at least one NR 3 R 4  group. 
       
     
     
         4 . The method of  claim 3 , comprising a chirally pure stereoisomer of compound of formula II when R 2  is substituted with at least one NR 3 R 4  group and a pharmaceutically acceptable carrier. 
     
     
         5 . The method of  claim 1 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         6 . A method for treating a hyperproliferative disease in a subject, the method comprising administering an effective amount of a compound of formula I to the subject: 
       
         
           
           
               
               
           
         
         wherein X is NR 2 ; 
         wherein L is R 3  or an optionally substituted cycloamine 
       
       
         
           
           
               
               
           
         
         wherein R 1  is a straight-chained or branched C 1 -C 6  hydrocarbon group (e.g., an alkyl group, an alkenyl group, an alkynyl group, alkylol group, hydroxyalkyl group, alkoxy group, alkoxyalkyl group, cyclic groups, whether substituted or unsubstituted, such as cyclopentyl, cyclohexyl, pyramido, phenyl, or benzyl, cycloalkyl, heterocyclyl, indole, wherein each of alkyl, aryl, or heterocyclyl moiety may be unsubstituted or substituted with one or more substituents selected from the group consisting of halo, hydroxy, carboxy, phosphoryl, phosphonyl, phosphono C 1 -C 6  alkyl, carboxy C 1 -C 6  alkyl, dicarboxy C 1 -C 6  alkyl, dicarboxy halo C 1 -C 6  alkyl, sulfonyl, cyano, nitro, alkoxy, alkylthio, acyl, acyloxy, thioacyl, acylthio, aryloxy, amino, alkylamino, di alkylamino, trialkylamino, arylalkylamino, guanidino, aldehydo, ureido, and aminocarbonyl, a branched or straight-chain alkylamino, dialkylamino, or alkyl or dialkylaminoalkyl, or thioalkyl, thioalkenyl, thioalkynyl, aryloxy, acyloxy, thioacyl, amido, sulphonamido, etc.), or the like; 
         when X is NR 2 , R 2  is H or a straight-chained C 1 -C 6  alkyl group; 
         when L is R 3 , R 3  is a straight-chained or branched C 2 -C 6  alkyl group; 
       
       when L is 
       
         
           
           
               
               
           
         
       
       m=1-8 and each Y is independently selected from (CH 2 ) n Y 1   p  wherein n=1-8, p=0-4 and the sum of n and p is at least 2, and each Y 1  is independently selected from NR 4 , O, S, or P, wherein R 4  is as hereinbefore defined for R 3 , and X≠O; or a pharmaceutically acceptable salt, solvate, stereoisomer, or a prodrug thereof. 
     
     
         7 . The method of  claim 6 , wherein L is R 3  and R 3  is a straight-chained or branched C 2 -C 6  alkyl group having at least one chiral carbon. 
     
     
         8 . The method of  claim 6 , wherein the compound has formula II, 
       
         
           
           
               
               
           
         
         wherein R 1 =H and R 2 =C 1 -C 6  alkyl, substituted with one or more C 1 -C 4  alkyl, OH, NH 2 , NR 3 R 4 , cyano, SO 2 R 3 , substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl (including but not limited to imidazolyl, imidazolidinonyl, pyridyl, indolyl, oxazolyl, thiazolyl, oxadiazolyl), substituted or unsubstituted cycloalkyl or substituted or unsubstituted nitrogen-containing heterocycles including, but not limited to azetidine, pyrrolidine, piperidine, piperazine, azapine, morpholino; wherein R 3  and R 4 , are independently selected from the group including H, C 1 -C 6  alkyl, and C 1 -C 4  alkoxyl alkyl, having at least one chiral carbon, when R 2  is substituted with at least one NR 3 R 4  group. 
       
     
     
         9 . The method of  claim 8 , comprising a chirally pure stereoisomer of compound of formula II when R 2  is substituted with at least one NR 3 R 4  group and a pharmaceutically acceptable carrier. 
     
     
         10 . The method of  claim 6 , wherein the compound selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         11 . The method of  claim 6 , wherein the hyperproliferative disease is cancer. 
     
     
         12 . The method of  claim 11 , further comprising administering to the subject at least one other biologically active agent.