Bifunctional heterocyclic compounds and methods of making and using same

Abstract

The invention provides a family of bifunctional heterocyclic compounds useful as anti-infective, anti-proliferative, anti-inflammatory, and prokinetic agents. The invention also provides methods of making the bifunctional heterocyclic compounds, and methods of using such compounds as anti-infective, anti-proliferative agents, anti-inflammatory, and/or prokinetic agents.

1 . A method of treating a disease in a mammal, wherein the disease is selected from microbial infection, fungal infection, proliferative disease, viral infection, inflammatory disease, and gastrointestinal motility disorder, comprising administering a compound having the formula:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or prodrug thereof,  
       wherein 
 A at each occurrence, is carbon;  
 B is selected from the group consisting of O, NR 2 , S(O) r , C═O, C═S, and C═NOR 3 ,  
 p is 0;  
 q, at each occurrence, independently is 0 or 1;  
 r is 0, 1, or 2;  
 R 2 , at each occurrence, independently is selected from the group consisting of: 
 a) hydrogen, b) S(O) r R 4 , c) formyl, d) C 1-8  alkyl, e) C 2-8  alkenyl, f) C 2-8  alkynyl,  
 
 g) C 1-8  alkoxy, h) C 1-8  alkylthio, i) C 1-8  acyl, j) saturated, unsaturated, or aromatic C 3-8  carbocycle, and k) saturated, unsaturated, or aromatic 5-10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, 
 wherein any of d)-k) optionally is substituted with one or more moieties selected from the group consisting of carbonyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, F, Cl, Br, I, CN, NO 2 , —NR 3 R 3 , —OR 3 —S(O) r R 4 , S(O) r NR 3 R 3 , —C(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —C(O)NR 3 R 3 , and —OC(O)NR 3 R 3 ;  
 
 alternatively, two R 2  groups, taken together with the atom to which they are bonded, form  
 i) 5-8 membered saturated or unsaturated carbocycle, or ii) 5-8 membered saturated or unsaturated heterocycle containing one or more atoms selected from the group consisting of nitrogen, oxygen, and sulfur, 
 wherein i)-ii) optionally is substituted with one or more moieties selected from the group consisting of carbonyl, F, Cl, Br, I, CN, NO 2 , —NR 3 R 3 , —OR 3 , —S(O) r R 4 —S(O) r NR 3 R 3 , —C(O)R 3 , —C(O)OR 3 , —OC(O)R 3 —C(O)NR 3 R 3 , —OC(O)NR 3 R 3 C 1-6  acyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;  
 
 R 3 , at each occurrence, independently is selected from the group consisting of: 
 a) hydrogen, b) C 1-8  alkyl, c) C 2-8  alkenyl, d) C 2-8  alkynyl, e) C 1-8  acyl, f) saturated, unsaturated, or aromatic C 3-8  carbocycle, and g) saturated, unsaturated, or aromatic 5-10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, 
 wherein any of b)-h) optionally is substituted with one or more moieties selected from the group consisting of carbonyl, F, Cl, Br, I, CN, NO 2 , —NR 6 R 6 , —OR 6 , —S(O) r R 6 , —S(O) r NR 6 R 6 , —C(O)R 6 —C(O)OR 6 , —OC(O)R 6 , —C(O)NR 6 R 6 , —OC(O)NR 6 R 6 , C 1-6  acyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;  
 
 
 alternatively, two R 3  groups, taken together with the atom to which they are bonded, form i) a 5-7 membered saturated or unsaturated carbocycle, or ii) a 5-7 membered saturated or unsaturated heterocycle containing one or more atoms selected from the group consisting of nitrogen, oxygen, and sulfur, 
 wherein i)-ii) optionally is substituted with one or more moieties selected from the group consisting of carbonyl, F, Cl, Br, I, CN, NO 2 , —NR 6 R 6 , —OR 6 , S(O) r R 6 , S(O) r NR 6 R 6 , —C(O)R 6 , —C(O)OR 6 , —OC(O)R 6 , —C(O)NR 6 R 6 , —OC(O)NR 6 R 6 , C 1-6  acyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;  
 
 R 4  is selected from the group consisting of: 
 a) hydrogen, b) —NR 3 R 3 , c) —NR 3 OR 3 , d) —NR 3 NR 3 R 3  e) —NHC(O)R 3 , f) —C(O)NR 3 R 3 , g) —N 3 , h) C 1-8  alkyl, i) C 2-8  alkenyl, j) C 2-8  alkynyl, k) saturated, unsaturated, or aromatic C 3-8  carbocycle, and 1) saturated, unsaturated, or aromatic 5-10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, 
 wherein any of h) —1) optionally is substituted with one or more moieties selected from the group consisting of carbonyl, F, Cl, Br, I, CN, NO 2 , —NR 3 R 3 , —OR 3 , —SR 3 , S(O) r R 5 , —S(O) r NR 3 R 3 , —C(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —C(O)NR 3 R 3 , —OC(O)NR 3 R 3 , C 1-6  alkyl, C 1-6  alkenyl, C 1-6  alkynyl, C 1-6  acyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;  
 
 
 R 5  is selected from the group consisting of: 
 a) hydrogen, b) —NR 3 R 3 , c) —NR 3 OR 3 , d) —NR 3 NR 3 R 3  e) —NHC(O)R 3 , f) —C(O)NR 3 R 3 , g) —N 3 , h) C 1-8  alkyl, i) C 2-8  alkenyl, j) C 2-8  alkynyl, k) saturated, unsaturated, or aromatic C 3-8  carbocycle, and l) saturated, unsaturated, or aromatic 5-10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, 
 wherein any of h)-l) optionally is substituted with one or more moieties selected from the group consisting of F, Cl, Br, I, CN, NO 2 , —NR 3 R 3 , —OR 3 —SR 3 —C(O)R 3 , —C(O)OR 3 , —OC(O)R 3 , —C(O)NR 3 R 3 , —OC(O)NR 3 R 3 ,  
 
 
 C 1-6  alkyl, C 1-6  alkenyl, C 1-6  alkynyl, C 1-6  acyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;  
 R 6 , at each occurrence, independently is selected from the group consisting of: 
 hydrogen, C 1-6  alkyl, C 1-6  alkenyl, C 1-6  alkynyl, C 1-6  acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl;  
 
 alternatively, two R 6 groups taken together are —(CH 2 ) s —, 
 wherein s is 1, 2, 3, 4, or 5;  
 
 D-E is:  
                     
 E is selected from the group consisting of:  
                     
 d) 5-10 membered aromatic heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally substituted with one or more R 13  groups; and  
 e) C 5-10  aromatic carbocycle, optionally substituted with one or more R 13  groups;  
 R 7  is selected from the group consisting of: 
 a) hydrogen, b) carbonyl, c) formyl, d) F, e) Cl, f) Br, g) I, h) CN, i) NO 2 , j) OR 3 , k) —S(O) r R 5 , l) —S(O) i N═R 2 , m) —C(O)R 2 , n) —C(O)OR 3 , o) —OC(O)R 2 , p) —C(O)NR 2 R 2 , q) —OC(O)NR 2 R 2 , r) —C(═NR 2 )R 2 , s) —C(R 2 )(R 2 )OR 3 , t) —C(R 2 )(R 2 )OC(O)R 2 , u) —C(R 2 )(OR 3 )(CH 2 ) r NR 2 R 2 , v) —NR 2 R 2 , w) —NR 2 OR 3 , x) —N(R 2 )C(O)R 2 , y) —N(R 2 )C(O)OR 3 , z) —N(R 2 )C(O)NR 2 R 2 , aa) —N(R 2 )S(O) r R 5 , bb) —C(OR 6 )(OR)R 2 , cc) —C(R 2 )(R 3 )NR 2 R 2 , dd) —C(R 2 )(R 3 )NR 2 R 2 , ee) ═NR 2 , ff) —C(S)NR 2 R 2 , gg) —N(R 2 )C(S)R 2 , hh) —OC(S)NR 2 R 2 , ii) —N(R 2 )C(S)OR 3 , jj) —N(R 2 )C(S)NR 2 R 2 , kk) —SC(O)R 2 , ll) C 1-8  alkyl, mm) C 2-8  alkenyl, nn) C 2-8  alkynyl, oo) C 1-8  alkoxy, pp) C 1-8  alkylthio, qq) C 1-8  acyl, m) saturated, unsaturated, or aromatic C 5-10  carbocycle, and ss) saturated, unsaturated, or aromatic 5-10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, 
 wherein any of ll)-ss) optionally is substituted with one or more moieties selected from the group consisting of:  
 carbonyl; formyl; F; Cl; Br; I; CN; NO 2 ; OR 3 ; —S(O) r R 5 ; —S(O) r N═R 2 , —C(O)R 2 ; —C(O)OR 3 ; —OC(O)R 2 ; —C(O)NR 2 R 2 ; —OC(O)NR 2 R 2 ; —C(═NR 10 )R 2 ; —C(R 2 )(R 2 )OR 3 ; —C(R 2 )(R 2 )OC(O)R 2 —C(R   2 )(OR 3 )(CH 2 ) r NR 2 R 2 ; —NR 2 R 2 ; —NR 2 OR′; —NR 2 C(O)R 2 ; —NR 2 C(O)OR 3 ; —NR 2 C(O)NR 2 R 2 ; —NR 2 S(O) r R 5 ; —C(OR 6 )(OR 6 )R 2 ; —C(R 2 )(R 3 )NR 2 R 2 ; —C(R 2 )(R 3 )NR 2 R 12 ; ═NR 12 ; —C(S)NR 2 R 2 ; —NR 2 C(S)R 2 ; —OC(S)NR 2 R 2 ; —NR 2 C(S)OR 3 ; —NR 2 C(S)NR 2 R 2 ; —SC(O)R 2 ; C 2-5  alkenyl; C 2-5  alkynyl; C 1-8  alkoxy; C 1-8  alkylthio; C 1-8  acyl; saturated, unsaturated, or aromatic C 5-10  carbocycle, optionally substituted with one or more R 8  groups; and saturated, unsaturated, or aromatic 5-10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally substituted with one or more R 8  groups;  
 
 
 R 8  is selected from the group consisting of: 
 hydrogen; F; Cl; Br; I; CN; NO 2 ; OR 6 ; aryl; substituted aryl; heteroaryl; substituted heteroaryl; and C 1-6  alkyl, optionally substituted with one or more moieties selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, F, Cl, Br, I, CN, NO 2 , and OR 6 ;  
 
 alternatively, R 7  and R 8  taken together are —O(CH 2 ) r C—;  
 R 9 , at each occurrence, independently is selected from the group consisting of: 
 hydrogen, F, Cl, Br, I, CN, OR 3 , NO 2 , —NR 2 R 2 , C 1-6  alkyl, C 1-6  acyl, and C 1-6  alkoxy;  
 
 R 10  is selected from the group consisting of: 
 a) saturated, unsaturated, or aromatic C 5-10  carbocycle, b) saturated, unsaturated, or aromatic 5-10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, c) —X—C 1-6  alkyl-saturated, unsaturated, or aromatic 5-10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, d) saturated, unsaturated, or aromatic 10-membered bicyclic ring system optionally containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, e) saturated, unsaturated, or aromatic 13-membered tricyclic ring system optionally containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and f) R 9 , 
 wherein  
 any of a)-e) optionally is substituted with one or more R 13 groups, and  
 X is O or NR 3 ;  
 
 
 alternatively, R 10  and one R 9  group, taken together with the atoms to which they are bonded, form a 5-7 membered saturated or unsaturated carbocycle, optionally substituted with one or more R 13  groups; or a 5-7 membered saturated or unsaturated heterocycle containing one or more atoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally substituted with one or more R 13  groups;  
 R 11  at each occurrence, independently is selected from the group consisting of: 
 hydrogen; an electron-withdrawing group; aryl; substituted aryl; heteroaryl; substituted heteroaryl; and C 1-6  alkyl, optionally substituted with F, Cl, or Br;  
 
 alternatively, any R 11  and R 8 , taken together with the atoms to which they are bonded, form a 5-7 membered saturated or unsaturated carbocycle, optionally substituted with one or more R 13  groups; or a 5-7 membered saturated or unsaturated heterocycle containing one or more atoms selected from the group consisting of nitrogen, oxygen, and sulfur, and optionally substituted with one or more R 13  groups;  
 R 12  is selected from the group consisting of: 
 —NR 2 R 2 , —OR 3 , —OC(O)R 2 , —OC(O)OR 3 , —NR 2 C(O)R 2 , —NR 2 C(O)NR 2 R 2 , —NR 2 C(S)NR 2 R 2 , and —NR 2 C(═NR 2 )NR 2 R 2 ;  
 
 R 13 , at each occurrence, independently is selected from the group consisting of: 
 a) hydrogen, b) carbonyl, c) formyl d) F, e) Cl, f) Br, g) I, h) CN, i) NO 2 , j) OR 3 , k) —S(O) r R 5 , l) —S(O) r N═R 3 , m) —C(O)R 2 , n) —C(O)OR 3 , o) —OC(O)R 2 , p) —C(O)NR 2 R 2 , q) —OC(O)NR 2 R 2 , r) —C(═NR 12 )R 2 , s) —C(R 2 )(R 2 )OR 3 , t) —C(R 2 )(R 2 )OC(O)R 2 , u) —C(R 2 )(OR 3 )(CH 2 ) r NR 2 R 2 , v) —NR 2 R 2 , w) —NR 1 OR 3 , x) —N(R 2 )C(O)R 2 , y) —N(R 2 )C(O)OR 3 , z) —N(R 2 )C(O)NR 2 R 2 , aa) —N(R 2 )S(O) r R 5 , bb) —C(OR 6 )(OR 6 )R 2 , cc) —C(R 2 )(R 3 )NR 2 R 2 , dd) —C(R 2 )(R 3 )NR 2 R 12 , ee) ═NR 12 , ff) —C(S)NR 2 R 2 , gg) —N(R 2 )C(S)R 2 , hh) —OC(S)NR 2 R 2 , ii) —N(R 2 )C(S)OR 3 , jj) —N(R 2 )C(S)NR 2 R 2 , kk) —SC(O)R 2 , ll) C 1-8  alkyl, mm) C 2-8  alkenyl, nn) C 2-8  alkynyl, oo) C 1-8  alkoxy, pp) C 1-8  alkylthio, qq) C 1-8  acyl, m) saturated, unsaturated, or aromatic C 5-10  carbocycle, ss) saturated, unsaturated, or aromatic 5-10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, tt) saturated, unsaturated, or aromatic 10-membered bicyclic ring system optionally containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and uu) saturated, unsaturated, or aromatic 13-membered tricyclic ring system optionally containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, 
 wherein any of ll)-uu) optionally is substituted with one or more moieties selected from the group consisting of: 
 carbonyl; formyl; F; Cl; Br; I; CN; NO 2 ; OR 3 ; —S(O) r R 5 ; —S(O) r N═R 2 , —C(O)R 2 ; —C(O)OR 3 ; —OC(O)R 2 ; —C(O)NR 2 R 2 ; —OC(O)NR 2 R 2 ; —C(═NR 12 )R 2 ; —C(R 2 )(R 2 )OR 3 ; —C(R 2 )(R 2 )OC(O)R 2 ; —C(R 2 )(OR 3 )(CH 2 ) r NR 2 R 2 ; —NR 2 R 2 ; —NR 2 OR 3 ; —NR 2 C(O)R 2 ; —NR 2 C(O)OR; —NR 2 C(O)NR 2 R 2 ; —NR 2 S(O) r R 5 ; —C(OR 6 )(OR 6 )R 2 ; —C(R 2 )(R 3 )NR 2 R 2 ; —C(R 2 )(R 3 )NR 2 R 2 ; ═NR 2 ; —C(S)NR 2 R 2 ; —NR 2 C(S)R 2 ; —OC(S)NR 2 R 2 ; —NR 2 C(S)OR 3 ; —NR 2 C(S)NR 2 R 2 ; —SC(O)R 2 ; C 1-8  alkyl, C 2-8  alkenyl; C 2-8  alkynyl; C 1-8  alkoxy; C 1-8  alkylthio; C 1-8  acyl; saturated, unsaturated, or aromatic C 3-10  carbocycle optionally substituted with one or more R 7  groups; and saturated, unsaturated, or aromatic 3-10 membered heterocycle containing one or more heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and substituted with one or more R 7  groups;  
 
 
 
 G is selected from the group consisting of:  
                     
 t, at each occurrence, independently is 0, 1, 2, or 3;  
 R 14  is selected from the group consisting of: 
 a) hydrogen, b) C 1-6 -alkyl, c) C 2-6  alkenyl, d) C 2-6  alkynyl, e) —C(O)—R 3 , f) —C(O)—C 1-6  alkyl-R 3 , g) —C(O)—C 2-6  alkenyl-R 3 , h) —C(O)—C 2-6  alkynyl-R 3 , i) —C 1-6  alkyl-J-R 3 , j) —C 2-6  alkenyl-J-R 3 ; and k) —C 2-6  alkynyl-J-R 3 ; 
 wherein  
 (i) any of b)-d) optionally is substituted with one or more substituents selected from the group consisting of: 
 F, Cl, Br, I, aryl, substituted aryl, heteroaryl, substituted heteroaryl, —OR 3 , —O—C 1-6  alkyl-R 22 , —O—C 2-6  alkenyl-R 22 , —O—C 2-6  alkynyl-R 3 , and —NR 2 R 2 ; and  
 
 (ii) J is selected from the group consisting of: —OC(O), —OC(O)O—, —OC(O)NR 2 —, —C(O)NR 2 —, —NR 2 C(O—, —NR 2 C(O)O—, —NR 2 C(O)NR 2 —, —NR 2 C(NH)NR 2 —, and S(O) r ; and  
 
 
 R 15  is selected from the group consisting of: 
 hydrogen; C 1-10  alkyl, optionally substituted with one or more R 13  groups; C 1-6  acyl, optionally substituted with one or more R 13  groups; aryl; substituted aryl; heteroaryl; substituted heteroaryl; arylalkyl; substituted arylalkyl; and a macrolide.  
 
 
     
     
         2 . The method of  claim 1 , wherein the compound is administered orally, paternally, or topically.  
     
     
         3 . The method of  claim 1 , wherein the disease is a microbial infection.  
     
     
         4 . The method of  claim 1 , wherein the disease is a fungal infection.  
     
     
         5 . The method of  claim 1 , wherein the disease is a proliferative disease.  
     
     
         6 . The method of  claim 1 , wherein the disease is a viral infection.  
     
     
         7 . The method of  claim 1 , wherein the disease is an inflammatory disease.  
     
     
         8 . The method of  claim 1 , wherein the disease is a gastrointestinal motility disorder.  
     
     
         9 . The method of  claim 1 , wherein the compound has the formula:  
       
         
           
           
               
               
           
         
       
       wherein A, E, and G are as defined in  claim 1 .  
     
     
         10 . The method of  claim 1 , wherein E has the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 9  and R 10 , at each occurrence, are as defined in  claim 1 .  
     
     
         11 . The method of  claim 1 , wherein E has the formula:  
       
         
           
           
               
               
           
         
       
       wherein R 10  is as defined in  claim 1 .  
     
     
         12 . The method of  claim 10 , wherein R 10  has the formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 K is selected from the group consisting of O, NR 2 , and S(O) r , and  
 x is 0, 1, 2, or 3.  
 
     
     
         13 . The method of  claim 12 , wherein K is oxygen.  
     
     
         14 . The method of  claim 12 , wherein x is 1.  
     
     
         15 . The method of  claim 1 , wherein G has the formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       and R 15  is a macrolide.  
     
     
         16 . The method of  claim 1 , wherein R 15  is selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts, esters and prodrugs thereof, wherein 
 R 17  is selected from the group consisting of: 
 hydrogen, hydroxy protecting group, R 3 , and —V—W—R 13 , 
 wherein 
 V is —C(O), —C(O)O—, —C(O)NR 2 —, or absent, and  
 W is C 1-6  alkyl, or absent;  
 
 
 
 alternatively R 17  and R 14 , taken together with the atoms to which they are bonded, form:  
                     
 Q is selected from the group consisting of: 
 —NR 2 CH 2 —, —CH 2 —NR 2 —, —C(O)—, —C(═NR 2 )—, —C(═NOR 3 )—, —C(═N—NR 2 R 2 )—, —CH(OR 3 )—, and —CH(NR 2 R 2 ;  
 
 R 18  is selected from the group consisting of: 
 i) C 1-6  alkyl, ii) C 2-6  alkenyl, and iii) C 2-6  alkynyl; 
 wherein any of i) —11i) optionally is substituted with one or more moieties selected from the group consisting of —OR 3 , aryl, substituted aryl, heteroaryl, and substituted heteroaryl;  
 
 
 R 19  is selected from the group consisting of: 
 a) —OR 17 , b) C 1-6 alkyl, c) C 2-6  alkenyl, d) C 2-6  alkynyl, e) —NR 2 R 2 , f) —C(O)R 3 ,  
 g) —C(O)—C 1-6  alkyl-R 13 , h) —C(O)—C 2-6  alkenyl-R 3 , and i) —C(O)—C 2-6  alkynyl-R 13 , 
 wherein any of b)-d) optionally is substituted with one or more R 13  groups;  
 
 
 alternatively, R 14  and R 19 , taken together with the atoms to which they are bonded, form:  
                     wherein 
 L is CH or N, and  
 R 23  is —OR 3 , or R 3 ;  
   
 R 20  is —OR 17 ;  
 alternatively, R 19  and R 20 , taken together with the atoms to which they are bonded, form a 5-membered ring by attachment to each other through a linker selected from the group consisting of:  
 —OC(R 2 )(R 2 )O—, —OC(O)O—, —OC(O)NR 2 —, —NR 2 C(O)O—, —OC(O)NOR 3 —, —N(OR 3 )C(O)O—, —OC(O)N—NR 2 R 2 —, —N(NR 2 R 2 )C(O)O—, —OC(O)CHR 2 —, —CHR 2 C(O)O—, —OC(S)O—, —OC(S)NR 2 —, —NR 2 C(S)O—, —OC(S)NOR 3 —, —N(OR 3 )C(S)O—, —OC(S)N—NR 2 R 2 —, —N(NR 2 R 2 )C(S)G, —OC(S)CHR 2 —, and —CHR 2 C(S)O—;  
 alternatively, Q, R 19 , and R 20 , taken together with the atoms to which they are bonded, form:  
                     wherein 
 M is O or NR 2 ;  
   
 R 21  is selected from the group consisting of: 
 hydrogen, F, Cl, Br, and C 1-6  alkyl;  
 
 R 22 , at each occurrence, independently is selected from the group consisting of: 
 hydrogen, —OR 3 , —O-hydroxy protecting group, —O—C-6 alkyl-J-R 13 , —O—C 2-6  alkenyl-J-R 1 , —O—C 1-6  alkynyl-J-R 3 , and —NR 2 R 2 ;  
 
 alternatively, two R 22  groups taken together are ═O, ═N—OR 3 , or ═N—NR 2 R 2 ; and  
 R 2 , R 3 , R 13 , R 14 , and J are as described in  claim 1 .  
 
     
     
         17 . The method of  claim 1 , wherein G has the formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       and R 15  has the formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         18 . The method of  claim 1 , wherein G has the formula:  
       
         
           
           
               
               
           
         
       
       wherein n=1, 2, 3, or 4.  
     
     
         19 . The method of  claim 1 , wherein G has the formula selected from the group consisting of:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         20 . The method of  claim 1 , comprising a compound having the structure corresponding to any of the structures listed below:  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, ester, or prodrug thereof.