Macrolide antibiotics

Abstract

A macrolide antibiotic of the formula wherein the variables are defined as described herein.

What is claimed is:  
     
         1 . A compound of the formula  
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, prodrugs and solvates thereof, wherein: 
 X is CR 9 R 10 , O, NR 11 , or S, or X may, together with R 2 , form a 4- to 10-membered carbocyclic or 4- to 10 membered heterocyclic group wherein said 4- to 10-membered carbocyclic or 4- to 10 membered heterocyclic group is optionally substituted by 1 to 4 R 14  groups;  
 Z is —C(═O)—, —C(═NOR 13 )—, —CH(NR 11 R 12 )—, —N(R 2 )CH 2 —, or —CH 2 N(R 2 )—;  
 R 1  is H, OR 16 , C 1 -C 6  alkyl, (4- to 10-membered heterocyclic) C 0 -C 6  alkyl, or (C 6 -C 10  aryl) C 0 -C 6  alkyl;  
 R 2  is selected from H, C 1 -C 16  alkyl, C 2 -C 16  alkenyl, C 2 -C 16  alkynyl, (4- to 10-membered heterocyclic) C 0 -C 6  alkyl, (4- to 10-membered heterocyclic) C 2 -C 6  alkenyl, (4- to 10-membered heterocyclic) C 2 -C 6  alkynyl, (C 6 -C 10  aryl) C 0 -C 6  alkyl, (C 6 -C 10  aryl) C 2 C 6  alkenyl, and (C 6 -C 10  aryl) C 2 -C 6  alkynyl, wherein the alkyl, alkenyl, and alkynyl moieties of the foregoing groups are optionally substituted by halo or C 1 -C 6  alkyl, wherein one to three carbons of said C 1 -C 16  alkyl, C 2 -C 16  alkenyl, and C 2 -C 16  alkynyl, are, where possible, optionally replaced by O, N, or S, and further wherein the aryl and heterocyclic moieties of each of the foregoing groups and optional substituents are optionally substituted by 1 to 4 R 14  groups, or XR 2  may form a 4- to 10-membered carbocyclic or 4- to 10 membered heterocyclic group wherein said 4- to 10-membered carbocyclic or 4- to 10 membered heterocyclic group is optionally substituted by 1 to 4 R 14  groups;  
 R is selected from C 1 -C 16  alkyl, C 2 -C 16  alkenyl, C 2 -C 16  alkynyl, (4- to 10-membered heterocyclic) C 0 -C 6  alkyl, (4- to 10-membered heterocyclic) C 2 -C 6  alkenyl, (4- to 10-membered heterocyclic) C 2 -C 6  alkynyl, (C 6 -C 10  aryl) C 0 -C 6  alkyl, (C 6 -C 10  aryl) C 2 -C 6  alkenyl, and (C 6 -C 10  aryl) C 2 -C 6  alkynyl, wherein the alkyl, alkenyl, and alkynyl moieties of the foregoing groups are optionally substituted by halo or C 1 -C 6  alkyl, and further wherein the aryl and heterocyclic moieties of each of the foregoing groups and optional substituents are optionally substituted by 1 to 4 R 14  groups;  
 R 1  and R 3  together can form ═O or ═NOR 13 ;  
 R 4 is H or OR 19 ;  
 or Z and R 4  together form a group of the formula  
                     
 wherein C 10 , C 8 , and C 6  indicate carbon atoms of the macrolide ring of formula I to which the group is attached;  
 
         V is O, or NR 17 ;  
         R 5  and R 7  are OH, or together form a group of the formula  
         
           
             
             
                 
                 
             
           
         
         wherein J is selected from O, NR 15 , NOR 15 , and N—NR 15 ;  
         R 6  is H, —C(O)C 1 -C 6  alkyl, benzyl, benzyloxycarbonyl, or (C 1 -C 6  alkyl) 3  silyl;  
         R 8  is selected from C 1 -C 10  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, (C 1 -C 6  alkoxy) C 1 -C 6  alkyl, (C 1 -C 6  alkylthio) C 1 -C 6  alkyl, (C 5 -C 8  cycloalkyl) C 2 -C 5  alpha branched alkyl, C 3 -C 8  cycloalkyl, C 5 -C 8  cycloalkenyl, (4- to 10-membered heterocyclic) C 1 -C 6  alkyl, (C 6 -C 10  aryl) C 1 -C 6  alkyl, wherein one or more carbons of R 8  may be replaced with one or more heteroatoms selected from O, S, N and R 8  is optionally substituted with from one to four R 14  groups;  
         R 9  and R 10  are independently selected from H and C 1 -C 6  alkyl;  
         each R 11  and R 12  is independently selected from H, C 1 -C 6  alkyl, C 6 -C 10  aryl, and 4- to 10-membered heterocyclic;  
         each R 13  is independently selected from H, C 1 -C 6  alkyl, (4- to 10-membered heterocyclic) C 0 -C 6  alkyl and (C 6 -C 10  aryl) C 0 -C 6  alkyl, wherein said aryl and heterocyclic groups are optionally substituted by 1 to 4 R 14  groups;  
         each R 14  is independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R 14a , —C(O)OR 14a , —OC(O)R 14a , —NR 11 C(O)R 14a , —C(O)NR 11 R 14a , —NR 11 R 14a , hydroxy, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, (C 6 -C 10  aryl) C 0 -C 6  alkyl, (4- to 10-membered heterocyclic) C 0 -C 6  alkyl, C 1 -C 6  alkoxy, C 6 -C 10  aryloxy, —S(O) j (C 0 -C 6  alkyl) wherein said C 0 -C 6  alkyl is optionally substituted by 1 to 10 R 14a  groups, —S(O) j (C 2 -C 6  alkenyl) wherein said C 2 -C 6  alkenyl is optionally substituted by 1 to 7 R 14a  groups, where each j is an integer from 0 to 2, and —SO 2 NR 11 R 14a , wherein said aryl or heterocyclic group is optionally substituted by 1 to 4 R 14a  groups;  
         each R 14a  is independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R 11 , —C(O)OR 11 , —OC(O)R 11 , —NR 11 C(O)R 12 , —C(O)NR 11 R 12 , —NR 11 R 12 , hydroxy, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, (C 6 -C 10  aryl) C 0 -C 6  alkyl, (4- to 10-membered heterocyclic) C 0 -C 6  alkyl, C 1 -C 6  alkoxy, C 6 -C 10  aryloxy, —S(O) k (C 0 -C 6  alkyl), —S(O) k (C 2 -C 6  alkenyl) where each k is an integer from 0 to 2, and SO 2 NR 11 R 12 , wherein said aryl or heterocyclic group is optionally substituted by from one to four groups selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R 11 , —C(O)OR 11 , —OC(O)R 11 , —NR 11 C(O)R 12 , —C(O)NR 11 R 12 , —NR 11 R 12 , hydroxy, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, (C 6 -C 10  aryl) C 0 -C 6  alkyl, (4- to 10-membered heterocyclic) C 0 -C 6  alkyl, C 1 -C 6  alkoxy, C 6 -C 10  aryloxy, —S(O) l (C 0 -C 6  alkyl), —S(O) l (C 2 -C 6  alkenyl) and —SO 2 NR 11 R 12  wherein each l is an integer from 0 to 2;  
         R 15  is selected from H, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 10  alkynyl, (4- to 10-membered heterocyclic) C 1 -C 6  alkyl, (4- to 10-membered heterocyclic) C 2 -C 6  alkenyl, (4- to 10-membered heterocyclic) C 2 -C 6  alkynyl, (C 6 -C 10  aryl) C 1 -C 6  alkyl, (C 6 -C 10  aryl) C 2 -C 6  alkenyl, and (C 6 -C 10  aryl) C 2 -C 6  alkynyl, wherein the alkyl, alkenyl, and alkynyl moieties of the foregoing groups are optionally substituted by halo or C 1 -C 6  alkyl, and wherein said heterocyclic moieties are optionally substituted by (4- to 10-membered heterocyclic) C 0 -C 6  alkyl, or (C 6 -C 10  aryl) C 0 -C 6  alkyl, and further wherein the aryl and heterocyclic moieties of each of the foregoing groups and optional substituents are optionally substituted by 1 to 4 R 14  groups; and  
         R 16  is selected from H and C 1 -C 6  alkyl, wherein one to three carbons of said alkyl are optionally replaced with a heteroatom selected from O, S, and N;  
         R 17  is H, OR 16 , NR 16 R 18 , C 1 -C 16  alkyl, (C 6 -C 10  aryl) C 0 -C 6  alkyl, or (4- to 10-membered heterocyclic) C 0 -C 6  alkyl;  
         R 18  is H, or C 1 -C 6  alkyl wherein one or more carbons of said C 1 -C 6  alkyl are optionally replaced with one or more heteroatoms selected from O, N, and S and optionally substituted by R 14 , and  
         R 19  is selected from H, C 1 -C 16  alkyl, C 2 -C 16  alkenyl, C 2 -C 16  alkynyl, (4- to 10-membered heterocyclic) C 0 -C 6  alkyl, (4- to 10-membered heterocyclic) C 2 -C 6  alkenyl, (4- to 10-membered heterocyclic) C 2 -C 6  alkynyl, (C 6 -C 10  aryl) C 0 -C 6  alkyl, (C 6 -C 10  aryl) C 2 -C 6  alkenyl, and (C 6 -C 10  aryl) C 2 -C 6  alkynyl, wherein the alkyl, alkenyl, and alkynyl moieties of the foregoing groups are optionally substituted by halo or C 1 -C 6  alkyl, wherein one to three carbons of said C 1 -C 16  alkyl, C 2 -C 16  alkenyl, and C 2 -C 16  alkynyl, are, where possible, optionally replaced by O, N, or S, and further wherein the aryl and heterocyclic moieties of each of the foregoing groups and optional substituents are optionally substituted by 1 to 4 R 14  groups.  
       
     
     
         2 . The compound of  claim 1  wherein X is O, CR 9 R 10  or NR 11 , R 1  is H, R 2  is H or optionally substituted C 1 -C 16  alkyl, C 2 -C 6  alkenyl, C 1 -C 6  thioalkyl, (C 6 -C 10  aryl) C 0 -C 6  alkyl, or (4 to 10 membered heterocyclic) C 0 -C 6  alkyl and R 3  is optionally substituted (4 to 10 membered heterocyclic) C 0 -C 6  alkyl or optionally substituted (C 6 -C 10  aryl) C 0 -C 6  alkyl.  
     
     
         3 . The compound of  claim 1  wherein R 6  is-H, R 4  is OMe, Z is (C═O), R 5  and R 7  together with the carbons to which they are attached form C 11 —NH—C(═O)—O—C 12 , and R 8  is ethyl.  
     
     
         4 . The compound of  claim 1  wherein R 6  is H, R 4  and Z together form a cyclic carbonate, R 5  and R 7  together form a cyclic carbonate, and R 8  is ethyl.  
     
     
         5 . The compound of  claim 1  wherein R 4  is OH, R 6  is H, Z is CHNH 2 , R 5  is OH, R 7  is OH, and R 8  is ethyl.  
     
     
         6 . The compound of  claim 1  wherein R 4  is OH, R 5  is OH, R 6  is H, R 7  is OH, R 8  is ethyl, and Z is —N(CH 3 )CH 2 —.  
     
     
         7 . The compound of  claim 1  wherein R 4  is OH, R 5  is OH, R 6  is H, R 7  is OH, R 8  is ethyl, and Z is —CH(NMe 2 ).  
     
     
         8 . The compound of  claim 1  selected from the group consisting of: 
 clarithromycin-11,12-carbamate-3-descladinose-3-(α-O-methoxymethyl)phenylacetic acid ester;  
 clarithromycin-11,12-carbamate-3-descladinose-3-(α-O-allyl)phenylacetic acid ester;  
 clarithromycin-11,12-carbamate-3-descladinose-3-(α-O-methylthiomethyl)phenylacetic acid ester;  
 clarithromycin-11,12-carbamate-3-descladinose-3-(α-R-amino-β-phenyl)propionic acid ester;  
 clarithromycin-11,12-carbamate-3-descladinose-3-(α-S-amino-β-phenyl)propionic acid ester;  
 clarithromycin-11,12-carbamate-3-[α-O-allyl-(p-methoxy)phenyl]acetic acid ester;  
 clarithromycin-11,12-carbamate-3-[α-O-allyl-(p-chloro)phenyl]acetic acid ester;  
 clarithromycin-11,12-carbamate-3-α-O-allyl-(o-methoxy)phenyl]acetic acid ester;  
 clarithromycin-11,12-carbamate-3-α-O-allyl-(m-methoxy)phenyl]acetic acid ester;  
 clarithromycin-11,12-carbamate-3-descladinose-3-(R-α-O-propyl)phenylacetic acid ester;  
 clarithromycin-11,12-carbamate-3-descladinose-3-(S-α-O-propyl)phenyl acetic acid ester;  
 clarithromycin-11,12-carbamate-3-(α-O-benzyl)-phenylacetic acid ester;  
 erythromycin 6,9-11,12-biscarbonate-3-descladinose-3-[R-α-(O-methoxymethyl)]phenyl acetic acid ester;  
 erythromycin 6,9-11,12-biscarbonate-3descladinose-3-[R-α-(O-allyl)]phenyl acetic acid ester;  
 erythromycin 6,9-11,12-biscarbonate-3-descladinose-3-[R-α-(O-methylthiomethyl)]phenyl acetic acid ester;  
 erythromycin 6,9-11,12-biscarbonate-3-descladinose-3-[α-O-allyl-(p-methoxy)phenyl]acetic acid ester;  
 erythromycin 6,9-11,12-biscarbonate-3descladinose-3-[α-O-allyl-(p-chloro)phenyl]acetic acid ester;  
 erythromycin 6,9-11,12-biscarbonate-3-descladinose-3-[α-O-allyl-(m-chloro)phenyl]acetic acid ester;  
 erythromycin 6,9-11,12-biscarbonate-3-descladinose-3-[α-O-allyl-(o chloro)phenyl]acetic acid ester;  
 erythromycin 6,9-11,12-biscarbonate-3-descladinose-3-α-O-phenyl-butyric acid ester;  
 erythromycin 6,9-11,12-biscarbonate-3descladinose-3-[α-(p-methoxybenzyl)]phenylacetic acid ester;  
 erythromycylamine 11,12-carbonate-3-descladinose-3-(α-O-methoxymethyl)phenylacetic acid ester;  
 erythromycylamine-11,12-carbonate-3-descladinose-3-(R-α-O-allyl)phenylacetic acid ester;  
 erythromycylamine-11,12-carbonate-3-descladinose-3-(R-) and 3-[(S)-α-O-methylthiomethyl]phenylacetic acid ester;  
 erythromycylamine-11,12-carbonate-3-descladinose-3-(R-) and 3-[(S)-α-O-3-(3-pyridyl)propyl]phenylacetic acid ester;  
 erythromycylamine-11,12-carbonate-3-descladinose-3-(R-) and 3-[(S)-α-O-3-(3-pyridyl)-2-propenyl]phenylacetic acid ester;  
 erythromycylamine-11,12-carbonate-3descladinose-3-(R-) and 3-[(S)-α-O-propyl]phenylacetic acid ester;  
 azithromycin-3-descladinose-3-(α-O-methoxymethyl)phenylacetic acid ester;  
 azithromycin-11,12-carbonate-3-descladinose-3-(α-O-methoxymethyl)phenylacetic acid ester;  
 azithromycin-11,12-carbonate-3-descladinose-3-R- and S-(α-O-allyl)phenylacetic acid ester;  
 N,N-dimethylerythromycylamine-11,12-carbonate-3-descladinose-3-(α-O-methoxymethyl)phenylacetic acid ester;  
 N,N-dimethylerythromycylamine-11,12-carbonate-3-descladinose-3-(α-O-allyl)phenylacetic acid ester;  
 clarithromycin 11,12-carbamate-3-descladinose-3-(α-oxo)phenylacetic acid ester;  
 clarithromycin 11,12-carbamate-3-descladinose-3-(α-benzyloxime)phenylacetic acid ester; and  
 clarithromycin 11,12-carbamate-3-descladinose-3-(α-methyloxime)phenylacetic acid ester,  
 and the foregoing compounds wherein R 8  is selected from methyl, n-propyl, isopropyl, cyclopropyl, propenyl, n-butyl, sec-butyl, isobutyl, and cyclobutyl.  
 
     
     
         9 . The compound of  claim 1  selected from the group consisting of compounds wherein: 
 R 6 =H, R 4  and Z taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, R 8 =methyl, R 1 =H, R 2 =methoxymethyl, R 3 =phenyl, and X=O;  
 R 8 =H, R 4  and Z taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, R 8 =cyclobutyl, R 1 =H, R 2 =methoxymethyl, R 3 =phenyl, and X=O;  
 R 6 =H, R 4  and Z taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, R 8 =methyl, R 1 =H, R 2 =allyl, R 3 =phenyl, and X=O;  
 R 6 =H, R 4  and Z taken together form a cyclic carbonate, R 5  and R 7  taken together to form a cyclic carbonate, R 8 =cyclobutyl, R 1 =H, R 2 =allyl, R 3 =phenyl, and X=O;  
 R 6 =H, R 1 =H, R 2 =allyl, R 3 =(2-fluoro)phenyl, X=O, R 4  and Z taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, and R 8 =ethyl;  
 R 6 =H, R 1 =H, R 2 =allyl, R 3 =(3-fluoro)phenyl, X=O, R 4  and Z taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, and R 8 =ethyl;  
 R 6 =H, R 1 =H, R 2 =allyl, R 3 =(4-fluoro)phenyl, X=O, R 4  and Z taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, and R 8 =ethyl;  
 R 6 =H, R 4 =OH, Z=CHNH 2 , R 5  and R 7  taken together form a cyclic carbonate, R 8 =methyl, R 1 =H, R 2 =methoxymethyl, R 3 =2-fluorophenyl, and X=O;  
 R 6 =H, R 4 =OH, Z=CHNH 2 , R 5  and R 7 taken together form a cyclic carbonate, R 8 =methyl, R 1 =H, R 2 =methoxymethyl, R 3 =phenyl, and X=O;  
 R 6 =H, R 4 =OH, Z=CHNH 2 , R 5  and R 7  taken together to a cyclic carbonate, R 8 =cyclobutyl, R 1 =H, R 2 =methoxymethyl, R 3 =phenyl, and X=O;  
 R 6 =H, R 4 =OH, Z=CHNH 2 , R 5  and R 7  taken together form a cyclic carbonate, R 8 =methyl, R 1 =H, R 2 =allyl, R 3 =2-fluorophenyl, and X=O;  
 R 6 =H, R 4 =OH, Z=CHNH 2 , R 5  and R 7 taken together form a cyclic carbonate, R 8 =methyl, R 1 =H, R 2 =allyl, R 3 =phenyl, and X=O;  
 R 6 =H, R 4 =OH, Z=CHNH 2 , R 5  and R 7  taken together to form a cyclic carbonate, R 8 =cyclobutyl, R 1 =H, R 2 =allyl, R 3 =phenyl and X=O;  
 R 6 =H, Z and R 4  taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 =propyl, R 3 =phenyl, and X=NH;  
 R 6 =H, Z and R 4  taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 =allyl, R 3 =phenyl, and X=NH;  
 R 6 =H, Z and R 4  taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, R 3 =ethyl, R 1 =H, R 2 =pyrid-3-yl, R 3 =phenyl, and X=NH;  
 R 6 =H, Z and R 4  taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, R 3 =ethyl, R 1 =H, R 2 =pyrid-2-yl, R 3 =phenyl, and X=NH;  
 R 6 =H, Z and R 4  taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 =2-fluorobenzyl, R 3 =phenyl, and X=NH;  
 R 6 =H, Z and R 4  taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 =2-(2′-fluorophenyl)ethyl, R 3 =phenyl, and X=NH;  
 R 6 =H, Z and R 4  taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 =2-(pyrid-2′-yl)ethyl, R 3 =phenyl, and X=NH;  
 R 6 =H, Z and R 4  taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, R 3 =ethyl, R 1 =H, R 2 X=pyrrolin-1-yl, and R 3 =phenyl;  
 R 6 =H, Z and R 4  taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =,H, R 2 X=piperidin-1-yl, and R 3 =phenyl;  
 R 6 =H, Z and R 4  taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, R 3 =ethyl, R 1 =H, R 2 X=morpholin-1-yl, and R 3 =phenyl;  
 R 5 =H, Z and R 4  taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 X=piperazin-1-yl, and R 3 =phenyl;  
 R 6 =H, Z and R 4  taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 X=4-N-methyl-piperazin-1-yl, and R 3 =phenyl;  
 R 6 =H, Z and R 4  taken together form a cyclic carbonate, R 5  and R 7  taken together to form a cyclic carbonate, R 3 =ethyl, R 1 =H, R 2 X=4-N-ethyl-piperazin-1-yl, and R 3 =phenyl;  
 R 6 =H, Z and R 4  taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 X=4-benzylpiperidin-1-yl, and R 3 =phenyl;  
 R 6 =H, Z and R 4  taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, R 3 =ethyl, R 1 =H, R 2 X=4-(3-phenyl)propylpiperidin-1-yl, and R 3 =phenyl;  
 R 6 =H, Z and R 4  taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, R 3 =ethyl, R 1 =H, R 2 =pyrid-3-yl, R 3 =2-fluorophenyl, and X=NH;  
 R 6 =H, Z and R 4  taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 =pyrid-2-yl, R 3 =2-fluorophenyl, and X=NH;  
 R 6 =H, Z and R 4  taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 X=pyrrolidin-1-yl, and R 3 =2-fluorophenyl;  
 R 6 =H, Z and R 4  taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 X=piperidin-1-yl, and R 3 =2-fluorophenyl;  
 R 6 =H, Z and R 4  taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, R 6 =ethyl, R 1 =H, R 2 X=morpholin-1-yl, and R 3 =2-fluorophenyl;  
 R 6 =H, Z and R 4  taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 X=4-N-methylpiperazin-1-yl, and R 3 =2-fluorophenyl;  
 R 6 =H, Z and R 4  taken together form a cyclic carbonate, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 X=piperazin-1-yl, and R 3 =2-fluorophenyl;  
 R 6 =H, Z=C=O, R 4 =OMe, R 5  and R 7 taken together form a cyclic carbamate, R 8 =ethyl, R 1 =H, R 2 =propyl, R 3 =phenyl, and X=NH;  
 R 6 =H, Z=CHNH 2 , R 4 =OH, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 =propyl, R 3 =phenyl, and X=NH;  
 R 6 =H, Z=CHNH 2 , R 4 =OH, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 =allyl, R 3 =phenyl, and X=NH;  
 R 6 =H, Z=CHNH 2 , R 4 =OH, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 =pyrid-3-yl, R 3 =phenyl, and X=NH;  
 R 6 =H, Z=CHNH 2 , R 4 =OH, R 5  and R 7  taken together form a cyclic carbonate, R 6 =ethyl, R 1 =H, R 2 =pyrid-2-yl, R 3 =phenyl, and X=NH;  
 R 6 =H, Z=CHNH 2 , R 4 =OH, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 =cyclopropyl, R 3 =phenyl, and X=NH;  
 R 6 =H, Z=CHNH 2 , R 4 =OH, R 5  and R 7  taken together form a cyclic carbonate, R 3 =ethyl, R 1 =H, R 2 =cyclobutyl, R 3 =phenyl, and X=NH;  
 R 6 =H, Z=CHNH 2 , R 4 =OH, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 =cyclopentyl, R 3 =phenyl, and X=NH;  
 R 6 =H, Z=CHNH 2 , R 4 =OH, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 =cyclohexyl, R 3 =phenyl, and X=NH;  
 R 8 =H, Z=CHNH 2 , R 4 =OH, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 =benzyl, R 3 =phenyl, and X=NH;  
 R 6 =H, Z=CHNH 2 , R 4 =OH, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 =2-fluorobenzyl, R 3 =phenyl, and X=NH;  
 R 6 =H, Z=CHNH 2 , R 4 =OH, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 X=pyrrolidin-1-yl, and R 3 =phenyl;  
 R 6 =H, Z=CHNH 2 , R 4 =OH, R 5  and R 7  taken together form a cyclic carbonate, R 3 =ethyl, R 1 =H, R 2 X=morpholin-1-yl, and R 3 =phenyl;  
 R 6 =H, Z=CHNH 2 , R 4 =OH, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 =pyrid-3-yl, R 3 =2-fluorophenyl, and X=NH;  
 R 6 =H, Z=CHNH 2 , R 4 =OH, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 =2-(pyrid-3-yl)ethylamine, R 3 =2-fluorophenyl, and X=NH;  
 R 6 =H, Z=CHNH 2 , R 4 =OH, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 X=pyrrolidin-1-yl, and R 3 =2-fluorophenyl;  
 R 6 =H, Z=CHNH 2 , R 4 =OH, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 X=piperidin-1-yl, and R 3 =2-fluorophenyl;  
 R 6 =H, Z=CHNH 2 , R 4 =OH, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 X=morpholin-1-yl, and R 3 =2-fluorophenyl;  
 R 6 =H, Z=CHNH 2 , R 4 =OH, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 X=piperazin-1-yl, and R 3 =2-fluorophenyl;  
 R 6 =H, Z=CHNH 2 , R 4 =OH, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 X=4-N-methyl-piperazin-1-yl, and R 3 =2-fluorophenyl; and  
 R 6 =H, Z=CHNH 2 , R 4 =OH, R 5  and R 7  taken together form a cyclic carbonate, R 8 =ethyl, R 1 =H, R 2 X=4-N-ethyl-piperazin-1-yl, and R 3 =2-fluorophenyl.  
 
     
     
         10 . A compound of  claim 1  wherein R 8  is selected from methyl, n-propyl, isopropyl, cyclopropyl, propenyl, n-butyl, sec-butyl, tert-butyl, isobutyl, and cyclobutyl.  
     
     
         11 .  
       
         
           
           
               
               
           
         
       
       wherein: 
 Z is —C(═O)—, —C(═NOR 13 )—, —CH(NR 11 R 12 )—, —N(R 2 )CH 2 —, or —CH 2 N(R 2 )—;  
 R 4 is H or OR 19 ;  
 or Z and R 4  together form a group of the formula  
                     
 wherein C 10 , C 8 , and C 6  indicate carbon atoms of the macrolide ring of formula I to which the group is attached;  
 V is O or NR 17 ;  
 R 5  and R 7  together form a group of the formula  
                     
 wherein J is selected from O, NR 15 , NOR 15 , and N—NR 15 ;  
 R 6  is H, —C(O)C 1 -C 6  alkyl, benzyl, benzyloxycarbonyl, or (C 1 -C 6  alkyl) 3  silyl;  
 R 8  is selected from methyl, C 3 -C 10  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, (C 1 -C 6  alkoxy) C 1 -C 6  alkyl, (C 1 -C 6  alkylthio) C 1 -C 6  alkyl, (C 5 -C 8  cycloalkyl) C 2 -C 5  alpha branched alkyl, C 3 -C 8  cycloalkyl, C 5 -C 8  cycloalkenyl, (4- to 10-membered heterocyclic) C 1 -C 6  alkyl, (C 6 -C 10  aryl) C 1 -C 6  alkyl, wherein one or more carbons of R 8  may be replaced with one or more heteroatoms selected from O, S, N and R 8  is optionally substituted with from one or four R 14  groups provided that R 8  is not ethyl;  
 each R 11  and R 12  is independently selected from H, C 1 -C 6  alkyl, C 6 -C 10  aryl, and 4- to 10-membered heterocyclic;  
 each R 13  is independently selected from H, C 1 -C 6  alkyl, (4- to 10-membered heterocyclic) C 0 -C 6  alkyl and (C 6 -C 10  aryl) C 0 -C 6  alkyl, wherein said aryl and heterocyclic groups are optionally substituted by 1 to 4 R 14  groups;  
 each R 14  is independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R 14a , —C(O)OR 14a , —OC(O)R 14a , —NR 11 C(O)R 11 , —C(O)NR 11 R 14a , —NR 11 R 14a , hydroxy, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, (C 6 -C 10  aryl) C 0 -C 6  alkyl, (4- to 10-membered heterocyclic) C 0 -C 6  alkyl, C 1 -C 6  alkoxy, C 6 -C 10  aryloxy, —S(O) j (C 0 -C 6  alkyl) wherein said C 0 -C 6  alkyl is optionally substituted by 1 to 10 R 14a  groups, —S(O) j (C 2 -C 6  alkenyl) wherein said C 2 -C 6  alkenyl is optionally substituted by 1 to 7 R 14a  groups, where each j is an integer from 0 to 2, and —SO 2 NR 11 R 14a , wherein said aryl or heterocyclic group is optionally substituted by 1 to 4 R 14a  groups;  
 each R 14a  is independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R 11 , —C(O)OR 11 , —OC(O)R 11 , —NR 11 C(O)R 12 , —C(O)NR 11 R 12 , —NR 11 R 12 , hydroxy, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, (C 6 -C 10  aryl) C 0 -C 6  alkyl, (4- to 10-membered heterocyclic) C 0 -C 6  alkyl, C 1 -C 6  alkoxy, C 6 -C 10  aryloxy, —S(O) k (C 0 -C 6  alkyl), —S(O) k (C 2 -C 6  alkenyl) where each k is an integer from 0 to 2, and SO 2 NR 11 R 12 , wherein said aryl or heterocyclic group is optionally substituted by from one to four groups selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —C(O)R 11 , —C(O)OR 11 , —OC(O)R 11 , —NR 11 C(O)R 12 , —C(O)NR 11 R 12 , —NR 11 R 12 , hydroxy, C 2 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, (C 6 -C 10  aryl) C 0 -C 6  alkyl, (4- to 10-membered heterocyclic) C 0 -C 6  alkyl, C 1 -C 6  alkoxy, C 6 -C 10  aryloxy, —S(O) l (C 0 -C 6  alkyl), —S(O) l (C 2 -C 6  alkenyl) and —SO 2 NR 11 R 12  wherein each l is an integer from 0 to 2;  
 R 15  is selected from H, C 1 -C 10  alkyl, C 2 -C 10  alkenyl, C 2 -C 1 Q alkynyl, (4- to 10-membered heterocyclic) C 1 -C 6  alkyl, (4- to 10-membered heterocyclic) C 2 -C 6  alkenyl, (4- to 10-membered heterocyclic) C 2 -C 6  alkynyl, (C 6 -C 10  aryl) C 1 -C 6  alkyl, (C 6 -C 10  aryl) C 2 -C 6  alkenyl, and (C 6 -C 10  aryl) C 2 -C 6  alkynyl, wherein the alkyl, alkenyl, and alkynyl moieties of the foregoing groups are optionally substituted by halo. or C 1 -C 6  alkyl, and wherein said heterocyclic moieties are optionally substituted by (4- to 10-membered heterocyclic) C 0 -C 6  alkyl, or (C 6 -C 10  aryl) C 0 -C 6  alkyl, and further wherein the aryl and heterocyclic moieties of each of the foregoing groups and optional substituents are optionally substituted by 1 to 4 R 14  groups; and  
 R 16  is selected from H and C 1 -C 6  alkyl, wherein one to three carbons of said alkyl are optionally replaced with a heteroatom selected from O, S, and N;  
 R 17  is H, OR 16 , NR 16 R 18 , C 1 -C 16  alkyl, (C 6 -C 10  aryl) C 0 -C 6  alkyl, or (4- to 10-membered heterocyclic) C 0 -C 6  alkyl;  
 R 18  is H, or C 1 -C 6  alkyl wherein one or more carbons of said C 1 -C 6  alkyl are optionally replaced with one or more heteroatoms selected from O, N, and S and optionally substituted by R 14 ; and  
 R 19  is selected-from H, C 1 -C 16  alkyl, C 2 -C 16  alkenyl, C 2 -C 16  alkynyl, (4- to 10-membered heterocyclic) C 0 -C 6  alkyl, (4- to 10-membered heterocyclic) C 2 -C 6  alkenyl, (4- to 10-membered heterocyclic) C 2 -C 6  alkynyl, (C 6 -C 10  aryl) C 0 -C 6  alkyl, (C 6 -C 10  aryl) C 2 -C 6  alkenyl, and (C 6 -C 10  aryl) C 2 -C 6  alkynyl, wherein the alkyl, alkenyl, and alkynyl moieties of the foregoing groups are optionally substituted by halo or C 1 -C 6  alkyl, wherein one to three carbons of said C 1 -C 16  alkyl, C 2 -C 16  alkenyl, and C 2 -C 16  alkynyl, are, where possible, optionally replaced by O, N, or S, and further wherein the aryl and heterocyclic moieties of each of the foregoing groups and optional substituents are optionally substituted by 1 to 4 R 14  groups.  
 
     
     
         12 . A pharmaceutical composition for the treatment of a bacterial infection or a protozoa infection in a mammal, fish, or bird which comprises a therapeutically effective amount of a compound of  claim 1  or a pharmaceutically acceptable salt, prodrug, or solvate thereof, and a pharmaceutically acceptable carrier.  
     
     
         13 . A method of treating a bacterial infection or a protozoa infection in a mammal, fish, or bird which comprises administering to said mammal, fish or bird a therapeutically effective amount of a compound of claim I or a pharmaceutically acceptable salt, prodrug, or solvate thereof.  
     
     
         14 . A process for making a compound of  claim 1  wherein R 6  is H comprising deprotecting a compound of the following formula  
       
         
           
           
               
               
           
         
       
       wherein R 6  is a protecting group.