N-benzyl-4-methyleneamino-3-hydroxy-2-pyridones

Abstract

Compounds of Formula (I) are effective in the treatment of a microbial infection.

1 .- 20 . (canceled) 
     
     
         21 . A compound of formula (I) 
       
         
           
           
               
               
           
         
         wherein: 
         each R 1  is independently: 
         i) hydrogen; 
         ii) halogen; 
         iii) cyano; or 
         iv) C 1 -C 3  alkoxy; 
         R 3  and R 4  are taken together to form a piperazin-1-yl ring, wherein said ring can be optionally substituted at the 4-position nitrogen atom by a unit chosen from:
 i) C 3 -C 9  monocyclic heterocycloalkyl; optionally substituted with C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, halogen, cyano, hydroxy, —C(═O)OH, —NH 2 ; —NHC(═O)R; —C(═O)NH 2 , phenyl, or combinations thereof; or 
 ii) C 5 -C 9  monocyclic heteroaryl; optionally substituted with C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, halogen, cyano, hydroxy, —C(═O)OH, —NH 2 ; —NHC(═)R; —C(═O)NH 2 , phenyl, or combinations thereof; 
 
         R 5  and R 6  are each independently: 
         i) C 1 -C 15  alkyl; 
         ii) C 3 -C 9  cycloalkyl; 
         iii) C 1 -C 12  haloalkyl; 
         iv) C 2 -C 15  alkenyl; 
         v) C 2 -C 15  alkynyl; 
         vi) halogen; 
         vii) cyano; or 
         viii) hydroxy; or 
         a pharmaceutically acceptable salt thereof. 
       
     
     
         22 . The compound according to  claim 21 , wherein R 5  and R 6  are both hydrogen. 
     
     
         23 . The compound according to  claim 21 , wherein the piperizin-1-yl ring formed when R 3  and R 4  are taken together is substituted at the 4-position nitrogen atom with a C 5 -C 9  monocyclic heteroaryl ring; wherein the monocyclic heteroaryl ring is optionally substituted with C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, halogen, cyano, hydroxy, —NH 2 ; —NHC(═O)R; —C(═O)NH 2 , phenyl, or combinations thereof. 
     
     
         24 . The compound according to  claim 23 , wherein the piperazin-1-yl ring formed when R 3  and R 4  are taken together is substituted at the 4-position nitrogen atom with a unit chosen from:
 i) pyridazinyl;   ii) pyridinyl; or   iii) pyrimidinyl;   wherein said units are optionally substituted with a unit chosen from C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, halogen, cyano, hydroxy, —C(═O)OH, —NH 2 ; —NHC(═O)R; —C(═O)NH 2 , phenyl, or combinations thereof.   
     
     
         25 . The compound according to  claim 24 , wherein the monocyclic heteroaryl ring is a pyridazin-3-yl ring. 
     
     
         26 . The compound according to  claim 21 , wherein the piperizin-1-yl ring formed when R 3  and R 4  are taken together is substituted at the 4-position nitrogen atom with a C 3 -C 9  monocyclic heterocycloalkyl; wherein the monocyclic heterocycloalkyl ring is optionally substituted with C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, halogen, cyano, hydroxy, —NH 2 ; —NHC(═O)R; —C(═O)NH 2 , phenyl, or combinations thereof. 
     
     
         27 . The compound according to  claim 26 , wherein the piperazin-1-yl ring formed when R 3  and R 4  are taken together is substituted at the 4-position nitrogen atom with a unit chosen from:
 i) pyrrolidinyl;   ii) piperidinyl; or   iii) piperazinyl;   wherein said units are optionally substituted with a unit chosen from C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, halogen, cyano, hydroxy, —C(═O)OH, —NH 2 ; —NHC(═O)R; —C(═O)NH 2 , phenyl, or combinations thereof.   
     
     
         28 . The compound according to  claim 21 , chosen from:
 1-benzyl-3-hydroxy-4-{[4-(6-chloropyridazin-3-yl)piperazin-1-yl]methyl}pyridine-2(1H)-one;   1-(3-methoxybenzyl)-3-hydroxy-4-{[4-(6-chloropyridazin-3-yl)piperazin-1-yl]methyl}pyridine-2(1H)-one;   1-(3-methylbenzyl)-3-hydroxy-4-{[4-(6-chloropyridazin-3-yl)piperazin-1-yl]methyl}pyridine-2(1H)-one; and   1-(3-chlorobenzyl)-3-hydroxy-4-{[4-(6-chloropyridazin-3-yl)piperazin-1-yl]methyl}pyridine-2(1H)-one.   
     
     
         29 . A composition comprising:
 a) one or more compounds having the formula:   
       
         
           
           
               
               
           
         
         wherein: 
         each R 1  is independently: 
         i) hydrogen; 
         ii) halogen; 
         iii) cyano; or 
         iv) C 1 -C 3  alkoxy; 
         R 3  and R 4  are taken together to form a piperazin-1-yl ring, wherein said ring can be optionally substituted at the 4-position nitrogen atom by a unit chosen from: 
         i) C 3 -C 9  monocyclic heterocycloalkyl; optionally substituted with C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, halogen, cyano, hydroxy, —C(═O)OH, —NH 2 ; —NHC(═O)R; —C(═O)NH 2 , phenyl, or combinations thereof; or
 ii) C 5 -C 9  monocyclic heteroaryl; optionally substituted with C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, halogen, cyano, hydroxy, —C(═O)OH, —NH 2 ; —NHC(═O)R; —C(═O)NH 2 , phenyl, or combinations thereof; 
 
         R 5  and R 6  are each independently: 
         i) C 1 -C 15  alkyl; 
         ii) C 3 -C 9  cycloalkyl; 
         iii) C 1 -C 12  haloalkyl; 
         iv) C 2 -C 15  alkenyl; 
         v) C 2 -C 15  alkynyl; 
         vi) halogen; 
         vii) cyano; or 
         viii) hydroxy; or
 a pharmaceutically acceptable salt thereof; and 
 
         b) one or more pharmaceutically acceptable excipients. 
       
     
     
         30 . The composition according to  claim 29 , wherein R 5  and R 6  are both hydrogen. 
     
     
         31 . The composition according to  claim 29 , wherein the piperizin-1-yl ring formed when R 3  and R 4  are taken together is substituted at the 4-position nitrogen atom with a C 5 -C 9  monocyclic heteroaryl ring; wherein the monocyclic heteroaryl ring is optionally substituted with C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, halogen, cyano, hydroxy, —NH 2 ; —NHC(═O)R; —C(═O)NH 2 , phenyl, or combinations thereof. 
     
     
         32 . The composition according to  claim 31 , wherein the piperazin-1-yl ring formed when R 3  and R 4  are taken together is substituted at the 4-position nitrogen atom with a unit chosen from:
 i) pyridazinyl;   ii) pyridinyl; or   iii) pyrimidinyl;   wherein said units are optionally substituted with a unit chosen from C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, halogen, cyano, hydroxy, —C(═O)OH, —NH 2 ; —NHC(═O)R; —C(═O)NH 2 , phenyl, or combinations thereof.   
     
     
         33 . The composition according to  claim 32 , wherein the monocyclic heteroaryl ring is a pyridazin-3-yl ring. 
     
     
         34 . The compound according to  claim 29 , wherein the piperizin-1-yl ring formed when R 3  and R 4  are taken together is substituted at the 4-position nitrogen atom with a C 3 -C 9  monocyclic heterocycloalkyl; wherein the monocyclic heterocycloalkyl ring is optionally substituted with C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, halogen, cyano, hydroxy, —NH 2 ; —NHC(═O)R; —C(═O)NH 2 , phenyl, or combinations thereof. 
     
     
         35 . The composition according to  claim 34 , wherein the piperazin-1-yl ring formed when R 3  and R 4  are taken together is substituted at the 4-position nitrogen atom with a unit chosen from:
 i) pyrrolidinyl;   ii) piperidinyl; or   iii) piperazinyl;   wherein said units are optionally substituted with a unit chosen from C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, halogen, cyano, hydroxy, —C(═O)OH, —NH 2 ; —NHC(═O)R; —C(═O)NH 2 , phenyl, or combinations thereof.   
     
     
         36 . The composition according to  claim 29 , wherein the compound is chosen from:
 1-benzyl-3-hydroxy-4-{[4-(6-chloropyridazin-3-yl)piperazin-l-yl]methyl}pyridine-2(1H)-one;   1-(3-methoxybenzyl)-3-hydroxy-4-{[4-(6-chloropyridazin-3-yl)piperazin-1-yl]methyl}pyridine-2(1H)-one;   1-(3-methylbenzyl)-3-hydroxy-4-{[4-(6-chloropyridazin-3-yl)piperazin-1-yl]methyl}pyridine-2(1H)-one; and   1-(3-chlorobenzyl)-3-hydroxy-4-{[4-(6-chloropyridazin-3-yl)piperazin-1-yl]methyl}pyridine-2(1H)-one.   
     
     
         37 . A method of treating a microbial infection, comprising administering a safe and effective of amount of a compound having the formula: 
       
         
           
           
               
               
           
         
         wherein: 
         each R 1  is independently: 
         i) hydrogen; 
         ii) halogen; 
         iii) cyano; or 
         iv) C 1 -C 3  alkoxy; 
         R 3  and R 4  are taken together to form a piperazin-1-yl ring, wherein said ring can be optionally substituted at the 4-position nitrogen atom by a unit chosen from:
 i) C 3 -C 9  monocyclic heterocycloalkyl; optionally substituted with C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, halogen, cyano, hydroxy, —C(═O)OH, —NH 2 ; —NHC(═O)R; —C(═O)NH 2 , phenyl, or combinations thereof; or 
 ii) C 5 -C 9  monocyclic heteroaryl; optionally substituted with C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, halogen, cyano, hydroxy, —C(═O)OH, —NH 2 ; —NHC(═O)R; —C(═O)NH 2 , phenyl, or combinations thereof; 
 
         R 5  and R 6  are each independently: 
         i) C 1 -C 15  alkyl; 
         ii) C 3 -C 9  cycloalkyl; 
         iii) C 1 -C 12  haloalkyl; 
         iv) C 2 -C 15  alkenyl; 
         v) C 2 -C 15  alkynyl; 
         vi) halogen; 
         vii) cyano; or 
         viii) hydroxy; or 
         a pharmaceutically acceptable salt thereof. 
       
     
     
         38 . The method according to  claim 37 , wherein the piperizin-1-yl ring formed when R 3  and R 4  are taken together is substituted at the 4-position nitrogen atom with a C 5 -C 9  monocyclic heteroaryl ring; wherein the monocyclic heteroaryl ring is optionally substituted with C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, halogen, cyano, hydroxy, —NH 2 ; —NHC(═O)R; —C(═O)NH 2 , phenyl, or combinations thereof. 
     
     
         39 . The method according to  claim 37 , wherein the piperizin-1-yl ring formed when R 3  and R 4  are taken together is substituted at the 4-position nitrogen atom with a C 3 -C 9  monocyclic heterocycloalkyl; wherein the monocyclic heterocycloalkyl ring is optionally substituted with C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, halogen, cyano, hydroxy, —NH 2 ; —NHC(═O)R; —C(═O)NH 2 , phenyl, or combinations thereof. 
     
     
         40 . The method according to  claim 37 , chosen from:
 1-benzyl-3-hydroxy-4-{[4-(6-chloropyridazin-3-yl)piperazin-1-yl]methyl}pyridine-2(1H)-one;   1-(3-methoxybenzyl)-3-hydroxy-4-{[4-(6-chloropyridazin-3-yl)piperazin-1-yl]methyl}pyridine-2(1H)-one;   1-(3-methylbenzyl)-3-hydroxy-4-{[4-(6-chloropyridazin-3-yl)piperazin-1-yl]methyl}pyridine-2(1H)-one; and   1-(3-chlorobenzyl)-3-hydroxy-4-{[4-(6-chloropyridazin-3-yl)piperazin-1-yl]methyl}pyridine-2(1H)-one.