Trna synthetase inhibitors

Abstract

Disclosed herein are secondary amine compounds that inhibit tRNA synthetase. The compounds of the invention are useful in inhibiting tRNA synthetase in Gram-negative bacteria and are useful in killing Gram-negative bacteria. The secondary amine compounds of the invention are also useful in the treatment of tuberculosis.

1 - 74 . (canceled) 
     
     
         75 . A compound having the structure of formula (I-A): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein: 
         R 1  is selected from the group consisting of (C 3 -C 8 )alkyl, (C 2 -C 8 )hydroxyalkyl, (C 1 -C 8 )aminoalkyl, (C 4 -C 8 )cycloalkyl, aryl, heteroaryl, (CH 3 SO 2 )(C 1 -C 8 )alkyl, and di((C 1 -C 8 )alkyl)amino; 
         each of R 2 , R 3 , R 4 , and R 5  is independently selected from H, OH, —NH 2 , halide, sulfonamido, (C 1 -C 6 )alkylsulfonyl, —OC(O)((C 1 -C 8 )alkyl), —C(O)O((C 1 -C 8 )alkyl), —C(O)OH, optionally substituted —NHC(O)(aryl), —C(O)NH 2 , —B(OH) 2 , tri((C 1 -C 8 )alkyl)silyl, optionally substituted (C 1 -C 8 )alkyl, optionally substituted (C 1 -C 8 )alkoxy, optionally substituted (C 1 -C 8 )aminoalkyl, optionally substituted (C 1 -C 8 )hydroxyalkyl, optionally substituted (C 1 -C 8 )haloalkyl, optionally substituted (C 1 -C 8 )haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted heteroaryloxy, optionally substituted heteroarylalkoxy, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted (C 3 -C 10 )cycloalkoxy, optionally substituted (C 2 -C 9 )heterocycloalkyl, optionally substituted (C 2 -C 9 )heterocycloalkoxy, (H 3 CSO 2 )(C 1 -C 8 )alkylene, optionally substituted (R b   2 NSO 2 )(C 1 -C 8 )alkylene, optionally substituted di((C 1 -C 8 )alkyl)amino, —NH—CH 2 —R 8 , —O—CH 2 —R 8 , and —O—CH 2 CH 2 —O—R 9 ; 
         or R 2  and R 3 , R 3  and R 4 , or R 4  and R 5 , taken together with the intervening atoms, form an optionally substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group; 
         R 6  is H or (C 1 -C 6 )alkyl; 
         R 7  is optionally substituted (C 3 -C 10 )cycloalkyl or (C 3 -C 10 )cycloalkenyl; 
         R 8  is selected from —C(O)((C 2 -C 9 )heterocycloalkyl), —C(O)NH((C 1 -C 8 )alkyl), —C(O)NH(aryl(C 1 -C 8 )alkyl), —C(O)NH((C 3 -C 8 )cycloalkyl), —C(O)NH((C 3 -C 8 )cycloalkyl(C 1 -C 8 )alkyl), —C(O)N(CH 3 )((C 3 -C 8 )cycloalkyl), —C(O)N(CH 3 )(aryl(C 1 -C 8 )alkyl), —C(O)NHC(O)NH((C 3 -C 8 )cycloalkyl), —C(O)NHC(O)NH((C 1 -C 8 )alkyl), —C(O)NHC(O)NH 2 , optionally substituted heteroaryl wherein the heteroaryl is not 4-pyridinyl, benzimidazole or thiazole, optionally substituted aryloxy(C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heterocycloalkyl(C 2 -C 8 )alkyl, heteroaryl(C 1 -C 8 )alkyl, (C 2 -C 8 )alkoxy, (C 3 -C 8 )hydroxyalkyl, (C 1 -C 8 )alkoxy(C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkoxy(C 1 -C 8 )alkyl, (C 1 -C 8 )thioalkoxy(C 1 -C 8 )alkyl, (CH 3 SO 2 )(C 1 -C 8 )alkyl, and ((C 1 -C 8 )alkylC(O))(C 1 -C 8 )alkyl; 
         R 9  is selected from (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkyl(C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, (C 1 -C 8 )hydroxyalkyl, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy(C 1 -C 8 )alkyl, and optionally substituted aryl; and 
         R b , independently for each occurrence, is selected from H, optionally substituted (C 1 -C 8 )alkyl, optionally substituted (C 1 -C 8 )haloalkyl, optionally substituted (C 1 -C 8 )hydroxyalkyl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted (C 3 -C 10 )cycloalkyl(C 1 -C 8 )alkyl, optionally substituted aryl, and optionally substituted aryl(C 1 -C 8 ) alkyl. 
       
     
     
         76 . The compound of  claim 75 , wherein R 6  is (C 1 -C 6 )alkyl. 
     
     
         77 . The compound of  claim 76 , wherein R 6  is methyl. 
     
     
         78 . The compound of  claim 75 , wherein R 6  is H. 
     
     
         79 . The compound of  claim 75 , wherein R 7  is optionally substituted cyclohexyl or cyclohexenyl. 
     
     
         80 . The compound of  claim 75 , wherein R 2 , R 3 , R 4 , and R 5  are each H. 
     
     
         81 . The compound of  claim 75 , wherein R 1  is selected from the group consisting of aryl and heteroaryl. 
     
     
         82 . A compound having the structure of formula (I-B): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein: 
         R 1  represents optionally substituted (R b   2 NSO 2 )(C 1 -C 8 )alkylene; 
         each of R 2 , R 3 , R 4 , and R 5  is independently selected from H, OH, —NH 2 , halide, sulfonamido, (C 1 -C 6 )alkylsulfonyl, —OC(O)((C 1 -C 8 )alkyl), —C(O)O((C 1 -C 8 )alkyl), —C(O)OH, optionally substituted —NHC(O)(aryl), —C(O)NH 2 , —B(OH) 2 , tri((C 1 -C 8 )alkyl)silyl, optionally substituted (C 1 -C 8 )alkyl, optionally substituted (C 1 -C 8 )alkoxy, optionally substituted (C 1 -C 8 )aminoalkyl, optionally substituted (C 1 -C 8 )hydroxyalkyl, optionally substituted (C 1 -C 8 )haloalkyl, optionally substituted (C 1 -C 8 )haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted heteroaryloxy, optionally substituted heteroarylalkoxy, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted (C 3 -C 10 )cycloalkoxy, optionally substituted (C 2 -C 9 )heterocycloalkyl, optionally substituted (C 2 -C 9 )heterocycloalkoxy, (H 3 CSO 2 )(C 1 -C 8 )alkylene, optionally substituted (R b   2 NSO 2 )(C 1 -C 8 )alkylene, optionally substituted di((C 1 -C 8 )alkyl)amino, —NH—CH 2 —R 8 , —O—CH 2 —R 8 , and —O—CH 2 CH 2 —O—R 9 ; 
         or R 2  and R 3 , R 3  and R 4 , or R 4  and R 5 , taken together with the intervening atoms, form an optionally substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group; 
         R 6  is H or (C 1 -C 6 )alkyl; 
         R 7  is optionally substituted (C 3 -C 10 )cycloalkyl or (C 3 -C 10 )cycloalkenyl; 
         R 8  is selected from —C(O)((C 2 -C 9 )heterocycloalkyl), —C(O)NH((C 1 -C 8 )alkyl), —C(O)NH(aryl(C 1 -C 8 )alkyl), —C(O)NH((C 3 -C 8 )cycloalkyl), —C(O)NH((C 3 -C 8 )cycloalkyl(C 1 -C 8 )alkyl), —C(O)N(CH 3 )((C 3 -C 8 )cycloalkyl), —C(O)N(CH 3 )(aryl(C 1 -C 8 )alkyl), —C(O)NHC(O)NH((C 3 -C 8 )cycloalkyl), —C(O)NHC(O)NH((C 1 -C 8 )alkyl), —C(O)NHC(O)NH 2 , optionally substituted heteroaryl wherein the heteroaryl is not 4-pyridinyl, benzimidazole or thiazole, optionally substituted aryloxy(C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heterocycloalkyl(C 2 -C 8 )alkyl, heteroaryl(C 1 -C 8 )alkyl, (C 2 -C 8 )alkoxy, (C 3 -C 8 )hydroxyalkyl, (C 1 -C 8 )alkoxy(C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkoxy(C 1 -C 8 )alkyl, (C 1 -C 8 )thioalkoxy(C 1 -C 8 )alkyl, (CH 3 SO 2 )(C 1 -C 8 )alkyl, and ((C 1 -C 8 )alkylC(O))(C 1 -C 8 )alkyl; 
         R 9  is selected from (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkyl(C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, (C 1 -C 8 )hydroxyalkyl, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy(C 1 -C 8 )alkyl, and optionally substituted aryl; and 
         R b , independently for each occurrence, is selected from H, optionally substituted (C 1 -C 8 )alkyl, optionally substituted (C 1 -C 8 )haloalkyl, optionally substituted (C 1 -C 8 )hydroxyalkyl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted (C 3 -C 10 )cycloalkyl(C 1 -C 8 )alkyl, optionally substituted aryl, and optionally substituted aryl(C 1 -C 8 ) alkyl. 
       
     
     
         83 . The compound of  claim 82 , wherein R 6  is (C 1 -C 6 )alkyl. 
     
     
         84 . The compound of  claim 82 , wherein R 6  is methyl. 
     
     
         85 . The compound of  claim 82 , wherein R 6  is H. 
     
     
         86 . The compound of  claim 82 , wherein R 7  is optionally substituted cyclohexyl or cyclohexenyl. 
     
     
         87 . The compound of  claim 82 , wherein R 2 , R 3 , R 4 , and R 5  are each H. 
     
     
         88 . A compound having the structure of formula (I-C): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein: 
         R 1  is selected from the group consisting of —O—CH 2 —R 8  and —O—CH 2 CH 2 —O—R 9 ; 
         each of R 2 , R 3 , R 4 , and R 5  is independently selected from H, OH, —NH 2 , halide, sulfonamido, (C 1 -C 6 )alkylsulfonyl, —OC(O)((C 1 -C 8 )alkyl), —C(O)O((C 1 -C 8 )alkyl), —C(O)OH, optionally substituted —NHC(O)(aryl), —C(O)NH 2 , —B(OH) 2 , tri((C 1 -C 8 )alkyl)silyl, optionally substituted (C 1 -C 8 )alkyl, optionally substituted (C 1 -C 8 )alkoxy, optionally substituted (C 1 -C 8 )aminoalkyl, optionally substituted (C 1 -C 8 )hydroxyalkyl, optionally substituted (C 1 -C 8 )haloalkyl, optionally substituted (C 1 -C 8 )haloalkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aryloxy, optionally substituted arylalkoxy, optionally substituted heteroaryloxy, optionally substituted heteroarylalkoxy, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted (C 3 -C 10 )cycloalkoxy, optionally substituted (C 2 -C 9 )heterocycloalkyl, optionally substituted (C 2 -C 9 )heterocycloalkoxy, (H 3 CSO 2 )(C 1 -C 8 )alkylene, optionally substituted (R b   2 NSO 2 )(C 1 -C 8 )alkylene, optionally substituted di((C 1 -C 8 )alkyl)amino, —NH—CH 2 —R 8 , —O—CH 2 —R 8 , and —O—CH 2 CH 2 —O—R 9 ; 
         or R 2  and R 3 , R 3  and R 4 , or R 4  and R 5 , taken together with the intervening atoms, form an optionally substituted aryl, heteroaryl, cycloalkyl, or heterocycloalkyl group; 
         R 6  is H or (C 1 -C 6 )alkyl; 
         R 7  is optionally substituted (C 3 -C 10 )cycloalkyl or (C 3 -C 10 )cycloalkenyl; 
         R 8  is selected from —C(O)((C 2 -C 9 )heterocycloalkyl), —C(O)NH((C 1 -C 8 )alkyl), —C(O)NH(aryl(C 1 -C 8 )alkyl), —C(O)NH((C 3 -C 8 )cycloalkyl), —C(O)NH((C 3 -C 8 )cycloalkyl(C 1 -C 8 )alkyl), —C(O)N(CH 3 )((C 3 -C 8 )cycloalkyl), —C(O)N(CH 3 )(aryl(C 1 -C 8 )alkyl), —C(O)NHC(O)NH((C 3 -C 8 )cycloalkyl), —C(O)NHC(O)NH((C 1 -C 8 )alkyl), —C(O)NHC(O)NH 2 , optionally substituted heteroaryl wherein the heteroaryl is not 4-pyridinyl, benzimidazole or thiazole, optionally substituted aryloxy(C 1 -C 8 )alkyl, (C 3 -C 8 )cycloalkyl, (C 2 -C 9 )heterocycloalkyl, (C 2 -C 9 )heterocycloalkyl(C 2 -C 8 )alkyl, heteroaryl(C 1 -C 8 )alkyl, (C 2 -C 8 )alkoxy, (C 3 -C 8 )hydroxyalkyl, (C 1 -C 8 )alkoxy(C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkoxy(C 1 -C 8 )alkyl, (C 1 -C 8 )thioalkoxy(C 1 -C 8 )alkyl, (CH 3 SO 2 )(C 1 -C 8 )alkyl, and ((C 1 -C 8 )alkylC(O))(C 1 -C 8 )alkyl; 
         R 9  is selected from (C 3 -C 10 )cycloalkyl, (C 3 -C 10 )cycloalkyl(C 1 -C 8 )alkyl, (C 1 -C 8 )haloalkyl, (C 1 -C 8 )hydroxyalkyl, (C 1 -C 8 )alkyl, (C 1 -C 8 )alkoxy(C 1 -C 8 )alkyl, and optionally substituted aryl; and 
         R b , independently for each occurrence, is selected from H, optionally substituted (C 1 -C 8 )alkyl, optionally substituted (C 1 -C 8 )haloalkyl, optionally substituted (C 1 -C 8 )hydroxyalkyl, optionally substituted (C 3 -C 10 )cycloalkyl, optionally substituted (C 3 -C 10 )cycloalkyl(C 1 -C 8 )alkyl, optionally substituted aryl, and optionally substituted aryl(C 1 -C 8 ) alkyl. 
       
     
     
         89 . The compound of  claim 88 , wherein R 6  is (C 1 -C 6 )alkyl. 
     
     
         90 . The compound of  claim 89 , wherein R 6  is methyl. 
     
     
         91 . The compound of  claim 88 , wherein R 6  is H. 
     
     
         92 . The compound of  claim 88 , wherein R 7  is optionally substituted cyclohexyl or cyclohexenyl. 
     
     
         93 . The compound of  claim 88 , wherein R 2 , R 3 , R 4 , and R 5  are each H. 
     
     
         94 . The compound of  claim 88 , wherein R 1  is —O—CH 2 —R 8  and R 8  is optionally substituted heteroaryl wherein the heteroaryl is not 4-pyridinyl, benzimidazole, or thiazole. 
     
     
         95 . A method of treating a bacterial infection in a subject, comprising administering to the subject a therapeutically effective amount of a compound of  claim 75 .