Novel macrolide antibiotics

Abstract

This invention relates to compounds of the formula wherein a, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and X are each as defined above, and to pharmaceutically acceptable salts thereof, useful as potent antibacterial and antiprotozoal agents that may be used to treat various bacterial and protozoal infections and disorders related to such infections. The invention also relates to pharmaceutical compositions containing the compounds of formula I and to methods of treating bacterial and protozoal infections by administering the compounds of formula I.

1 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       or the pharmaceutically acceptable salt thereof; wherein the dashed line between positions 10 and 11 represents an optional double bond; 
 a is 0 or 1;  
 R 1  is hydrogen or (C 1 -C 10 )alkyl optionally substituted by fluoro, cyano, R 7 , R 7 O 2 C, R 7 C(O)NH and R 7 S(O), wherein n is 0, 1 or 2 and R 7  is (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three halo, (C 1 -C 3 )alkoxy, hydroxy, nitro, cyano, (C 6 -C 10 )aryl, (C 2 -C 9 )heteroaryl, R 8 R 9 N, R 8 C(O), R 8 C(O)O, R 8 OC(O), R 8 C(O)NH, R 8 NHC(O), R 8 R 9 NC(O) and R 8 OC(O) 2  wherein R 8  and R 9  are each independently hydrogen, (C 1 -C 6 )alkyl optionally substituted by (C 6 -C 10 )aryl or (C 2 -C 9 )heteroaryl;  
 R 2  is hydrogen or a hydroxy protecting group;  
 R 3  is amino, cyano, N 3 , R 10 NH, R 10 C(O)NH, R 10 NHC(O)NH, R 10 NHC(S)NH, R 10 NHNHC(O)NH, R 10 ONHC(O)NH, R 10 O, R 10 OC(O)NH, R 10 S(O) n , R 10 phosphoramido, R 10 sulfonamido, SH, R 10 S wherein n is defined above and R 10  is (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 6 )alky), (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C 1 -C 3 )alkoxy, hydroxy, nitro, cyano, (C 6 -C 10 )aryl, (C 2 -C 9 )heteroaryl, R 8 R 9 N, R 8 C(O), R 8 C(O)O, R 8 OC(O), R 8 C(O)NH, R 8 NHC(O), R 8 R 9 NC(O) and R 8 OC(O) 2  wherein R 8  and R 9  are each independently hydrogen, (C 1 -C 6 )alkyl optionally substituted by (C 6 -C 10 )aryl or (C 2 -C 9 )heteroaryl; or R 3  is R 12 R 13 N wherein R 12  and R 13  are each independently hydrogen, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl (C 1 -C 6 )alkyl;  
 R 4  is hydrogen, methyl optionally substituted by one to two nitro, cyano, R 14 C(O) and R 14 OC(O); or R 4  is N 3 , R 14 O, R 14 NH, R 14 S wherein R 14  is (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C 1 -C 3 )alkoxy, hydroxy, nitro, cyano, (C 6 -C 10 )aryl, (C 2 -C 9 )heteroaryl, R 8 R 9 N, R 8 C(O), R 8 C(O)O, R 8 OC(O), R 8 C(O)NH, R 8 NHC(O), R 8 R 9 NC(O) and R 8 OC(0) 2 , wherein R 8  and R 9  are each independently hydrogen, (C 1 -C 6 )alkyl optionally substituted by (C 6 -C 10 )aryl or (C 2 -C 9 )heteroaryl; or R 4  is R 15 N(C 1 -C 6 )alkyl wherein R 15  is hydrogen, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl;  
 X is oxygen or NOR 16  wherein R 16  is (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C 1 -C 3 )alkoxy, hydroxy, nitro, cyano, (C 6 -C 10 )aryl, (C 2 -C 9 )heteroaryl, R 8 R 9 N, R 8 C(O), R 8 C(O)O, R 8 OC(O), R 8 C(O)NH, R 8 NHC(O), R 8 R 9 NC(O) and R 8 OC(O) 2 , wherein R 8  and R 9  are each independently hydrogen or (C 1 -C 6 )alkyl optionally substituted by (C 6 -C 10 )aryl or (C 2 -C 9 )heteroaryl;  
 R 5  is hydrogen or methyl;  
 or R 3  and R 4  may be taken together with the carbons to which they are attached to form  
                     
  wherein the dashed line, between the nitrogen and the variable W of formula II, represents an optional double bond;  
 W is C═O, C═S, SO 2  or C═NR 10  wherein R 10  is as defined above;  
 Y is oxygen, sulfur or NR 17  wherein R 17  is hydrogen, R 19 , R 19 O or R 19 NH wherein R 19  is hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C 1 -C 3 )alkoxy, hydroxy, nitro, cyano, (C 6 -C 10 )aryl, (C 2 -C 9 )heteroaryl, R 8 R 9 N, R 8 C(O), R 8 C(O)O, R 8 OC(O), R 8 C(O)NH, R 8 NHC(O), R 8 R 9 NC(O) and R 8 OC(O) 2  wherein R 8  and R 9  are each independently hydrogen, (C 1 -C 6 )alkyl optionally substituted by (C 5 -C 10 )aryl or (C 2 -C 9 )heteroaryl;  
 R 18  is hydrogen, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl; wherein the aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C 1 -C 3 )alkoxy, hydroxy, nitro, cyano, (C 6 -C 10 )aryl, (C 2 -C 9 )heteroaryl, R 20 R 21 N, R 20 C(O), R 20 C(O)O, R 20 OC(O), R 20 C(O)NH, R 20 NHC(O), R 20 R 21 NC(O), and R 20 OCO 2  wherein R 20  and R 21  are each independently hydrogen, (C 1 -C 6 )alkyl optionally substituted by (C 6 -C 10 )acyl or (C 5 -C 10 )aryl or (C 2 -C 9 )heteroaryl;  
 R 6  is hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl or (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally substituted by one to three substituents independently selected from hydroxy and halo; or R 6  is (C 3 -C 10 )cycloalkyl or (C 5 -C 10 )cycloalkenyl optionally substituted by (C 1 -C 6 )alkyl or halo; or R 6  is (C 2 -C 8 )heterocycloalkyl or (C 2 -C 9 )heteroaryl optionally substituted by (C 1 -C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 10 )cycloalkyl, (C 5 -C 10 )cycloalkenyl or aryl wherein the aryl group is optionally substituted by alkyl, (C 1 -C 6 )alkoxy or halo;  
 with the proviso that at least one of R 17  or R 18  is hydrogen;  
 with the proviso that when the dashed line between positions 10 and 11 represents a double bond, R 4  is hydrogen; and  
 with the proviso that when a is zero, R 1  is hydrogen.  
 
     
     
         2 . A compound according to  claim 1 , wherein a is 1 and R 1  is (C 1 -C 10 )alkyl.  
     
     
         3 . A compound according to  claim 1 , wherein R 2  is hydrogen.  
     
     
         4 . A compound according to  claim 1 , wherein R 3  is N 3 , R 10 NH, R 10 C(O)NH, R 10 NHC(O)NH or R 10 NHNHC(O)NH.  
     
     
         5 . A compound according to  claim 1 , wherein R 4  is hydrogen, R 14 NH or R 14 S.  
     
     
         6 . A compound according to  claim 1 , wherein R 6  is ethyl.  
     
     
         7 . A compound according to  claim 1 , wherein W is C═O and Y is NR 17 .  
     
     
         8 . A compound according to  claim 1 , wherein a is 1; R 1  is (C 1 -C 10 )alkyl; R 2  is hydrogen; R 3  is N 3 , R 10 NH, R 10 C(O), R 10 NHC(O)NH or R 10 NHNHC(O)NH; R 4  is hydrogen, R 14 NH or R 14 S and R 6  is ethyl.  
     
     
         9 . A compound according to  claim 1 , wherein a is 1; R 1  is (C 1 -C 10 )alkyl; R 2  is hydrogen; R 3  and R 4  are taken together with the carbons to which they are attached to form the compound of formula II; W is C═O and Y is NR 17 .  
     
     
         10 . A compound according to  claim 1 , wherein said compound is selected from the group consisting of: 
 11,12-Dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl)oxy)-6-O-methyl-12,11-(iminocarbonyl(2-(3-(4-quinolinyl)propyl)hydrazono))-3-oxoerythromycin;    11,12-Dideoxy-10,11-didehydro-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl)oxy)-6-O-methyl-12-iminocarbonyl((4-(4-(3-pyridinyl)-1H-imidazol-1-yl)butylimino))-3-oxoerythromycin;    11,12-Dideoxy-11,12-didehydro-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyrano-5yl)oxy-6-O-methyl-10-iminocarbonyl((4-(4-(3-pyridinyl)-(H-imidazol-1-yl)butylimino))-3-oxoerythiomycin;    11-Deoxy-10,11-didehydro-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl)-oxy)-6-O-methyl-3-oxoerythromycin-1,2-enol-1,12-cyclicether-2′-acetate;    11-Deoxy-10,11-didehydro-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl)-oxy)-6-O-methyl-8-epi-3-oxoerythromycin-1,2-enol-1,12-cyclicether-2′-acetate;    11,12-Dideoxy-10,11-didehydro-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-3-O-methyl-α-L-ribohexopyranosyl)oxy)-12-β-azido-6-O-methyl-3-oxoerythromycin-2′-acetate;    11,12-Dideoxy-10,11-didehydro-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-rihexopyranosyl)oxy)-12-β-azido-6-O-methyl-3-oxo-8-epierythromycin-2′-acetate;    11,12-Dideoxy-10,11-didehydro-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl)oxy)-12-β-amino-6-O-methyl-3-oxoerythromycin-2′-acetate;    11,12-Dideoxy-10,11-didehydro-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl)oxy)-12-β-amino-6-O-methyl-3-oxo-8-erythromycin-2′-acetate;    11,12-Dideoxy-10,11-didehydro-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl)ox)-12-β-acetamino-6-O-methyl-3-oxoerythromycin-2′acetate;    11,12-Dideoxy-11,12-dehydro-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl)oxy)-10-β-azido-6-O-methyl-3-oxoerythromycin-2′-acetate;    11,12-Dideoxy-11,12-dehydro-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl)oxy)-10-β-amino-6-O-methyl-3-oxoerythromycin-2′-acetate;    11,12-Dideoxy-11,12-dehydro-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl)oxy)-10-β-acetamino-6-O-methyl-3-oxoerythromycin-2′-acetate;    11,12-Dideoxy-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl)oxy)-6-O-methyl-3-oxo-12,11-(iminocarbonylhydrazono)erythromycin-2′-acetate;    11,12-Dideoxy-11,12-dehydro-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl)oxy)-10-β-iminocarbonylhydrazono-6-O-methyl-3-oxo-erythromycin-2′-acetate;    11,12-Dideoxy-10,11-didehydro-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl)oxy)-12-β-isothiocyanato-6-O-methyl-3-oxoerythromycin-2′-acetate;    11,Deoxy-10,11-didehydro-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl)oxy)-12-β-propagyloxy-6-O-methyl-3-oxoerythromycin-2′-acetate;    11-Deoxy-10,11-didehydro-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl)oxy)-6-O-methyl-11-nitromethyl-3-oxoerythromycin-1,2-enol-1,12-cyclicether-2′-acetate; and    11-Deoxy-10,11-didehydro-3-de((2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribohexopyranosyl)oxy)-6-O-methyl-11-nitromethyl-8-epi-3-oxoerythromycin-1,2-enol-1,12-cyclicether-2′-acetate.    
     
     
         11 . A pharmaceutical composition for the treatment of a disorder selected from a bacterial infection, a protozoal infection, and a disorder related to a bacterial infection or protozoal infection in a mammal, fish, or bird which comprises a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         12 . The pharmaceutical composition of  claim 11  wherein said disorder is pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, or mastoiditis related to infection by  Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus,  or Peptostreptococcus spp.; pharynigitis, rheumatic fever, or glomerulonephritis related to infection by  Streptococcus pyogenes,  Groups C and G streptococci,  Clostridium diptheriae,  or  Actinobacillus haemolyticum;  a respiratory tract infections related to infection by  Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae,  or  Chlamydia pneumoniae;  uncomplicated skin or soft tissue infection, abscess or osteomyelitis, or puerperal fever related to infection by  Staphylococcus aureus,  coagulase-positive staphylococci (i.e.,  S. epidermidis, S. hemolyticus,  etc.),  Streptococcus pyogenes, Streptococcus agalactiae,  Streptococcal groups C-F (minute-colony streptococci), viridans streptococci,  Corynebacterium minutissimum,  Clostridium spp., or  Bartonella henselae;  uncomplicated acute urinary tract infection related to infection by  Staphylococcus saprophyticus  or Enterococcus spp.; urethritis, or cervicitis; a sexually transmitted disease related to infection by  Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum,  or  Neiserria gonorrheae;  toxin disease related to infection by  S. aureus  (food poisoning or toxic shock syndrome), or Groups A, B, and C streptococci; ulcer related to infection by  Helicobacter pylori;  systemic febrile syndrome related to infection by  Borrelia recurrent is;  Lyme disease related to infection by  Borrelia burgdorferi;  conjunctivitis, keratitis, and dacrocystitis related to infection by  Chlamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H. influenzae,  or Listeria spp.; disseminated  Mycobacterium avium  complex (MAC) disease related to infection by  Mycobacterium avium,  or  Mycobacterium intracellulare;  gastroenteritis related to infection by  Campylobacter jejuni;  intestinal protozoa related to infection by Cryptosporidium spp.; odontogenic infection related to infection by viridans streptococci; persistent cough related to infection by  Bordetella pertussis;  gas gangrene related to infection by  Clostridium perfringens  or Bacteroides spp.; atherosclerosis or cardiovascular disease related to infection by  Helicobacter pylori  or  Chlamydia pneumoniae;  bovine respiratory disease related to infection by  P. haemolytica, P. multocida, Mycoplasma bovis,  or Bordetella spp.; cow enteric disease related to infection by  E. coli  or protozoa; dairy cow mastitis related to infection by  Staph. aureus, Strep. uberis, Strep. agalactiae, Strep. dysgalactiae,  Klebsiella spp., Corynebacterium, or Enterococcus spp.; swine respiratory disease related to infection by  A. pleuro., P. multocida,  or Mycoplasma spp.; swine enteric disease related to infection by  E. coli, Lawsonia intracellularis,  Salmonella, or  Serpulina hyodysinteriae;  cow footrot related to infection by Fusobacterium spp.; cow metritis related to infection by  E. coli;  cow hairy warts related to infection by  Fusobacterium necrophorum  or  Bacteroides nodosus;  cow pink-eye related to infection by  Moraxella bovis;  cow premature abortion related to infection by protozoa; urinary tract infection in a dog or cat related to infection by  E. coli;  skin or soft tissue infection in a dog or cat related to infection by  Staph. epidermidis, Staph. intermedius,  coagulase neg. Staph. or  P. multocida;  or dental or mouth infection in a dog or cat related to infection by Alcaligenes spp., Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacterium, Peptostreptococcus, Porphyromonas, or Prevotella.  
     
     
         13 . A method of treating a disorder selected from a bacterial infection, a protozoal infection, and a disorder related to a bacterial infection or protozoal 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 1 .  
     
     
         14 . The method of  claim 13 , wherein said disorder is pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, or mastoiditis related to infection by  Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus,  or Peptostreptococcus spp.; pharynigitis, rheumatic fever, or glomerulonephritis related to infection by  Streptococcus pyogenes,  Groups C and G streptococci,  Clostridium diptheriae,  or  Actinobacillus haemolyticum;  a respiratory tract infections related to infection by  Mycoplasma pneumoniae, Legionella pneumophlla, Streptococcus pneumoniae, Haemophilus influenzae,  or  Chlamydia pneumoniae;  uncomplicated skin or soft tissue infection, abscess or osteomyelitis, or puerperal fever related to infection by  Staphylococcus aureus,  coagulase-positive staphylococci (i.e.,  S. epidermidis, S. hemolyticus,  etc.),  Streptococcus pyogenes, Streptococcus agalactiae,  Streptococcal groups C-F (minute-colony streptococci), viridans streptococci,  Corynebacterium minutissimum,  Clostridium spp., or  Bartonella henselae;  uncomplicated acute urinary tract infection related to infection by  Staphylococcus saprophyticus  or Enterococcus spp.; urethritis, or cervicitis; a sexually transmitted disease related to infection by  Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum,  or  Neiserria gonorrheae;  toxin disease related to infection by  S. aureus  (food poisoning or toxic shock syndrome), or Groups A, B, and C streptococci; ulcer related to infection by  Helicobacter pylori;  systemic febrile syndrome related to infection by  Borrelia recurrentis;  Lyme disease related to infection by  Borrelia burgdorferi;  conjunctivitis, keratitis, and dacrocystitis related to infection by  Chlamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H. influenzae,  or Listeria spp.; disseminated  Mycobacterium avium  complex (MAC) disease related to infection by  Mycobacterium avium,  or  Mycobacterium intracellulare;  gastroenteritis related to infection by  Campylobacter jejuni;  intestinal protozoa related to infection by Cryptosporidium spp.; odontogenic infection related to infection by viridans streptococci; persistent cough related to infection by  Bordetella pertussis;  gas gangrene related to infection by  Clostridium perfringens  or Bacteroides spp.; atherosclerosis or cardiovascular disease related to infection by  Helicobacter pylori  or  Chlamydia pneumoniae;  bovine respiratory disease related to infection by  P. haemolytica, P. multocida, Mycoplasma bovis,  or Bordetella spp.; cow enteric disease related to infection by  E. coil  or protozoa; dairy cow mastitis related to infection by  Staph. aureus, Strep. uberis, Strep. agalactiae, Strep. dysgalactiae,  Klebsiella spp., Corynebacterium, or Enterococcus spp.; swine respiratory disease related to infection by  A. pleuro., P. multocida,  or Mycoplasma spp.; swine enteric disease related to infection by  E. coli, Lawsonia intracellularis,  Salmonella, or  Serpulina hyodysinteriae;  cow footrot related to infection by Fusobacterium spp.; cow metritis related to infection by  E. coli;  cow hairy warts related to infection by  Fusobacterium necrophorum  or  Bacteroides nodosus;  cow pink-eye related to infection by  Moraxella bovis;  cow premature abortion related to infection by protozoa; urinary tract infection in a dog or cat related to infection by  E. coli;  skin or soft tissue infection in a dog or cat related to infection by  Staph. epidermidis, Staph. intermedius,  coagulase neg. Staph. or  P. multocida;  or dental or mouth infection in a dog or cat related to infection by Alcaligenes spp., Bacteroides spp., Clostridium spp., Enterobacter spp., Eubacterium, Peptostreptococcus, Porphyromonas, or Prevotella.  
     
     
         15 . A pharmaceutical composition for the treatment of cancer in a mammal which comprises a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         16 . The pharmaceutical composition of  claim 13 , wherein said cancer is non-small cell lung cancer.  
     
     
         17 . A method of treating cancer in a mammal which comprises administering to said mammal a therapeutically effective amount of a compound of  claim 1 .  
     
     
         18 . The method of  claim 16 , wherein said cancer is non-small cell lung cancer.  
     
     
         19 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       or the pharmaceutically acceptable salt thereof; wherein the dashed line between positions 10 and 11 represents an optional double bond; 
 a is 0 or 1;  
 R 1  is hydrogen or (C 1 -C 10 )alkyl optionally substituted by fluoro, cyano, R 7 , R 7 O 2 C, R 7 C(O)NH and R 7 S(O) n  wherein n is 0, 1 or 2 and R 7  is (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three halo, (C 1 -C 3 )alkoxy, hydroxy, nitro, cyano, (C 6 -C 10 )aryl, (C 2 -C 9 )heteroaryl, R 8 R 9 N, R 8 C(O), R 8 C(O)O, R 8 OC(O), R 8 C(O)NH, R 8 NHC(O), R 8 R 9 NC(O) and R 8 OC(O) 2  wherein R 8  and R 9  are each independently hydrogen, (C 1 -C 6 )alkyl optionally substituted by (C 6 -C 10 )aryl or (C 2 -C 9 )heteroaryl;  
 R 2  is hydrogen or a hydroxy protecting group;  
 R 3  is N 3 , R 10 NH, R 10 C(O)NH, R 10 NHC(O)NH, R 10 NHC(S)NH, R 10 NHNHC(O)NH, R 10 ONHC(O)NH or R 10 OC(O)NH, wherein R 10  is (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C 1 -C 3 )alkoxy, hydroxy, nitro, cyano, (C 6 -C 10 )aryl, (C 2 -C 9 )heteroaryl, R 8 R 9 N, R 8 C(O), R 8 C(O)O, R 8 OC(O), R 8 C(O)NH, R 8 NHC(O), R 8 R 9 NC(O) and R 8 OC(O) 2  wherein R 8  and R 9  are each independently hydrogen, (C 1 -C 6 )alkyl optionally substituted by (C 6 -C 10 )aryl or (C 2 -C 9 )heteroaryl; or R 3  is R 11 (C 2 -C 4 )alkynyl wherein R 11  is (C 1 -C 6 )alkyl, (C 6 -C 10 )alkyl(C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl; or R 3  is R 12 R 13 N wherein R 12  and R 13  are each independently hydrogen, (C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl (C 1 -C 6 )alkyl;  
 X is oxygen or NOR 16  wherein R 16  is (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C 1 -C 3 )alkoxy, hydroxy, nitro, cyano, (C 6 -C 10 )aryl, (C 5 -C 9 )heteroaryl, R 8 R 9 N, R 8 C(O), R 8 C(O)O, R 8 OC(O), R 8 C(O)NH, R 8 NHC(O), R 8 R 9 NC(O) and R 8 OC(O) 2 , wherein R 8  and R 9  are each independently hydrogen or (C 1 -C 6 )alkyl optionally substituted by (C 6 -C 10 )aryl or (C 2 -C 9 )heteroaryl;  
 R 5  is hydrogen or methyl; and  
 R 6  is hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -c 6 )alkoxy(C 1 -C 6 )alkyl or (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally substituted by one to three substituents independently selected from hydroxy and halo; or R 6  is (C 3 -C 10 )cycloalkyl or (C 5 -C 10 )cycloalkenyl optionally substituted by (C 1 -C 6 )alkyl or halo; or R 6  is (C 2 -C 8 )heterocycloalkyl or (C 2 -C 9 )heteroaryl optionally substituted by (C 1 -C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 10 )cycloalkyl, (C 5 -C 10 )cycloalkenyl or aryl wherein the aryl group is optionally substituted by alkyl, (C 1 -C 6 )alkoxy or halo;  
 with the proviso that when a is zero, R 1  is hydrogen.  
 
     
     
         20 . A pharmaceutical composition for the treatment of a disorder selected from a bacterial infection, a protozoal infection, and a disorder related to a bacterial infection or protozoal infection in a mammal, fish, or bird which comprises a therapeutically effective amount of a compound of  claim 19  and a pharmaceutically acceptable carrier.  
     
     
         21 . A method of treating a disorder selected from a bacterial infection, a protozoal infection, and a disorder related to a bacterial infection or protozoal 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 19 .  
     
     
         22 . A compound of the formula  
       
         
           
           
               
               
           
         
         a is 0 or 1;  
         R 1  is hydrogen or (C 1 -C 10 )alkyl optionally substituted by fluoro, cyano, R 7 , R 7 O 2 C, R 7 C(O)NH and R 7 S(O) n  wherein n is 0, 1 or 2 and R 7  is (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C 1 -C 3 )alkoxy, hydroxy, nitro, cyano, (C 6 -C 10 )aryl, (C 2 -C 9 )heteroaryl, R 8 R 9 N, R 8 C(O), R 8 C(O)O, R 8 OC(O), R 8 C(O)NH, R 8 NHC(O), R 8 R 9 NC(O) and R 8 OC(O) 2  wherein R 8  and R 9  are each independently hydrogen, (C 1 -C 6 )alkyl optionally substituted by (C 6 -C 10 )aryl or (C 2 -C 9 )heteroaryl;  
         R 2  is hydrogen or a hydroxy protecting group;  
         R 3  is NH 2 , N 3 , O═C═N or S═C═N;  
         X is oxygen or NOR 16  wherein R 16  is (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C 1 -C 3 )alkoxy, hydroxy, nitro, cyano, (C 6 -C 10 )aryl, (C 2 -C 9 )heteroaryl, R 8 R 9 N, R 8 C(O), R 8 C(O)O, R 8 OC(O), R 8 C(O)NH, R 8 NHC(O), R 8 R 9 NC(O) and R 8 OC(O) 2 , wherein R 8  and R 9  are each independently hydrogen or (C 1 -C 6 )alkyl optionally substituted by (C 6 -C 10 )aryl or (C 2 -C 9 )heteroaryl;  
         R 5  is hydrogen or methyl; and  
         R 6  is hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -c 6 )alkoxy(C 1 -C 6 )alkyl or (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally substituted by one to three hydroxy or halo groups; or R 6  is (C 3 -C 10 )cycloalkyl or (C 6 -C 10 )cycloalkenyl optionally substituted by (C 1 -C 6 )alkyl or halo; or R 6  is (C 2 -C 8 )heterocycloalkyl or (C 2 -C 9 )heteroaryl optionally substituted by (C 1 -C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 10 )cycloalkyl, (C 5 -C 10 )cycloalkenyl or aryl wherein the aryl group is optionally substituted by alkyl, (C 1 -C 6 )alkoxy or halo.  
       
     
     
         23 . A compound of the formula  
       
         
           
           
               
               
           
         
         a is 0 or 1;  
         R 1  is hydrogen or (C 1 -C 10 )alkyl optionally substituted by fluoro, cyano, R 7 , R 7 O 2 C, R 7 C(O)NH and R 7 S(O) n  wherein n is 0, 1 or 2 and R 7  is (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three halo, (C 1 -C 3 )alkoxy, hydroxy, nitro, cyano, (C 6 -C 10 )aryl, (C 2 -C 9 )heteroaryl, R 8 R 9 N, R 8 C(O), R 8 C(O)O, R 8 OC(O), R 8 C(O)NH, R 8 NHC(O), R 8 R 9 NC(O) and R 8 OC(O) 2  wherein R 8  and R 9  are each independently hydrogen, (C 1 -C 6 )alkyl optionally substituted by (C 6 -C 10 )aryl or (C 2 -C 9 )heteroaryl;  
         R 2  is hydrogen or a hydroxy protecting group;  
         R 3  is NH 2  or N 3 ;  
         X is oxygen or NOR 16  wherein R 16  is (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three substituents independently selected from halo, (C 1 -C 3 )alkoxy, hydroxy, nitro, cyano, (C 6 -C 10 )aryl, (C 2 -C 9 )heteroaryl, R 8 R 9 N, R 8 C(O), R 8 C(O)O, R 8 OC(O), R 8 C(O)NH, R 8 NHC(O), R 8 R 9 NC(O) and R 8 OC(O) 2 , wherein R 8  and R 9  are each independently hydrogen or (C 1 -C 6 )alkyl optionally substituted by (C 6 -C 10 )aryl or (C 2 -C 9 )heteroaryl;  
         R 5  is hydrogen or methyl; and  
         R 6  is hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -c 6 )alkoxy(C 1 -C 6 )alkyl or (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally substituted by one to three substituents independently selected from hydroxy and halo; or R 6  is (C 3 -C 10 )cycloalkyl or (C 5 -C 10 )cycloalkenyl optionally substituted by (C 1 -C 6 )alkyl or halo; or R 6  is (C 2 -C 8 )heterocycloalkyl or (C 2 -C 9 )heteroaryl optionally substituted by (C 1 -C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 10 )cycloalkyl, (C 5 -C 10 )cycloalkenyl or aryl wherein the aryl group is optionally substituted by alkyl, (C 1 -C 6 )alkoxy or halo.  
       
     
     
         24 . A compound of the formula  
       
         
           
           
               
               
           
         
         a is 0 or 1;  
         R 1  is hydrogen or (C 1 -C 10 )alkyl optionally substituted by fluoro, cyano, R 7 , R 7 O 2 C, R 7 C(O)NH and R 7 S(O) n  wherein n is 0, 1 or 2 and R 7  is (C 1 -C 6 )alkyl, (C 2 -C 12 )alkenyl, (C 2 -C 12 )alkynyl, (C 3 -C 10 )cycloalkyl(C 1 -C 6 )alkyl, (C 2 -C 9 )heterocycloalkyl(C 1 -C 6 )alkyl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl or (C 2 -C 9 )heteroaryl(C 1 -C 6 )alkyl wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl groups are optionally substituted by one to three halo, (C 1 -C 3 )alkoxy, hydroxy, nitro, cyano, (C 6 -C 10 )aryl, (C 2 -C 9 )heteroaryl, R 8 R 9 N, R 8 C(O), R 8 C(O)O, R 8 OC(O), R 8 C(O)NH, R 8 NHC(O), R 8 R 9 NC(O) and R 8 OC(O) 2  wherein R 8  and R 9  are each independently hydrogen, (C 1 -C 6 )alkyl optionally substituted by (C 6 -C 10 )aryl or (C 2 -C 9 )heteroaryl;  
         R 2  is hydrogen or a hydroxy protecting group;  
         R 5  is hydrogen or methyl; and  
         R 6  is hydrogen, (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 1 -C 6 )alkoxy(C 1 -C 6 )alkyl or (C 1 -C 6 )alkylthio(C 1 -C 6 )alkyl wherein the alkyl, alkenyl, alkynyl or alkoxy groups are optionally substituted by one to three substituents independently selected from hydroxy and halo; or R 6  is (C 3 -C 10 )cycloalkyl or (C 5 -C 10 )cycloalkenyl optionally substituted by (C 1 -C 6 )alkyl or halo; or R 6  is (C 2 -C 8 )heterocycloalkyl or (C 2 -C 9 )heteroaryl optionally substituted by (C 1 -C 6 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 3 -C 10 )cycloalkyl, (C 5 -C 10 )cycloalkenyl or aryl wherein the aryl group is optionally substituted by alkyl, (C 1 -C 6 )alkoxy or halo.