Antimicrobial Compounds And Methods Of Making And Using The Same

Abstract

The present invention relates generally to the field of antimicrobial compounds and to methods of making and using them. These compounds are useful for treating, preventing, and reducing the risk of microbial infections in humans and animals.

1 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
       wherein Z is selected from the group consisting of NR 4 , NR 4 CO, and NR 4 CONR 4 ,
 -D-E-F is hydrogen; 
 A is selected from the group consisting of:
 (a) a single bond, (b) —(C 1-8  alkyl)-, wherein
 i) 0-4 carbon atoms in (b) immediately above optionally is replaced by a moiety selected from the group consisting of —NR 6 — and —(C═O)—, 
 
 ii) (b) immediately above optionally is substituted with one or more R 5  groups, and 
 iii) (b) immediately above optionally is substituted with —(C 1-8  alkyl)-R 5  groups; 
 (f) —NR 6  and (m) —NR 6 CO—, 
 
 G is selected from the group consisting of:
 (a) a single bond, (b) —(C 1-8  alkyl)-, wherein
 i) 0-4 carbon atoms in (b) immediately above optionally is replaced by a moiety selected from the group consisting of —NR 6 — and —(C═O)—, 
 ii) (b) immediately above optionally is substituted with one or more R 5  groups, and 
 iii) (b) immediately above optionally is substituted with —(C 1-8  alkyl)-R 5  groups; 
 
 (f) —NR 6 —, (h) —C(O)—, and (l) —C(O)NR 6 —, 
 
 B is selected from the group consisting of:
 (a) a single bond, 
 (d) —(C 1-8  alkyl)-, wherein
 i) 0-4 carbon atoms in (d) immediately above optionally is replaced by a moiety selected from the group consisting of —NR 6 —, —(C═O)—, and —C(═NR 6 )—, 
 ii) (d) immediately above optionally is substituted with one or more R 5  groups, and 
 iii) (d) immediately above optionally is substituted with one or more —(C 1-8  alkyl)-R 5  groups; 
 
 and (g) —(CR 6 R 6 ) t —, 
 
 H is selected from the group consisting of:
 (a) a single bond, 
 (b) a 3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, 
 
 wherein (b) is optionally substituted with one or more R 5  groups;
 (d) —(C 1-8  alkyl)-, wherein
 i) 0-4 carbon atoms in (d) immediately above optionally is replaced by a moiety selected from the group consisting of —O—, —NR 6 —, and —(C═O)—, 
 ii) (d) immediately above optionally is substituted with one or more R 5  groups, and 
 iii) (d) immediately above optionally is substituted with one or more —(C 1-8  alkyl)-R 5  groups; 
 
 and (g) —(CR 6 R 6 ) t —, 
 
 C is selected from the group consisting of:
 (a) hydrogen, (k) —NR 6 (CR 6 R 6 ) t R 8 , (l) —OR 8 —, (r) —NR 6 C(O)(CR 6 R 6 ) t R 8 , (s) —C(O)NR 6 (CR 6 R 6 ) t R 8 , (t) —C(═NR 6 )(CR 6 R 6 ) t R 8 , (dd) —NR 6 R 8 , (ee) —NR 6 (CR 6 R 6 )R 8 , (ff) —OH, (gg) —NR 8 R 8 , (jj) —NC(O)R 8 , (kk) —NR 6 C(NR 6 )NR 6 R 8 , (ll) a C 1-8  alkyl group, (oo) a 3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (qq) —(CR 6 R 6 ) t NR 6 (CR 6 R 6 ) t R 8 , (rr) —N[(CR 6 R 6 ) t R 8 ][C═O(CR 6 R 6 ) t R 8 ], (ss) —(CR 6 R 6 ) t N[(CR 6 R 6 ) t R 8 ][(CR 6 R 6 ) t R 8 ], (tt) —(CR 6 R 6 ) t NR 6 (C═O)(CR 6 R 6 ) t R 8 , (vv) —C(O)(CR 6 )[(CR 6 R 6 ) t R 8 ]R 8 , (yy) —NR 6 C(O)CR 8 R 8 R 8 , and (zz) —N[(CR 6 R 6 ) t R 8 ]C(O)R 8 ; 
 
 wherein (ll) and (oo) are optionally substituted with one or more R 7  groups; 
 J is selected from the group consisting of:
 (a) hydrogen, (k) —NR 6 (CR 6 R 6 )R, (l) —OR, (n) —C(O)(CR 6 R 6 )R, (s) —C(O)NR 6 (CR 6 R 6 ) t R 8 , (dd) —NR 6 R 8 , (ee) —NR 6 (CR 6 R 6 )R 8 , (ff) —OH, (gg) —NR 8 R 8 , (qq) —(CR 6 R 6 ) t NR 6 (CR 6 R 6 ) t R 8 , (ss) —(CR 6 R 6 ) t N[(CR 6 R 6 ) t R 8 ][(CR 6 R 6 ) t R 8 ], and (ww) —(CR 6 R 6 ) t C(O)NR 8 R 8 ; 
 
 R 5  is selected from (a) hydrogen, (b) F, (l) —NR 6 (CNR 6 )NR 6 R 6 , (m) —C 1-8  alkyl, (p) —(C 1-8  alkyl)-(3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), and (t) -3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur,
 wherein (m), (p), and (t) are optionally substituted with one or more R 8 ; 
 
 R 6  is selected from (a) hydrogen and (b) —C 1-8  alkyl;
 wherein (b) is optionally substituted with one or more R 8 ; 
 
 R 7  is selected from (a) hydrogen, (b) F, (j) —NR 6 R 6 , (k) —OR 6 , (l) —NR 6 (CNR 6 )NR 6 R 6 , (m) —C 1-8  alkyl, (p) —(C 1-8  alkyl)-(3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (s) —NR 6 R 8 , (t) —OR 8 , (u) —(CR 6 R 6 ) t NR 6 R 8 , (v) —CR 6 R 8 R 8 , (x) -3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (cc) —NR 6 C(O)R 6 , and (dd) —C(═NR 6 )NR 6 R 6 ;
 wherein (m), (p), and (x) are optionally substituted with one or more R 9 ; 
 
 R 8  is selected from (a) hydrogen, (b) F, (j) —NR 6 R 9 , (k) —OR 9 , (l) —NR 6 (CNR 6 )NR 6 R 6 , (m) —C 1-8  alkyl, (p) —(C 1-8  alkyl)-(3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (r) -3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (u) —C(O)(CR 6 R 6 ) t R 9 , (z) —NR 6 (CNR 9 )(NR 6 R 6 ), (bb) —C(═NR 9 )NR 6 R 6 , (dd) —(CR 6 R 6 ) t C(O)NR 6 R 9 , (ee) —(CR 6 R 6 ) t OR 9 , and (ff) —(CR 6 R 6 ) t NR 6 R 9 ;
 wherein (m), (p), and (r) are optionally substituted with one or more R 9 ; 
 
 R 9  is selected from (a) hydrogen, (b) F, (j) —NR 6 R 10 , (k) —OR 6 , (l) —NR 6 (CNR 6 )NR 6 R 6 , (n) —C 1-8  alkyl, (q) -3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (t) —(CR 6 R 6 ) t OR 6 , (z) —(C 1-8  alkyl)-(3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (cc) —C(═NR 6 )NR 6 R 6 , and (hh) —(CR 6 R 6 ) t NR 6 R 10 ;
 wherein (n), (q), and (z) are optionally substituted with one or more R 10 ; 
 
 R 10  is selected from (a) hydrogen, (b) F, (j) —NR 6 R 6 , (k) —OR 6 , (l) —NR 6 (CNR 6 )NR 6 R 6 , (q) -3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, (t) —(CR 6 R 6 ) t OR 6 , (z) —(C 1-8  alkyl)-(3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), (cc) —C(═NR 6 )NR 6 R 6 , and (hh) —(CR 6 R 6 ) t NR 6 R 6 ; 
 p is 0, 1, or 2, and 
 t is 0, 1, 2, or 3, 
 or a pharmaceutically acceptable salt, ester, or tautomer thereof. 
 
     
     
         2 . The compound according to  claim 1 , wherein Z is selected from the group —NR 4 , —NR 4 CO—, and —NR 4 CONR 4 —; or a pharmaceutically acceptable salt, ester, or tautomer thereof. 
     
     
         3 . The compound according to  claim 2 , wherein Z is —NR 4 CONR 4 —; or a pharmaceutically acceptable salt, ester, or tautomer thereof. 
     
     
         4 . The compound according to  claim 3 , wherein Z is —NHCONH—; or a pharmaceutically acceptable salt, ester, or tautomer thereof. 
     
     
         5 . The compound according  claim 4 , wherein:
 A is (c) a single bond,   B is selected from (a) —(C 1-8  alkyl)- and (d) a single bond, wherein
 i) 0-4 carbon atoms in (a) immediately above optionally is replaced by a moiety selected from the group consisting of —NR 6 —, —(C═O)—, and —C(═NR 6 )—, 
 ii) (a) immediately above optionally is substituted with one or more R 5  groups, and 
 iii) (a) immediately above optionally is substituted with —(C 1 -C 8  alkyl)-R 5  groups, and 
   C is selected from (a) NH 2 , (b) —NHC(═NH)NH 2  and (c) hydrogen;   or a pharmaceutically acceptable salt, ester, or tautomer thereof.   
     
     
         6 . The compound according to  claim 5 , wherein:
 A is a single bond;   B is (a) —(C 1-8  alkyl)-, wherein
 i) 0-4 carbon atoms in (a) immediately above optionally is replaced by a moiety selected from the group consisting of —NR 6 — and —(C═O)—, 
 ii) (a) immediately above optionally is substituted with one or more R 5  groups, and 
 iii) (a) immediately above optionally is substituted with —(C 1-8  alkyl)-R 5  groups; and 
   alternatively, B is a single bond;   C is selected from (a) NH 2 , (b) —NHC(═NH)NH 2  and (c) hydrogen;   or a pharmaceutically acceptable salt, ester, or tautomer thereof.   
     
     
         7 . The compound according to  claim 4 , wherein G is (c) a single bond;
 or a pharmaceutically acceptable salt, ester, or tautomer thereof.   
     
     
         8 . The compound according to  claim 5 , wherein R 5  is selected from (a) hydrogen, (b) F, (j) —NH 2 , (l) —NHC(═NH)NH 2 , (m) —C 1-8  alkyl, (p) —(C 1-8  alkyl)-(3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur), and (t) -3-14 member saturated, unsaturated, or aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; or a pharmaceutically acceptable salt, ester, or tautomer thereof. 
     
     
         9 . The compound according to  claim 5 , wherein R 6  is (b) —C 1-8  alkyl; or a pharmaceutically acceptable salt, ester, or tautomer thereof. 
     
     
         10 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt, ester, or tautomer thereof. 
       
     
     
         11 . A pharmaceutical composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable carrier. 
     
     
         12 . A pharmaceutical composition comprising a compound according to  claim 10 , or a pharmaceutically acceptable salt or tautomer thereof, and a pharmaceutically acceptable carrier.