DNA Polymerase IIIC Inhibitors and Use Thereof

Abstract

The present invention relates to compounds and methods useful for inhibiting the DNA polymerase IIIC enzyme. The invention also provides pharmaceutically acceptable compositions comprising compounds of the present invention and methods of using said compositions in the treatment of Gram-positive bacteria infections.

What is claimed is: 
     
         1 . A compound corresponding to formula I 
       
         
           
           
               
               
           
         
         wherein A and B are, independently, N or CH; 
         wherein n is 0-3; 
         wherein R 1  is (CH 2 ) m —{(V) o —(CH 2 ) p } q —W; 
         wherein V is CH 2 , CH═CH, C≡C, CO, O, S, SO, SO 2 , NR 4 , CHR 5 , OC(O), (O)CO, CONR 6 , NR 7 CO, SO 2 NH, NHSO 2 ; C 3-8  cycloalkyl, 
         wherein each of R 4 , R 6 , and R 7  is, independently, H or C 1-6  alkyl; 
         wherein R 5  is OH or C 1-6  alkyl, CH(R 8 R 9 ), 
         wherein each of R 8  and R 9  is, independently, H, halo, or C 1-6  alkyl; 
         wherein W is H, halo, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 3-8  cycloalkyl, substituted or unsubstituted C 2-8  heterocyclyl, substituted or unsubstituted C 6-14  aryl, substituted or unsubstituted C 1-10  heteroaryl, NH 2 , CN, OR 10 , SR 11 , COR 12 , OCOR 13 , NR 14 COR 15 , NR 16 R 17 , NR 18 (CO)NHR 19 , CH(CO 2 R 20 ) 2 , CO 2 R 21 , NHSO 2 R 22 , CONR 23 R 24 , CH 2 CO 2 R 25 , S(O)R 26  or S(O 2 )R 27    
         wherein each of R 10 —R 27  is, independently, H, substituted or unsubstituted C 1-6  alkyl, substituted or unsubstituted C 3-8  cycloalkyl, substituted or unsubstituted C 2-8  heterocyclyl, substituted or unsubstituted C 6-14  aryl, substituted or unsubstituted C 1-10  heteroaryl, 
         in which m is 1-5, o is 0-4, p is 0-4, and q is 0-4; 
         wherein R 2  is H, halo, CN, substituted or unsubstituted C 1-6  alkyl, CO 2 R 21  CONR 23 R 24 , substituted or unsubstituted C 2-8  heterocyclyl or substituted or unsubstituted C 1-10  heteroaryl, 
         wherein R 3  is C 6-14  aryl or C 1-10  heteroaryl with substituted by one or more substituents selected from the group of Cl, F, Br, I, OH, CN, C 1-6  alkyl, CF 3 , CHF 2 , CF 3 CH 2  and OCF 3 ; 
         wherein R 0  is H, CH 2 OPO(OH) 2 , CH 2 OCONHCH 2 (CH 2 ) t OPO(OH) 2 , CH 2 OCOCH 2 (CH 2 ) t OPO(OH) 2 , COO(CH 2 ) t OPO(OH) 2 , CH 2 OPO(OH)OPO(OH) 2 , or (CR 30 R 31 O)s-X—Y—(CR 30 R 31 ) t —OPO(OR 28 )(OR 29 ); 
       
       wherein X is a direct bond or (C═O), Y is a direct bond or oxygen 
       s is 0 or 1 
       t is 1, 2, or 3 
       R 28  and R 29  each are independently hydrogen or a hydrolysable ester group, wherein when R 28  is hydrogen, R 29  may be —P(O)OR 32 OR 33 ; 
       R 30  and R 31  each are independently hydrogen or C 1-4  alkyl; and 
       R 32  and R 33  each are independently hydrogen or a hydrolysable ester group, 
       or an optical isomer thereof, an isotopic isomer thereof, a prodrug or a pharmaceutically acceptable salt thereof. 
     
     
         2 . A compound as in  claim 1 ,
 wherein A and B are, independently, N or CH;   wherein n is 0-3;   wherein R 1  is (CH 2 ) m —{(V) o —(CH 2 ) P } q —W;   wherein V is CH 2 , CO, O, OC(O), or (O)CO,   wherein W is H, halo, substituted or unsubstituted C1-6 alkyl, NH 2 , CN, or OR 10 ,   wherein R 10  is H or substituted or unsubstituted C 1-6  alkyl,   in which m is 1-5, o is 0-4, p is 0-4, and q is 0-4;   wherein R 2  is H, halo, CN, substituted or unsubstituted C 1-6  alkyl, CO 2 R 21  CONR 23 R 24 , substituted or unsubstituted C 2-8  heterocyclyl or substituted or unsubstituted C 1-10  heteroaryl,   wherein R 3  is C 6-14  aryl or C 1-10  heteroaryl with substituted by one or more substituents selected from the group of Cl, F, Br, I, OH, CN, C 1-6  alkyl, CF 3 , CHF 2 , CF 3 CH 2  and OCF 3 ;   wherein R 0  is H,   or an optical isomer thereof, an isotopic isomer thereof, a prodrug or a pharmaceutically acceptable salt thereof.   
     
     
         3 . A compound as in  claim 2 ,
 wherein A and B are N;   wherein n is 0-1;   wherein R 1  is (CH 2 ) m —{(V) o —(CH 2 ) p } q —W;   wherein V is CO, O, OC(O), or (O)CO,   wherein W is H, halo, NH 2 , CN, or OR 10 ,   wherein R 10  is H or substituted or unsubstituted C 1-6  alkyl,   in which m is 1-5, o is 0-1, p is 0-4, and q is 0-4;   wherein R 2  is H or halo or CN,   wherein R 3  is C 6-14  aryl or C 1-10  heteroaryl with substituted by one or more substituents selected from the group of Cl, F, CF 3 , CHF 2 , CF 3 CH 2  and OCF 3 ;   wherein R 0  is H,   or an optical isomer thereof, an isotopic isomer thereof, a prodrug or a pharmaceutically acceptable salt thereof.   
     
     
         4 . A compound as in  claim 3 ,
 wherein A and B are N;   wherein n is 1;   wherein R 1  is (CH 2 ) m —{(V) o —(CH 2 ) p } q —W;   wherein V is CO, O, OC(O), or (O)CO,   wherein W is H, halo, NH 2 , CN, or OR 10 ,   wherein R 10  is H or substituted or unsubstituted C 1-6  alkyl,   in which m is 1-2, o is 1, p is 1-2, and q is 0-1;   wherein R 2  is H or halo or CN,   wherein R 3  is C 6-14  aryl or C 1-10  heteroaryl with substituted by one or more substituents selected from the group of Cl, F, CF 3 , CHF 2 , CF 3 CH 2  and OCF 3 ;   wherein R 0  is H,   or an optical isomer thereof, an isotopic isomer thereof, a prodrug or a pharmaceutically acceptable salt thereof.   
     
     
         5 . A compound as in  claim 4 ,
 wherein A and B are N;   wherein n is 1;   wherein R 1  is (CH 2 ) m —{(V) o —(CH 2 ) P } q —W;   wherein V is O, OC(O), or (O)CO,   wherein W is H, halo, NH 2 , or OR 10 ,   wherein R 10  is H or substituted or unsubstituted C 1-6  alkyl,   in which m is 1-2, o is 1, p is 1-2, and q is 0-1;   wherein R 2  is H or halo or CN,   wherein R 3  is C 6-14  aryl or C 1-10  heteroaryl with substituted by one or more substituents selected from the group of Cl, F, CF 3 , CHF 2 , CF 3 CH 2  and OCF 3 ;   wherein R 0  is H,   or an optical isomer thereof, an isotopic isomer thereof, a prodrug or a pharmaceutically acceptable salt thereof.   
     
     
         6 . A compound as in  claim 5 ,
 wherein A and B are N;   wherein n is 1;   wherein R 1  is (CH 2 ) m —{(V) o —(CH 2 ) P } q —W;   wherein V is O,   wherein W is H, halo, NH 2 , or OR 10 ,   wherein R 10  is H,   in which m is 2, o is 1, p is 2, and q is 1;   wherein R 2  is H or halo or CN,   wherein R 3  is C 6-14  aryl or C 1-10  heteroaryl with substituted by one or more substituents selected from the group of Cl, F, CF 3 , CHF 2 , CF 3 CH 2  and OCF 3 ;   wherein R 0  is H,   or an optical isomer thereof, an isotopic isomer thereof, a prodrug or a pharmaceutically acceptable salt thereof.   
     
     
         7 . A pharmaceutical composition comprising a compound of  claim 1  and at least one pharmaceutically acceptable carrier. 
     
     
         8 . A method of inhibiting the growth of Gram-positive bacteria, said method comprising contacting a medium with an effective amount of a compound of  claim 1 . 
     
     
         9 . The method of  claim 8 , wherein said surface is a surface of a medical device. 
     
     
         10 . A method of treating a Gram-positive bacterial infection in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of  claim 1 . 
     
     
         11 . A surface coating comprising a compound of  claim 1  and a coating agent, wherein said coating agent is capable of adhering said compound to a medium. 
     
     
         12 . A compound selected from the group consisting of:
 5-((3,4-Dichlorobenzyl)amino)-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   5-((3,4-Dichlorobenzyl)amino)-3-fluoro-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   1-Allyl-5-((3,4-dichlorobenzyl)amino)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   4-(5-((3,4-Dichlorobenzyl)amino)-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-1-yl)butyl acetate,   1-(Cyclobutylmethyl)-5-((3,4-dichlorobenzyl)amino)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   5-[(3,4-Cichlorophenyl)methylamino]-1-phenyl-6H-pyrazolo[4,3-d]pyrimidin-7-one,   1-Cyclopropyl-5-((3,4-dichlorobenzyl)amino)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   Cyclopentyl-5-((3,4-dichlorobenzyl)amino)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   Cethyl 5-(5-chloro-7-methoxy-pyrazolo[4,3-d]pyrimidin-1-yl) pentanoate,   5-[(3,4-Cichlorophenyl)methylamino]-1-(4-pyridyl)-6H-pyrazolo[4,3-d]pyrimidin-7-one,   3-Chloro-5-((3,4-dichlorobenzyl)amino)-1-(2-methoxyethyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   5-((3,4-Cichlorobenzyl)amino)-3-fluoro-1-(2-methoxy ethyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   3-Chloro-5-((3,4-dichlorobenzyl)amino)-1-(oxazol-4-ylmethyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   1-(2-(4-Acetylpiperazin-1-yl)ethyl)-5-((3,4-dichlorobenzyl)amino)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one hydrochloride,   5-((3,4-Dichlorobenzyl)amino)-1-(2-(2-hydroxy ethoxy)ethyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   5-((3,4-Dichlorobenzyl)amino)-1-(2-methoxyethyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   5-((3,4-Dichlorobenzyl)amino)-1-((4-methylmorpholin-2-yl)methyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one hydrochloride,   5-((3,4-Dichlorobenzyl)amino)-1-(1-(3-methylpicolinoyl) piperidin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one hydrochloride,   5-((3,4-Difluorobenzyl)amino)-3-fluoro-1-(2-(2-hydroxy ethoxy)ethyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   5-((4-Chloro-3-methylbenzyl)amino)-1-methyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   5-((3,4-Dichlorobenzyl)amino)-1,3-dimethyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   5-((3,4-Dichlorobenzyl)amino)-1-(2-morpholinoethyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one hydrochloride,   5-((3,4-Dichlorobenzyl)amino)-1-(4-hydroxybutyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one),   5-((3,4-Dichlorobenzyl)amino)-1-(thiazol-2-ylmethyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   5-((3,4-Dichlorobenzyl)amino)-1-(oxetan-3-ylmethyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   5-((3,4-Dichlorobenzyl)amino)-1-((tetrahydrofuran-3-yl)methyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   5-((3,4-Dichlorobenzyl)amino)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   5-((3,4-Dichlorobenzyl)amino)-1-(oxetan-2-ylmethyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   5-((3,4-Dichlorobenzyl)amino)-1-(3-hydroxypropyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   5-((3,4-Dichlorobenzyl)amino)-1-(2-(pyrazin-2-yl)ethyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one hydrochloride,   5-((3,4-Dichlorobenzyl)amino)-1-isopropyl-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   5-((3,4-Dichlorobenzyl)amino)-1-(5-methoxypentyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   5-((3,4-Dichlorobenzyl)amino)-1-((2-methoxy ethoxy)methyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   5-((3,4-Dichlorobenzyl)amino)-1-(oxetan-3-yl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   5-((3,4-Dichlorobenzyl)amino)-1-(1-(pyridin-3-ylsulfonyl)piperidin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one hydrochloride,   (E)-5-((3,4-dichlorobenzyl)amino)-1-(4-methoxybut-2-en-1-yl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   Ethyl 5-(5-((3,4-dichlorobenzyl)amino)-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-1-yl)pentanoate,   Isopropyl 5-(5-((3,4-dichlorobenzyl)amino)-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-1-yl)pentanoate,   Ethyl 4-(5-((3,4-dichlorobenzyl)amino)-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-1-yl)butanoate,   Methyl 3-(5-((3,4-dichlorobenzyl)amino)-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-1-yl)propanoate,   5-((3,4-Dichlorobenzyl)amino)-1-(1-(pyridin-2-ylmethyl) piperidin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one dihydrochloride,   5-((3,4-Dichlorobenzyl)amino)-1-(1-(pyridin-3-ylmethyl)piperidin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one dihydrochloride,   5-((3,4-Dichlorobenzyl)amino)-1-(1-(pyridin-4-ylmethyl) piperidin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one dihydrochloride,   5-[(3,4-Dichlorophenyl)methylamino]-1-[1-(oxazole-4-carbonyl)-4-piperidyl]-6H-pyrazolo[4,3-d]pyrimidin-7-one,   5-[(3,4-Dichlorophenyl)methylamino]-1-[1-(thiazole-2-carbonyl)-4-piperidyl]-6H-pyrazolo[4,3-d]pyrimidin-7-one,   5-((3,4-Dichlorobenzyl)amino)-1-(1-(4-methoxypicolinoyl)piperidin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one hydrochloride,   5-((3,4-Dichlorobenzyl)amino)-1-(1-(4-methylpicolinoyl)piperidin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one hydrochloride,   5-[(3,4-Dichlorophenyl)methylamino]-3-fluoro-1-[2-(2-hydroxy ethoxy)ethyl]-6H-pyrazolo[4,3-d]pyrimidin-7-one,   3-Chloro-5-[(3,4-dichlorophenyl)methylamino]-1-[2-(2-hydroxyethoxy)ethyl]-6H-pyrazolo[4,3-d]pyrimidin-7-one,   5-((3,4-Difluorobenzyl)amino)-3-fluoro-1-(oxazol-4-ylmethyl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one,   3-Chloro-5-((3,4-dichlorobenzyl)amino)-1-(1-nicotinoylpiperidin-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one hydrochloride,   Ammonium (2-(2-(5-((3,4-dichlorobenzyl)amino)-7-oxo-6,7-dihydro-1H-pyrazolo[4,3-d]pyrimidin-1-yl)ethoxy)ethoxy)methyl phosphate,   (5-((3,4-Dichlorobenzyl)amino)-1-(2-(2-hydroxy ethoxy)ethyl)-7-oxo-1H-pyrazolo[4,3-d]pyrimidin-6(7H)-yl)methyl dihydrogen phosphate,
 and pharmaceutically acceptable salts thereof. 
   
     
     
         13 . A pharmaceutical composition comprising a compound of  claim 12  and at least one pharmaceutically acceptable carrier. 
     
     
         14 . A method of inhibiting the growth of Gram-positive bacteria, said method comprising contacting a medium with an effective amount of a compound of  claim 12 . 
     
     
         15 . The method of  claim 14 , wherein said surface is a surface of a medical device. 
     
     
         16 . A method of treating a Gram-positive bacterial infection in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of  claim 12 . 
     
     
         17 . A surface coating comprising a compound of  claim 12  and a coating agent, wherein said coating agent is capable of adhering said compound to a medium.