WO2008071964A1

WO2008071964A1 - Naphthyridine bactericides

Info

Publication number: WO2008071964A1
Application number: PCT/GB2007/004771
Authority: WO
Inventors: Gloria Breault; Vincent Galullo; Folkert Reck
Original assignee: Astrazeneca Ab; Astrazeneca Uk Limited
Priority date: 2006-12-15
Filing date: 2007-12-13
Publication date: 2008-06-19

Abstract

The present invention relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof, to their use in the treatment of bacterial infections, and to their methods preparation.

Description

NAPHTHYRIDINE BACTERICIDES

Field of Invention

The present invention relates to novel piperidines, pharmaceutical compositions thereof, and methods of use. In addition, the present invention relates to therapeutic methods for the treatment of bacterial infections.

Background

The international health community continues to express serious concern that the evolution of antibacterial resistance will result in strains against which currently available antibacterial agents will be ineffective. For example, resistant strains of Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative staphylococci (MRCNS), penicillin-resistant Streptococcus pneumoniae and multiple resistant Enterococcus faecium are both difficult to treat and difficult to eradicate. Consequently, in order to overcome the threat of widespread multi-drug resistant organisms, there is an on-going need to develop new antibiotics, particularly those with either a novel mechanism of action and/or containing new pharmacophoric groups.

Summary

In accordance with the present invention, the applicants have hereby discovered compounds that possess the ability to act as antimicrobials. Accordingly, the present invention relates to compounds that demonstrate antibacterial activity, processes for their preparation, pharmaceutical compositions containing them as the active ingredient, their use as medicaments, and their use in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as humans. Accordingly the present invention provides a compound of Formula (I):

Formula (I) or a pharmaceutically acceptable salt thereof, wherein

A is selected from CH and N;

D is selected from C-R⁷ and N; wherein at least one of A and D is carbon;

G is selected from O and S;

R² is selected from H, halo, cyano, C^aUcyl, C_2-6alkenyl, C_2-6alkynyl, -OR^2a, and -N(R^2a)₂, wherein said C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are optionally substituted with one or more R²⁰;

R^2a in each occurrence is independently selected from H and Ci^alkyl, wherein said C_1-6alkyl are optionally substituted with one or more R²⁰;

R³ is selected from H, halo, cyano, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, -OR^3a, and -N(R^3a)₂, wherein said C^alkyl, C_2-6alkenyl, and C_2-6alkynyl are optionally substituted with one or more R³⁰;

R^3a is selected from H and C^aHcyl, wherein said Q^alkyl are optionally substituted with one or more R³⁰;

R⁴ is selected from H, halo, cyano, -CO₂H, d^alkyl, C_2-6alkenyl, and C_2-6alkynyl, wherein said

C_2-6alkenyl, and C_2-6alkynyl are optionally substituted with one or more R⁴⁰;

R⁷ is selected from H, halo, cyano, C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl, wherein said Ci_-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are optionally substituted with one or more R⁷⁰;

R²⁰, R³⁰, R⁴⁰, and R⁷⁰ in each occurrence are each, independently, selected from halo, hydroxy, cyano, -CO₂H, C^alkoxy, C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl. Detailed Description of the Invention

In this specification the prefix C_x-y as used in terms such as C_x-yalkyl and the like (where x and y are integers) indicates the numerical range of carbon atoms that are present in the group; for example, C_1-4alkyl includes Qalkyl (methyl), C₂alkyl (ethyl), C₃alkyl (propyl and isopropyl) and C₄alkyl (butyl, 1-methylpropyl, 2-methylpropyl, and t-butyl).

As used herein the term "alkyl" refers to both straight and branched chain saturated hydrocarbon radicals having the specified number of carbon atoms. References to individual alkyl groups such as "propyl" are specific for the straight chain version only and references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched chain version only.

The term "alkenyl" refers to both straight and branched chain hydrocarbon radicals having the specified number of carbon atoms and containing at least one carbon-carbon double bond. For example, "C_2-8alkenyl" includes, but is not limited to, groups such as C_2-6alkenyl, C_2-4alkenyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, and 2-methyl- 1 -heptenyl.

The term "alkynyl" refers to both straight and branched chain hydrocarbon radicals having the specified number of carbon atoms and containing at least one carbon-carbon triple bond. For example, "C_2-8alkynyl" includes, but is not limited to, groups such as C₂.₆alkynyl, C_2-4alkynyl, ethynyl, 2-propynyl, 2-methyl-2-propynyl, 3-butynyl, 4-pentynyl, 5-hexynyl, 2-heptynyl, and 4-methyl-5-heptynyl.

The term "halo" refers to fluoro, chloro, and bromo.

Where optional substituents are chosen from "one or more" groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.

The term "carbocyclyl" refers to a saturated, partially saturated, or unsaturated, mono or bicyclic carbon ring that contains 3-12 ring atoms, wherein one or more -CH₂- groups can optionally be replaced by a corresponding number of -C(O)- groups. In one aspect, the term "carbocyclyl" may refer to a monocyclic ring containing 3 to 6 ring atoms or a bicyclic ring containing 9 or 10 atoms. In another aspect, the term "carbocyclyl" may refer to a monocyclic ring containing 5 or 6 atoms. Illustrative examples of "carbocyclyl" include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1-oxocyclopentyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl. A particular example of a "carbocyclyl" group is phenyl.

The term "heterocyclyl" refers to a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 ring atoms of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH₂- group can optionally be replaced by a -C(O)-. Ring sulfur atoms may be optionally oxidized to form S-oxides. Ring nitrogen atoms may be optionally oxidized to form N-oxides. Illustrative examples of the term "heterocyclyl" include, but are not limited to, 1,3-benzodioxolyl, 3,5-dioxopiperidinyl, imidazolyl, indolyl, isoquinolone, isothiazolyl, isoxazolyl, morpholino, 2-oxopyrrolidinyl, 2-oxo-l,3-thiazolidinyl, piperazinyl, piperidyl, pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrrolinyl, pyrimidyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridone, quinolyl, tetrahydropyranyl, thiazolyl, thiadiazolyl, thiazolidinyl, thienyl, thiomorpholino, thiophenyl, pyridine-N-oxide and quinoline-N-oxide. In one aspect of the invention the term "heterocyclyl" may refer to a saturated, partially saturated or unsaturated, monocyclic ring containing 5 or 6 atoms of which at least one atom is selected from nitrogen, sulfur, andr oxygen, and may, unless otherwise specified, be carbon or nitrogen linked, and a ring nitrogen atom may be optionally oxidized to form an Ν-oxide.

Where a particular R group is present in a compound of Formula (I) more than once, it is intended that each selection for that R group is independent at each occurrence.

Unless specifically stated, the bonding atom of a group may be any suitable atom of that group; for example, propyl includes prop-1-yl and prop-2-yl.

As used herein, the term "optionally substituted," indicates that substitution is optional and therefore it is possible for the designated group to be either substituted or unsubstituted. In the event a substitution is desired, any number of hydrogens on the designated group may be replaced with a selection from the indicated substituents, provided that the normal valency of the atoms on a particular substituent is not exceeded, and that the substitution results in a stable compound which exhibits an antibacterial effect.

As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, the phrase "effective amount" means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically-acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.

Compounds and substituent definitions of the present invention have been named with the aid of ACD/Name by ACD/Labs®.

Compounds of Formula (I) may form stable pharmaceutically acceptable acid or base salts, and in such cases administration of a compound as a salt may be appropriate, and pharmaceutically acceptable salts may be made by conventional methods well-known in the art.

A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, citric or maleic acid. In addition a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

Some compounds of Formula (I) may have chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers that possess antibacterial activity. The invention further relates to any and all tautomeric forms of the compounds of Formula (I) that possess antibacterial activity.

It is also to be understood that certain compounds of Formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess antibacterial activity.

Additional embodiments of the invention are as follows. These additional embodiments relate to compounds of Formula (I). Such specific substituents may be used, where appropriate, with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.

E²

In one aspect, R² may be selected from halo, cyano, and -OR^2a; and R^2a may be C_1-6alkyl.

In another aspect, R² may be selected from halo.

In still another aspect, R² may be selected from cyano.

In still another aspect, R² may be selected from -OR^2a; and R^2a may be C_1-6alkyl.

In another aspect, R² may be selected from cyano, chloro, and methoxy. R-

In one aspect, R³ may be H.

E-

In one aspect, R⁴ may be H.

A

In one aspect, A may be N.

D

In one aspect, D may be CH

G

In one aspect, G may be S.

In another aspect, G may be O.

In one aspect, there is provided a compound of Formula (I), wherein:

R² may be selected from halo, cyano, and -OR^2a;

R^2a may be d.₆alkyl;

R³ may be H;

R⁴ may be H;

A may be N;

D may be CH; and

G may be selected from O and S.

In another aspect, there is provided a compound of Formula (I), wherein:

R² may be selected from chloro, cyano, and methoxy;

R³ may be H;

R⁴ may be H;

A may be N;

D may be CH; and

G may be selected from O and S. Biological Activity

The compounds of Formula (I) are of interest due to their antibacterial effects. The ability of the invention compounds disclosed herein to achieve an antibacterial effect may be demonstrated by the following test.

Bacterial Susceptibility Testing Methods

Compounds were tested for antimicrobial activity by susceptibility testing in liquid media in a 96 well format. Compounds were dissolved in dimethylsulfoxide and tested in 10 doubling dilutions in the susceptibility assays. The organisms used in the assay were grown overnight on suitable agar media and then suspended in a liquid medium appropriate for the growth of the organism. The suspension was a 0.5 McFarland and a further 1 in 10 dilution was made into the same liquid medium to prepare the final organism suspension in 100 μL. Plates were incubated under appropriate conditions at 37 °C for 24 hours prior to reading. The Minimum Inhibitory Concentration (MIC) was determined as the lowest drug concentration able to reduce growth by 80% or more.

Compounds were evaluated against a panel of Gram-positive species, including Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and Enterococcus faecium. In addition, compounds were evaluated against a panel of Gram- negative species including Haemophilus influenzae, Escherichia coli and Moraxella catarrhalis. Compounds of the present invention have MICs less than or equal to 8 μg/ml versus one or more of the organisms named above.

The compound of Example 3 had an MIC of 0.13 (mg/L) against Staphylococcus aureus and an MIC of 0.25 (mg/L) against Escherichia coli.

Thus, in one aspect there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.

In still another aspect, there is provided the use a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a bacterial infection in a warm-blooded animal such as man. In yet another aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a bacterial infection caused by one or more pathogenic organism such as Acinetobacter baumanii, Aeromis hydrophila, Bacillus anthracis, Bacteroides fragilis, Bordatella pertussis, Burkholderia cepacia, Chlamyida pneumoniae, Citrobacter freundii, Clostridium difficile, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusobacterium necrophorum, Haemophilus influenzae, Haemophilus paramfluenzae, Haemophilus somnus, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Salmonella typhi, Salmonella typhimurium, Serratia marcesens, Shigella flexneria, Shigella dysenteriae, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus intermedius, Staphylococcus saprophyticus, Stenotrophomonas maltophila, Streptococcus agalactiae, Streptococcus mutans, Streptococcus pneumoniae, and Streptococcus pyrogenes, in a warm-blooded animal such as man.

In a further aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of an infection such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intra-abdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections, and urinary tract infections, in a warm-blooded animal such as man.

In still a further aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a bacterial infection, wherein the bacteria is of a genus selected from Aeromonas, Acinetobacter, Bacillus, Bacteroides, Bordetella, Burkholderia, Chlamydophila, Citrobacter, Clostridium, Enterobacter, Enterococcus, Escherichia, Flavobacterium, Fusobacterium, Haemophilus, Klebsiella, Legionella, Listeria, Morganella, Moraxella, Mycoplasma, Neisseria, Pasteurella, Peptococci, Peptostreptococci, Prevotella, Proteus Salmonella, Pseudomonas, Serratia, Shigella, Stenotrophomonas, Streptococcus, and Staphylococcus, in a warm-blooded animal such as man.

In another aspect, there is provided a method for treating a bacterial infection in a warmblooded animal such as man, said method comprising administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In still another aspect, there is provided a method for treating a bacterial infection caused by one or more pathogenic organism such as Acinetobacter baumanii, Aeromis hydrophila, Bacillus anthracis, Bacteroides fragilis, Bordatella pertussis, Burkholderia cepacia, Chlamyida pneumoniae, Citrobacter freundii, Clostridium difficile, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusobacterium necrophorum, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus somnus, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Salmonella typhi, Salmonella typhimurium, Serratia marcesens, Shigella flexneria, Shigella dysenteriae, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus intermedius, Staphylococcus saprophyticus, Stenotrophomonas maltophila, Streptococcus agalactiae, Streptococcus mutans, Streptococcus pneumoniae, and Streptococcus pyrogenes, in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In yet another aspect, there is provided a method for treating an infection such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intraabdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections, and urinary tract infections, in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In a further aspect, there is provided a method for treating a bacterial infection, wherein the bacteria is of a genus selected from Aeromonas, Acinetobacter, Bacillus, Bacteroides, Bordetella, Burkholderia, Chlamydophila, Citrobacter, Clostridium, Enterobacter, Enterococcus, Escherichia, Flavobacterium, Fusobacterium, Haemophilus, Klebsiella, Legionella, Listeria, Morganella, Moraxella, Mycoplasma, Neisseria, Pastenrella, Peptococci, Peptostreptococci, Prevotella, Proteus Salmonella, Pseudomonas, Serratia, Shigella, Stenotrophomonas, Streptococcus, and Staphylococcus, in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In still a further aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a bacterial infection in a warm-blooded animal, such as man.

hi another aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a bacterial infection caused by one or more pathogenic organism such as Acinetobacter baumanii, Aeromis hydrophila, Bacillus anthracis, Bacteroides fragilis, Bordatella pertussis, Burkholderia cepacia, Chlamyida pneumoniae, Citrobacter freundii, Clostridium difficile, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusobacterium necrophorum, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus somnus, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Salmonella typhi, Salmonella typhimurium, Serratia marcesens, Shigella flexneria, Shigella dysenteriae, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus intermedius, Staphylococcus saprophyticus, Stenotrophomonas maltophila, Streptococcus agalactiae, Streptococcus mutans, Streptococcus pneumoniae, and Streptococcus pyrogenes, in a warm-blooded animal such as man.

In still another aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating an infection such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intra-abdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections, and urinary tract infections, in a warm-blooded animal such as man.

In yet another aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a bacterial infection, wherein the bacteria is of a genus selected from Aeromonas, Acinetobacter, Bacillus, Bacteroides, Bordetella, Burkholderia, Chlamydophila, Citrobacter, Clostridium, Enterobacter, Enterococcus, Escherichia, Flavobacterium, Fusobacterium, Haemophilus, Klebsiella, Legionella, Listeria, Morganella, Moraxella, Mycoplasma, Neisseria, Pasteurella, Peptococci, Peptostreptococci, Prevotella, Proteus Salmonella, Pseudomonas, Serratia, Shigella, Stenotrophomonas, Streptococcus, and Staphylococcus, in a warm-blooded animal such as man.

In one aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Acinetobacter baumanii. In another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Aeromis hydrophila. In still another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Bacillus anthracis. In yet another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Bacteroides fragilis. In a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Bordatella pertussis. In still a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Burkholderia cepacia. In yet a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Chlamyida pneumoniae. In one aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Citrobacter freundii. In another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Clostridium difficile. In still another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Enterobacter cloacae. In yet another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Enterococcus faecalis. In a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Enterococcus faecium. In still a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Enterobacter aerogenes. In yet a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Escherichia coli. In one aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Fusobacterium necrophorum. In another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Haemophilus influenzae. In still another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Haemophilus parainfluenzae. In yet another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Haemophilus somnus. In a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Klebsiella oxytoca. In still a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Klebsiella pneumoniae. In yet a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Legionella pneumophila. In one aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Listeria monocytogenes. In another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Moraxella catarrhalis. In still another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Morganella morganii. In yet another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Mycoplasma pneumoniae. In a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Neisseria gonorrhoeae. In still a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Neisseria meningitidis. In yet a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Pasteurella multocida. In one aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Proteus mirabilis. In another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Proteus vulgaris. In still another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Pseudomonas aeruginosa. In yet another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Salmonella typhi. In a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Salmonella typhimurium. In still a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Serratia marcesens. In yet a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Shigella flexneria. In one aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Shigella dysenteriae. In another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Staphylococcus aureus. In still another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Staphylococcus epidermidis. In yet another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Staphylococcus haemolyticus. In a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Staphylococcus intermedius. In still a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Staphylococcus saprophyticus. In yet a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Stenotrophomonas maltophila. In one aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Streptococcus agalactiae. In another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Streptococcus mutans. In a still another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Streptococcus pneumoniae. In yet another aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by Streptococcus pyrogenes.

In one aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Aeromonas. In another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Acinetobacter. In still another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Bacillus. In yet another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Bacteroides. In a further aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Bordetella. In still a further aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Burkholderia. In yet a further aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Chlamydophila. In one aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Citrobacter. In another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Clostridium. In still another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Enterobacter. In yet another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Enterococcus. In a further aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Escherichia. In still a further aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Flavobacterium. In yet a further aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Fusobacterium. In one aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Haemophilus. In one aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Klebsiella. In another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Legionella. In still another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Listeria. In yet another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Morganella. In a further aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Moraxella. In still a further aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Mycoplasma. In yet a further aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Neisseria. In one aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Pasteurella. In another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Peptococci. In still another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Peptostreptococci. In yet another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Prevotella. In a further aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Proteus. In still a further aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Pseudomonas. In still another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Salmonella. In yet a further aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Serratia. In one aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Shigella. In yet another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Staphylococcus. In another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Stenotrophomonas. In still another aspect, the terms "infection and "bacterial infection" may refer to a bacterial infection caused by a bacteria of the genus Streptococcus.

In one aspect, the terms "infection" and "bacterial infection" may refer to a gynecological infection. In another aspect the terms "infection" and "bacterial infection" may refer to a respiratory tract infection (RTI). In still another, the terms "infection" and "bacterial infection" may refer to a sexually transmitted disease. In yet another aspect, the terms "infection" and "bacterial infection" may refer to a urinary tract infection. In a further aspect, the terms "infection" and "bacterial infection" may refer to acute exacerbation of chronic bronchitis (ACEB). In yet a further aspect, the terms "infection" and "bacterial infection" may refer to acute otitis media. In one aspect, the terms "infection" and "bacterial infection" may refer to acute sinusitis. In another aspect, the terms "infection" and "bacterial infection" may refer to an infection caused by drug resistant bacteria. In still another aspect, the terms "infection" and "bacterial infection" may refer to catheter-related sepsis. In yet another aspect, the terms "infection" and "bacterial infection" may refer to chancroid. In a further aspect, the terms "infection" and "bacterial infection" may refer to chlamydia. In still a further aspect, the terms "infection" and "bacterial infection" may refer to community-acquired pneumonia (CAP). In yet a further aspect, the terms "infection" and "bacterial infection" may refer to complicated skin and skin structure infection. In one aspect, the terms "infection" and "bacterial infection" may refer to uncomplicated skin and skin structure infection. In another aspect, the terms "infection" and "bacterial infection" may refer to endocarditis. In still another aspect, the terms "infection" and "bacterial infection" may refer to febrile neutropenia. In yet another aspect, the terms "infection" and "bacterial infection" may refer to gonococcal cervicitis. In a further aspect, the terms "infection" and "bacterial infection" may refer to gonococcal urethritis. In still a further aspect, the terms "infection" and "bacterial infection" may refer to hospital- acquired pneumonia (HAP). In yet another aspect, the terms "infection" and "bacterial infection" may refer to osteomyelitis. In a further aspect, the terms "infection" and "bacterial infection" may refer to sepsis. In still a further aspect, the terms "infection" and "bacterial infection" may refer to syphilis.

In a further aspect, there is provided a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl />-hydroxybenzoate; and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.

Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finely powdered form or in the form of nano or micronized particles together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives such as ethyl or propyl p_- hydroxybenzoate; anti-oxidants such as ascorbic acid); coloring agents; flavoring agents; and/or sweetening agents such as sucrose, saccharine or aspartame.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil or in a mineral oil such as liquid paraffin. The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preservative agents. Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent.

The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.

Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.

For further information on formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 4 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. In addition to the compounds of the present invention, the pharmaceutical composition of this invention may also contain or be co-administered (simultaneously, sequentially or separately) with one or more known drugs selected from other clinically useful classes of antibacterial agents (for example, macrolides, quinolones, β-lactams or aminoglycosides) and/or other anti- infective agents (for example, an antifungal triazole or amphotericin). These may include carbapenems, for example meropenem or imipenem, to broaden the therapeutic effectiveness. Compounds of this invention may also contain or be co-administered with bactericidal/permeability-increasing protein (BPI) products or efflux pump inhibitors to improve activity against gram negative bacteria and bacteria resistant to antimicrobial agents.

As stated above the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. Preferably a daily dose in the range of 1-50 mg/kg is employed. Accordingly, the optimum dosage may be determined by the practitioner who is treating any particular patient.

In addition to its use in therapeutic medicine, the compound of Formulas (I) and its pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardization of in vitro and in vivo test systems for the evaluation of antibacterial effects in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.

In any of the above-mentioned pharmaceutical composition, process, method, use, medicament, and manufacturing features of the instant invention, any of the alternate embodiments of the compounds of the invention described herein also apply.

Process

If not commercially available, the necessary starting materials for the procedures such as those described herein may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the described procedure or the procedures described in the Examples. It is noted that many of the starting materials for synthetic methods as described herein are commercially available and/or widely reported in the scientific literature, or could be made from commercially available compounds using adaptations of processes reported in the scientific literature. The reader is further referred to Advanced Organic Chemistry, 5^th Edition, by Jerry March and Michael Smith, published by John Wiley & Sons 2001, for general guidance on reaction conditions and reagents.

It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in compounds. The instances where protection is necessary or desirable are known to those skilled in the art, as are suitable methods for such protection. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Greene, Protective Groups in Organic Synthesis, published by John Wiley and Sons, 1991).

Examples of suitable protecting groups for a hydroxy group are, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, a silyl group such as trimethylsilyl or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively a silyl group such as trimethylsilyl may be removed, for example, by fluoride or by aqueous acid; or an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation in the presence of a catalyst such as palladium-on-carbon.

A suitable protecting group for an amino group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or t-butoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric, phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid, for example boron ^rø(trifluoroacetate). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group, which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine or 2-hydroxyethylamine, or with hydrazine. Another suitable protecting group for an amine is, for example, a cyclic ether such as tetrahydrofuran, which may be removed by treatment with a suitable acid such as trifluoroacetic acid.

The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art, or they may be removed during a later reaction step or work-up.

Thus, the present invention also provides that the compounds of the invention and pharmaceutically-acceptable salts and in vivo hydrolysable esters thereof, can be prepared by a process (a) to (g); and thereafter if necessary:

i) removing any protecting groups; ii) forming a pro-drug (for example an in- vivo hydrolysable ester); and/or iii) forming a pharmaceutically-acceptable salt;

wherein said processes (a) to (g) are as follows (wherein the variables are as defined above unless otherwise stated):

a) By modifying a substituent in, or introducing a substituent into another compound of the invention by using standard chemistry (see for example, Comprehensive Organic Functional Group Transformations (Pergamon), Katritzky, Meth-Cohn & Rees). For example:

• a hydroxy group may be converted into a fluoro group, an acyloxy group (such as an acetoxy group), an alkoxy group, an amino group, a heterocyclyl group linked through nitrogen (optionally substituted on a carbon other than a carbon atom adjacent to the linking nitrogen ring atom, such as an optionally substituted amino group). The skilled artisan understands that such reactions of the hydroxy group take place directly (such as by acylation or Mitsunobu reaction) or through the intermediacy of one or more derivatives (such as a mesylate or an azide);

• an acyloxy group may be converted into a hydroxy group or into the groups that may be obtained from a hydroxy group (either directly or through the intermediacy of a hydroxy group); an alkyl halide group may be converted to a hydroxyl group, an amino group, a thioalkyl group or a heterocyclyl group linked through nitrogen; a keto group may be reduced to a hydroxyl group or an saturated alkyl group;

• A suitable leaving group like bromo or triflate on an aromatic system may be converted into a cyano group by reaction with copper (I) cyanate or by reaction with cyanide ions in the presence of a palladium catalyst;

b) As depicted in Scheme 1, by alkylation of a suitable bicyclic ring system containing a NH group in the ring with a suitable alkylating reagent containing a leaving group (such as an O-mesylate, chloro, bromo or iodo) in the presence of a base. Alkylation may be followed by functional group manipulations and/or further alkylations or reductive aminations in the presence of a dehydrating agent, such as molecular sieves (MS 3A);

Scheme 1

The aldehydes for the reductive ammination steps may be obtained by procedures described in the patent literature, such as in PCT Pub. No. WO 2004/048144;

c) A substituent may also be introduced into the molecule at a later stage. For example, as depicted in Scheme 2, a chloro substitutent in a l,8-naphthyridin-2(lH)-one may be substitued for a cyano group using cyanation reagents such as zinc cyanide under palladium (0) catalysis;

Scheme 2

d) As depicted in Scheme 3, by reaction of a suitable bicyclic ring system containing an acidic NH group in the ring with a suitable alcohol under Mitsunobu conditions, followed by deprotection and reductive amination with an aldehyde. This sequence may be followed by functional group manipulations and/or further alkylations or reductive aminations.

Scheme 3

diisopropylazodicarboxylate triphenyl phosphine

e) As depicted in Scheme 4, by alkylation of a suitable bicyclic ring system containing a NH group in the ring with bromo- or chloroethanol or bromo-or chloro acetaldehyde or with a protected derivative thereof, followed by deprotection and oxidation in case of an alcohol derivative to the aldehyde. The aldehyde may then be subjected to reductive ammination, followed by deprotection of the amino group and a second reductive ammination step.

Scheme 4

1 ) MS 3A°

f) An O-mesylate alkylating reagent may be prepared by alkylation of a suitable protected 4-arninopiperidine derivative with bromoethanol or a derivative thereof in the presence of a base, followed by reaction of the alcohol intermediate with mesyl chloride, in the presence of a base, such as a trialkyl amine or an immobilized version thereof on a resin, as depicted in Scheme 5. It is understood, that such an alkylating reagent is potentially unstable, may represent a mixture with the corresponding chloride (arising from attack of chloride on the mesyl group) and needs to be prepared fresh under careful controlled conditions; Scheme 5

PG= protecting group

g) Naphthyridones may be prepared following a general approach published in the literature (J.A. Turner, J. Org. Chem. 1990, 55, 4744-4750). For example, 1,8- naphthyridin-2(lH)-ones may be prepared by formylation of a suitable protected 2- aminopyridine derivative, followed by condensation with lithiated t-butylacetate and then cyclization under acidic conditions, as depicted in Scheme 6;

Scheme 6

With respect to (a)-(g) and Schemes 1-6 above, the removal of any protecting groups, formation of pharmaceutically-acceptable salts and/or formation of in-vivo hydrolysable esters or amides are within the skill of an ordinary organic chemist using standard techniques. Furthermore, details regarding these transformations; for example, the preparation of in-vivo hydrolysable ester prodrugs has been described in the section above on such esters.

When an optically active form of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using a pure enantiomer as a starting material, or by resolution of a mixture of the enantiomers or diastereomers of the final products or chiral intermediates using a Standard procedure. The resolution of enantiomers may be achieved by chromatography on a chiral stationary phase, such as a Chiralpak AD column. Consideration has to be given to solubility as well as resolution. Alternatively, resolution may be obtained by preparation and selective crystallization of a diastereomeric salt of a chiral intermediate or chiral product with a chiral acid, such as camphersulfonic acid. Alternatively, a method of stereoselective synthesis may be employed, for example by using a chiral variant of a protection group, a chiral catalyst or a chiral reagent where appropriate in the reaction sequence.

Enzymatic techniques may also be useful for the preparation of optically active compounds and/or intermediates.

Similarly, when a pure regioisomer of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using a pure regioisomer as a starting material, or by resolution of a mixture of the regioisomers or intermediates using a standard procedure.

The skilled organic chemist will be able to use and adapt the information contained and referenced within the above references, and accompanying Examples therein and also the Examples herein, to obtain necessary starting materials and products.

Examples

The invention is now illustrated by but not limited to the following Examples, for which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids by filtration;

(ii) temperatures are quoted as °C; operations were carried out at room temperature, that is typically in the range 18-26 ⁰C and without the exclusion of air unless otherwise stated, or unless the skilled person would otherwise work under an inert atmosphere;

(iii) column chromatography (by the flash procedure) was used to purify compounds and was performed on Merck Kieselgel silica (Art. 9385) unless otherwise stated;

(iv) in general, the course of reactions was followed by TLC, HPLC, or LC/MS and reaction times are given for illustration only; yields are given for illustration only and are not necessarily the maximum attainable;

(v) the structure of the end-products of the invention were generally confirmed by NMR and mass spectral techniques. Proton magnetic resonance spectra were generally determined in DMSOd₆ unless otherwise stated, using a Bruker DRX-300 spectrometer or a Bruker DRX-400 spectrometer, operating at a field strength of 300 MHz, or 400 MHz, respectively. In cases where the NMR spectrum is complex, only diagnostic signals are reported. Chemical shifts are reported in parts per million downfield from tetramethylsilane as an internal standard (δ scale) and peak multiplicities are shown thus: s, singlet; d, doublet; dd, doublet of doublets; dt, doublet of triplets; dm, doublet of multiplets; t, triplet, m, multiplet; br, broad. Fast-atom bombardment (FAB) mass spectral data were generally obtained using a Platform spectrometer (supplied by Micromass) run in electrospray and, where appropriate, either positive ion data or negative ion data were collected or using Agilent 1100 series LC/MSD equipped with Sedex 75ELSD, and where appropriate, either positive ion data or negative ion data were collected. The lowest mass major ion is reported for molecules where isotope splitting results in multiple mass spectral peaks (for example when chlorine is present). Reverse Phase HPLC was carried out using YMC Pack ODS-AQ (100x20 mmID, S-5μ particle size, 12 nm pore size) on Agilent instruments;

(vi) each intermediate was purified to the standard required for the subsequent stage and was characterized in sufficient detail to confirm that the assigned structure was correct; purity was assessed by HPLC, TLC, or NMR and identity was determined by infra-red spectroscopy (IR), mass spectroscopy or NMR spectroscopy as appropriate; and (vii) the following abbreviations may be used:

TLC is thin layer chromatography; HPLC is high pressure liquid chromatography; MPLC is medium pressure liquid chromatography; NMR is nuclear magnetic resonance spectroscopy; DMSO is dimethylsulfoxide; CDCl₃ is deuterated chloroform; MeOD is deuterated methanol, i.e. D₃COD; MS is mass spectroscopy; ESP (or ES) is electrospray; EI is electron impact; APCI is atmospheric pressure chemical ionization; THF is tetrahydrofuran; DCM is dichloromethane; MeOH is methanol; DMF is dimethylformamide; EtOAc is ethyl acetate; LC/MS is liquid chromatography/mass spectrometry; h is hour(s); min is minute(s); d is day(s); MTBD is N-methyl-l,5,7-triazabicyclo[4.4.0]dec-5-ene; TFA is trifluoroacetic acid; v/v is ratio of volume/volume; Boc denotes t-butoxycarbonyl; Cbz denotes benzyloxycarbonyl; Bz denotes benzoyl; atm denotes atmospheric pressure; rt denotes room temperature; mg denotes milligram; g denotes gram; μL denotes microliter; mL denotes milliliter; L denotes liter; μM denotes micromolar; mM denotes millimolar; M denotes molar; N denotes normal; nm denotes nanometer.

Intermediate 1 fert-Butyl [ 1 -(2-hvdroxyethyr)piperidin-4-yl1 carbamate

A mixture of fers-butyl piperidin-4-ylcarbamate (5 g, 25 mmol), 2-bromoethanol (1.77 mL, 25 mmol) and triethylamine (3.86 mL, 27.5 mmol) in acetonitrile (20 mL) was heated in a sealed tube at 5O⁰C for 16 hours. The solvent was removed under reduced pressure, and the residue was taken up in ethyl acetate (300 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (100 mL). The aqueous phase was back-extracted once with ethyl acetate (100 mL) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with dichloromethane/ methanol (4:1) gave 4.04 g (66% yield) of product as a colourless solid, mp 66⁰C. MS (ES): 245.28 (MH⁺) for C₁₂H₂₄N₂O₃

¹H-NMR (DMSO-φ δ: 1.33 (m, 2H); 1.36 (s, 9H); 1.62 (m, 2H); 1.92 (t, 2H); 2.32 (t, 2H); 2.77 (m, 2H); 3.17 (m, IH); 3.43 (m, 2H); 4.34 (t, IH); 6.73 (d, IH).

Intermediate 2

2-{4-r(ferS-Butoxycarbonyl)aminolpiperidin-l-yl|ethyl methanesulfonate

A mixture of tert-butyl [l-(2-hydroxyethyl)piperidin-4-yl] carbamate (Intermediate 1, 1.7 g,

7 mmol) in dry dichloromethane (20 mL) and triethyl amine (1.4 mL, 9.8 mmol) was treated at O⁰C with methanesulfonyl chloride (0.65 mL, 8.4 mmol). After 45 minutes the reaction was complete by TLC (chloroform/methanol 6:1, rf -0.54). Potassium phosphate buffer (pH

7, IM, 50 mL) was added, dichloromethane was removed under reduced pressure and it was extracted with ice cold ethyl acetate (2 x 100 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure and the crude preparation of the mesylate was used without delay for the next step.

MS (ES): 323.18 (MH⁺) for Ci₃H₂₆N₂O₅S

Intermediate 3 fert-Butyl { 1 -r2-(7-chloro-2-oxo- 1.8-naphthyridin- 1 (2HVyl)ethvHpiρeridin-4-yll carbamate A solution of 7-chloro-l,8-naρhthyridin-2(lH)-one rJ.Org.Chem. 1990, 55, 4744-4750] in dry DMF (20 mL) (540 mg, 3.0 mmol) at O⁰C was treated with sodium hydride (144 mg, 60% in mineral oil, -3.6 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction was cooled using an ice bath. A solution of 2-{4-[(tert- butyoxycarbonyl)amino]piperidin-lyl} ethyl methanesulfonate in DMF (Intermediate 2), 0.33 mmol/ mL, 10 mL, ~3.3 mmol) was then added over 1 hour. The reaction was allowed to warm to room temperature and stirred overnight. It was diluted with water and extracted with dichloromethane (3 X 50 mL). The combined organic layers were washed with saturated sodium chloride solution (3 X 10 mL), dried over sodium sulfate and evaporated. Chromatography on silica gel using methanol in dichloromethane (0-15%) gave the title compound as a brown foam (711 mg, 58%). MS (ESV 407 (MH)⁺ for C₂₀H₂₇ClN₄O₃

¹H NMR (CDClO δ ppm 1.42 (s, HH); 1.84-1.99 (m, 2H); 2.12-2.22 (m, IH); 2.22-2.37 (m, 2H); 2.66-2.80 (m, 2H); 3.03-3.19 (m, IH); 3.39-3.55 (m, IH); 4.34-4.48 (m, IH); 4.62 (t, 2H); 6.72 (d, IH); 7.15 (d, IH); 7.61 (d, IH); 7.78 (d, IH).

Intermediate 4

1 -[2-(4- Aminopiperidin- 1 -yDethy 1] -7-chloro- 1 , 8-naphthyridin-2( 1 HVone

To a solution of tert-butyl-{l-[2-(7-chloro-2-oxo-l,8-naphthyridin-l(2H)-yl)ethyl]piperidin-

4-yl} carbamate (1.7g, 4.06 mmol) (Intermediate 3) in dichloromethane (1OmL) at O⁰C was added HCl in 1,4 dioxane (4M, 3 mL). After stirring for one hour at room temperature the reaction mixture was concentrated under reduced pressure to give a solid. The solid was triturated with acetonitrile/ ethyl acetate (2:1,10 mL) and filtered to give the bis hydrochloride salt of the product as a colourless solid (0.88 g, 57%).

MS (ESl: 307.15 (MH⁺) for C₁₅Hi₉N₄ClO

Intermediate 5

8-r2-(4-Aminopiperidin-l-vDethvn-7-oxo-7,8-dihvdro-l,8-naphthyridine-2-carbonitrile fert-Butyl{l-[2-(7-cyano-2-oxo-l,8-naphthyridin-l-(2H)-yl)ethyl]piperidine-4-yl}carbamate

(Intermediate 6) (0.59 g, 1.5 mmol) in dichloromethane (8 mL) was treated at room temperature under vigorous stirring with a trifluoroacetic acid (0.75 mL, 10 mmol). After 2 hours, the reaction mixture was concentrated under reduced pressure to give the crude trifluoro acetate of the product, which was used without further purification for the next step

(0.71 g, quantitative yield).

MS (ES): 298 (MH⁺) for C₁₆Hi₉N₅O Intermediate 6 fert-Butyl ( 1 -|^"2-(7-cyano-2-oxo- 1.8-naphthyridin- 1 -(2HVvDethyl1piperidine-4-yl| carbamate

To a solution of oxalyl chloride in dichloromethane (2M, 4.2 mmol) at -78⁰C was added dimethylsulfoxide (0.65 g, 8.4 mmol). It was stirred at -78⁰C for one hour and then 8-(2- hydroxyethyl)-7-oxo-7,8-dihydro-l,8-naphthyridine-2-carbonitrile (Intermediate 7) (0.70 g, 3.5 mmol) in dimethylsulfoxide/ HMPA (5:l/v:v) was added. The mixture was stirred at - 78⁰C for one hour and then N,N-diisopropylethylamine (2.26 g, 17.5 mmol) was added. The reaction mixture was warmed to room temperature and then quenched with water. It was extracted with methylene chloride, the organic phase was washed with brine then dried over sodium sulfate and concentrated under reduced pressure to afford 7-oxo-8-(2-oxoethyl)-7,8- dihydro-l,8-naphthyridine-2-carbonitrile (3.5 mmol) as an oil, MS (ES): 214.05 (MH⁺) for C_nH₇N₃O₂.

A solution of tert-butyl piperidin-4-ylcarbamate (0.77 g, 3.85 mmol) and in N,N- dimethylformamide (10 mL) was added to the above aldehyde. The solution was cooled to O⁰C, and sodium triacetoxyborohydride (1.62 g, 7.7 mmol) was added portion wise. The slurry was allowed to stir at room temperature overnight then quenched with water. The reaction product was extracted with ethyl acetate, and the organics washed with brine, and dried over sodium sulfate. Chromatography on silica gel with 40% acetone in n-hexane gave the product as a colourless solid (1.01 g, 72 %). MS TES): 398 (MH⁺) for C₂₁H₂₇N₅O₃

¹H NMR (MeOH^: δ ppm 1.26 - 1.38 (s, 9H); 1.66 (s, IH); 1.69 - 1.78 (m, 2H); 2.06 - 2.17 (m, 2H); 2.52 -2.64 (m, 2H); 2.99 (d, 2H); 3.17 - 3.26 (m, 2H); 3.40 - 3.51 (m, IH); 4.50 - 4.61 (m, 2H); 6.69 - 6.76 (m, IH); 7.56 - 7.65 (m, IH); 7.80 - 7.89 (m, IH); 8.12 - 8.20 (m, IH).

Intermediate 7

8-(2-HvdroxyethyD-7-oxo-7,8-dihvdro-1.8-naphthyridine-2-carbonitrile

To a solution of 8-(2-{[fer/-butyl(dimethyl)silyl]oxy}ethyl)-7-oxo-7,8-dihydro-l,8- naphthyridine-2-carbonitrile (2.4 g, 7.3 mmol) (Intermediate 8) in tetrahydrofuran (20 mL) at O⁰C was added tetrabutylammonium fluoride (1.0M in THF, 14.6 mL). After 30 minutes the reaction was quenched with water and the tetrahydrofuran was removed under reduced pressure. The product was extracted with ethyl acetate then washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was triturated with ether then dried under reduced pressure to give the product as a colourless solid (1.2 g, 77%). MS (ESl: 216.09 (MH⁺) for CnH₉N₃O₂

¹HNMR (MeOH^: δ: 3.85 (t, 2H); 4.66 (t, 2H); 6.85 (d, IH); 7.72 (d, IH); 7.97 (d, IH); 8.27 (d, IH).

Intermediate 8

8-(2- { rfe?^-Butyl(dimethvDsilyl1oxy) ethylV7-oxo-7,8-dihydro- 1 ,8-naphthyridine-2- carbonitrile

To a degassed slurry of l-(2-{/ert-butyl(dimethylsilyl)oxy}ethyl)-7-chloro-l,8-naphthyrin-

2(lH)-one (3.2 g, 9.56 mmol) (Intermediate 9) and zinc cyanide (1.22 g, 10.4 mmol) in N₅N- dimethylformamide (20 mL)was added tetrakis(triphenylphosphine)palladium (0) (0.16 g) under nitrogen. The reaction was heated at 100⁰C for three hours then cooled to room temperature. The reaction mixture was quenched with water and the product extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with 20% acetone in n- hexane gave the product as an oil (2.49 g, 77%).

MS (ESV 330 (MH⁺) for C₁₇H₂₃N₃O₂Si

¹HNMR (DMSO^: δ ppm -0.10 (s, 6H); 0.71 (s, 9H); 3.83(t, 2H); 4.48 (t, 2H); 6.86 (d,

IH); 7.90 (d, IH); 8.04 (d, IH); 8.40 (d, IH).

Intermediate 9 l-(2-(tert-Butyl(dimethylsilvπoxyiethylV7-chloro-1.8-naphthyrin-2(lH)-one To a solution of 7-chloro-l,8-naphthyridin-2(lH)-one (2.7 g, 15.2 mmol) (J.Org.Chem. 1990, 55, 4744-4750) in N,N-dimethylformamide (4OmL) under nitrogen at O⁰C was added sodium hydride (0.73 g, 18.3 mmol). The slurry was stirred for ten minutes and then (2- bromoethoxy)-t-butyl dimethylsilane (4.3 g, 18.3 mmol) was added. The mixture was heated at 8O⁰C for two hours then cooled to room temperature. The reaction mixture was quenched with water and the product extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with 20% acetone in n-hexane gave the product as an oil (3.2 g, 62%).

MS CES): 338 (MH⁺) for C₁₆H₂₃N₂SiClO₂

¹H NMR fDMSO-dό): δ ppm -0.00 (s, 6H); 0.81 (s, 9H); 3.91 (t, 2H); 4.53 (t, 2H); 6.80 (d,

IH); 7.45 (d, 1 H); 8.06 (d, IH); 8.29 (d, IH).

Example 1

6-IY { 1 -r2-(7-Chloro-2-oxo-l .8-naphthyridin- 1 (^"2H)-vnethyllpiperidin-4-vU amino)methyll- 2H-pyridor3.2-άiri.41oxazin-3f4HVone

To a slurry of l-{2-(4-aminopiperidin-l-yl) ethyl]-7-chloro-l, 8-naphthyridin-2(lH)-one (0.88 g, 2.4 mmol) (Intermediate 4) and molecular sieves 3 A (600 mg) in dichloroethane / methanol (10:1, 11 mL) and N,N-diisopropylethylamine (0.81 mL, 4.9 mmol) was added 3- oxo-3,4-dihydro-2Hpyrido[3,2-δ][l,4]oxazine-6-carbaldehyde (0.42 g, 2.4 mmol) and it was heated to 8O⁰C for one hour then cooled. At O⁰C, sodium triacetoxyborohydride (1.26 g, 5.95 mmol) was added and allowed to stir for on hour at room temperature. The reaction mixture was quenched with water and the product extracted with methylene chloride. The organics were washed with brine then dried over sodium sulfate. The organics were concentrated under vacuum to afford an oil. Chromatography on silica gel with 95% methylene chloride in methanol (containing 0.5% ammonium hydroxide) gave the product as an oil (612 mg). MS (ESV 469.13 (MH⁺) for C₂₃H₂₅N₆ClO₃

¹H NMIUDMSO^: δ: 1.16 (t, 2H); 1.20-1.32 (m, IH); 1.75 (d, 2H); 1.92-2.05 (m, 2H); 2.42-2.56 (m, 2H); 2.91 (d, 2H); 3.62-3.76 (m, 2H); 4.01 (q, 2H); 4.40 (t, 2H); 4.60 (s, 2H); 6.70 (d, IH); 7.01 (d, IH); 7.30 (d, IH); 7.39 (d, IH); 7.97 (d, IH); 8.21 (d, 1 H).

Example 2

2H-pyridor3.2-6iri.41oxazin-3C4H)-one

A solution of 6-[({l-[2-(7-chloro-2-oxo-l,8-naphthyridin-l(2H)-yl)ethyl]piperidin-4- yl}amino)methyl]-2H-ρyrido[3,2-&][l,4]oxazin-3(4H)-one (0.97 g, 2.06 mmol) (Example 1) and sodium methoxide (3.09 mmol) in methanol (10 mL) was heated in a sealed tube at 14O⁰C for thirty minutes using microwave irradiation. The reaction mixture was concentrated under reduced pressure and then quenched with water. The product was extracted with ethyl acetate, and the organics washed with brine then dried over sodium sulfate. Chromatography on silica gel with 95% ethyl acetate in methanol, containing 0.5% ammonium hydroxide, afforded the product as a yellow solid (0.18 g, 20%). MS (ES); 465.25 (MH⁺) for C₂₄H₂₈N₆O₄

¹H NMR fMeOH-d4): δ: 0.99-1.12 (m, 2H); 1.13 - 1.27 (m, 2H); 1.81 m, 2H); 1.87 - 2.00 (m, 2H); 2.29 - 2.44 (m, 2H); 2.51 (t, 2H); 2.96 (d, 2H); 3.11 (d, 2H); 3.62 (s, 2H); 3.89 (q, IH); 4.41 (t, 3H); 6.51 (d, IH); 6.80 (d, IH); 7.11 (d, IH); 7.46 (dlH); 7.71 (d, IH); 7.88 (d, 1 H).

Example 3

7-Oxo-8-r2-r4([(^'3-oxo-3,4-dihvdro-2H-pyridor3.2-diri.41oxazin-6- vDmethyll amino jpiperidine- 1 -yl)ethyl]-7.8-dihvdro- 1.8-naphthyridine-2-carbonitrile

To a degassed slurry of 6-[({l-[2-(7-chloro-2-oxo-l,8-naphthyridin-l(2H)-yl)ethyl]piperidin- 4-yl}ammo)methyl]-2H-pyrido[3,2-ό][l,4]oxazm-3(4H)-one (0.66 g, 1.41 mmol) (Example 1) and zinc cyanide (0.33 g, 2.82 mmol) in N,N-dimethylformamide (9 mL) was added tetrakis(triphenylphosphine)palladium (0) (0.16 g). The reaction was heated in a sealed tube at 12O⁰C for thirty minutes using microwave irradiation. The reaction mixture was quenched with water and the product extracted with methylene chloride. The organic phase was washed with brine then dried over sodium sulfate, then concentrated under reduced pressure. Chromatography on silica gel with 5% methanol in methylene chloride (containing 0.5% ammonium hydroxide) gave the product as a yellow oil (52 mg, 8%).

MS (ES): 460.18 (MH⁺) for C₂₄H₂₅N₇O₃

¹H NMR (MeOH-d4): δ: 0.80 (m, 2H); 1.11-1.23 (m, 2H); 2.02 (dd, 2H); 2.38 (m, 2H);

3.19 (d, 4H); 3.51 m, 2H); 4.02 m, 2H); 4.22 (m, 2H); 4.59 (s, IH); 6.79 (d, IH); 7.01 (d,

IH); 7.26 (d, IH); 7.70 (d, IH); 7.92 (d, IH); 8.24 (d, IH).

Alternative procedure for Example 3:

A mixture 8-[2-(4-aminopiperidin-l-yl)ethyl]-7-oxo-7,8-dihydro-l,8-naphthyridine-2- carbonitrile trifluoroacetic acid salt (Intermediate 5) (0.62 g, 1.5 mmol), N₅N- diisopropylethylamine (0.39 g, 0.3 mmol), molecular sieves (3A, 150 mg) and 3-oxo-3,4- dihydro-2H pyrido[3,2-έ][l,4]oxazine-6-carbaldehyde (0.27 g, 1.5 mmol) in chloroform/ methanol (10 mL, 1/1) was and heated at 8O⁰C for one hour. It was cooled to O⁰C, sodium triacetoxyborohydride (0.8 g, 3.8 mmol) was added and it was allowed to stir for one hour at room temperature. The reaction mixture was quenched with water and the product extracted with methylene chloride. The organics were washed with brine, dried over sodium sulfate and concentrated under vacuum to afford an oil. Chromatography on silica gel with 95% methylene chloride in methanol (containing 0.5% ammonium hydroxide) gave the product as an oil (650 mg, 95%, purity 80%). Further purification was achieved by reverse-phase chromatography on an Atlantis dC-18 OBD column (5um, 19xl00mm) using 5-95% acetonitrile in water (0.1%TFA) over a 7 minute gradient. Fractions containing product were combined and acetonitrile was removed under reduced pressure. The remaining aqueous layer was neutralized to a pΗ of 8 with saturated sodium bicarbonate solution and the desired product extracted with copious amounts of dichloromethane. The organics were dried over sodium sulfate and filtered. The filtrate was concentrated under vacuum to give the title compound as an oil (0.09 g, 14%).

Example 4

6-IY { 1 -r2-(7-chloro-2-oxo- 1.8-naphthyridin-l (2HVvflethyllpiperidin-4-vπ aminotmethyll-ΣH- pyridor32-bλ \ 1 ,41thiazin-3 f 4HVone

To a slurry of l-{2-(4-aminopiperidin-l-yl)ethyl]-7-chloro-l,8-naphthyridin-2(lH)-one bis hydrochloride (Intermediate 4) (0.13 g, 0.35 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2- 6][l,4]thiazine-6-carbaldehyde (0.07 g, 0.35 mmol) in N,N-dimethylformamide (10 mL) was added drop wise N,N-diisopropyethylamine (0.14 mL) at room temperature. The solution was allowed to stir for ten minutes, then triacetoxyborohydride (0.18 g, 0.88 mmol) was added. The slurry was allowed to stir at room temperature overnight then quenched with water. The reaction mixture was extracted with ethyl acetate, the organic phase washed with brine and dried over sodium sulfate. Chromatography on silica gel with 5% methanol in dichloromethane (containing 0.5% ammonium hydroxide) afforded the product as a yellow solid (0.06 g, 36%).

MS (ES): 485 (MH⁺) for C₂₃H₂₅N₆SClO₂

¹H NMR (MeOH^): δ: 0.99-1.12 (m, 2H); 1.13-1.27 (m, 2H); 1.81 (m, IH) 1.87-2.00 (m, 2H); 2.29-2.44 (m, 2H); 2.51 (t, 2H); 2.96 (d, 2H); 3.11 (d, IH); 3.62 (s, 2H); 3.89 (q, IH); 4.41 (t, 2H); 6.51 (d, IH); 6.80 (d, IH); 7.11 (d, IH); 7.46 (d, IH); 7.71 (d, IH); 7.88 (d, IH).

Example 5

7-Oxo-8-r2-r4{[r3-oxo-3.4-dihvdro-2H-pyrido[3.2-^πi.41thiazin-6- yl)methyllamino>piperidine-l-yl)ethyl1-7.8-dihvdro-L8-naphthyridine-2-carbonitrile

6-[( { 1 -[2-(7-Chloro-2-oxo- 1 ,8-naphthyridin- 1 (2H)-yl)ethyl]piperidin-4-yl} amino)methyl] -2H-pyrido[3,2-έ][l,4]thiazin-3(4Η)-one (0.42 g, 0.86 mmol) (Example 4) and zinc cyanide (0.20gm, 1.7mmol) were reacted under catalysis with tetrakis(triphenylphosphine)palladium (0) (0.09 mg) using a procedure analogous to the one described for the synthesis of Example 3 to give the product as a yellow oil (32 mg, 8%). MS (ES): 476.18 (MH⁺) for C₂₄H₂₅N₇SO₂

¹H NMR (MeOH-d4V δ: 0.98-1.08 (m, 2H); 1.22-1.38 (m, 2H); 1.78-1.86 (m, 2H); 1.89- 2.04 (m, 2H); 2.52-2.68 (m, 2H); 3.02 (d, 2H); 3.09 (dt, IH); 3.82 (s, 2H); 3.87 (q, 2H); 4.43 (t, 2H); 6.62 (d, IH); 6.84 (d, IH); 7.51 (dd, 2H); 7.76 (d, IH); 8.08 (d, 1 H).

Claims

Claims What is claimed is:

1. A compound of Formula (I):

Formula (I)

or a pharmaceutically acceptable salt thereof, wherein

A is selected from CH and N;

D is selected from C-R⁷ and N; wherein at least one of A and D is carbon;

G is selected from O and S;

R² is selected from H, halo, cyano, C^aUcyl, C_2-6alkenyl, C_2-6alkynyl, -OR^2a, and -N(R^2a)₂, wherein said C_1-6allcyl, C_2-6alkenyl, and C_2-6alkynyl are optionally substituted with one or more R²⁰;

R^2a in each occurrence is independently selected from H and C^aHcyl, wherein said Ci-βalkyl are optionally substituted with one or more R²⁰;

R³ is selected from H, halo, cyano, C^aHcyl, C_2-6alkenyl, C_2-6alkynyl, -OR^3a, and -N(R^3a)₂, wherein said C^aHcyl, C_2-6alkenyl, and C_2-6alkynyl are optionally substituted with one or more R³⁰; R^3a is selected from H and C_1-6alkyl, wherein said C_1-6alkyl are optionally substituted with one or more R³⁰;

R⁴ is selected from H, halo, cyano, -CO₂H, C^aUcyl, C_2-6alkenyl, and C_2-6alkynyl, wherein said Ci-βalkyl, C_2-6alkenyl, and C_2-6alkynyl are optionally substituted with one or more R⁴⁰;

R⁷ is selected from H, halo, cyano, C_1-6alkyl, C_2-6alkenyl, and C_2-6alkynyl, wherein said Ci_-6alkyl, C_2-6alkenyl, and C_2-6alkynyl are optionally substituted with one or more

R⁷⁰;

R²⁰, R³⁰, R⁴⁰, and R⁷⁰ in each occurrence are each, independently, selected from halo, hydroxy, cyano, -CO₂H, C^alkoxy, d-βalkyl, C_2-6alkenyl, and C_2-6alkynyl.

2. The compound of Formula (I), as claimed in claim 1, wherein:

R² is selected from halo, cyano, and -0R^2a; and R^2a is Ci-βalkyl.

3. The compound of Formula (I), as claimed in any one of claims 1 and 2, wherein R³ is H.

4. The compound of Formula (I), as claimed in any one of claims 1 to 3, wherein R⁴ is H

5. The compound of Formula (I), as claimed in any one of claims 1 to 4, wherein A is N.

6. The compound of Formula (I), as claimed in any one of claims 1 to 5, wherein D is CH.

7. The compound of Formula (I), as claimed in any one of claims 1 to 5, wherein G is selected from O and S.

8. A compound of Formula (I) :

Formula (I)

or a pharmaceutically acceptable salt thereof, wherein

R² is chloro, cyano, or methoxy;

R³ is H;

R⁴ is H;

A is N;

D is CH; and

G is selected from O and S.

9. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 8, for use as a medicament.

10. The use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 8, in the manufacture of a medicament for the treatment of a bacterial infection in a warm-blooded animal such as man.

11. The use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 8, in the manufacture of a medicament for the treatment of a bacterial infection caused by one or more pathogenic organism such as Acinetobacter baumanii, Aeromis hydrophila, Bacillus anthracis, Bactei'oides fragilis, Bordatella pertussis, Burkholderia cepacia, Chlamyida pneumoniae, Citrobacter fi'eundii, Clostridium difficile, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusobacterium necrophorum, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus somnus, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Listeria monocytogenes, Morάxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, , Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Salmonella typhi, Salmonella typhimurium, Serratia marcesens, Shigella flexneria, Shigella dysenteriae, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus intermedius, Staphylococcus saprophyticus, Stenotrophomonas maltophila, Streptococcus agalactiae, Streptococcus mutans, Streptococcus pneumoniae, and Streptococcus pyrogenes, in a warm-blooded animal such as man.

12. The use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 8, in the manufacture of a medicament for the treatment of an infection such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intra-abdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections, and urinary tract infections, in a warm-blooded animal such as man.

13. The use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 8, in the manufacture of a medicament for the treatment of a bacterial infection, wherein the bacteria is of a genus selected from Aeromonas, Acinetobacter, Bacillus, Bacteroides, Bordetella, Burkholderia, Chlamydophila, Citrobacter, Clostridium, Enterobacter, Enterococcus, Escherichia, Flavobacterium, Fusobacterium, Haemophilus, Klebsiella, Legionella, Listeria, Morganella, Moraxella, Mycoplasma, Neisseria, Pasteurella, Peptococci, Peptostreptococci, Prevotella, Proteus Salmonella, Pseudomonas, Serratia, Shigella, Stenotrophomonas, Streptococcus, and Staphylococcus, in a warm-blooded animal such as man.

14. A method for treating a bacterial infection in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of formula (I), as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

5. A method for treating a bacterial infection caused by one or more pathogenic organism such as Acinetobacter baumanii, Aeromis hydrophila, Bacillus anthracis, Bacteroides fragilis, Bordatella pertussis, Burkholderia cepacia, Chlamyida pneumoniae, Citrobacter freundii, Clostridium difficile, Enterobacter cloacae, Enter ococcus faecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusobacterium necrophorum, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus somnus, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Salmonella typhi, Salmonella typhimurium, Serratia marcesens, Shigella flexneria, Shigella dysenteriae, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus intermedius, Staphylococcus saprophyticus, Stenotrophomonas maltophila, Streptococcus agalactiae, Streptococcus mutans, Streptococcus pneumoniae, and Streptococcus pyrogenes, in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

16. A method for treating a bacterial infection such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intra-abdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections, and urinary tract infections, in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

17. A method for treating a bacterial infection, wherein the bacteria is of a genus selected from Aeromonas, Acinetobacter, Bacillus, Bacteroides, Bordetella, Burkholderia, Chlamydophila, Citrobacter, Clostridium, Enterobacter, Enterococcus, Escherichia, Flavobacterium, Fusobacterium, Haemophilus, Klebsiella, Legionella, Listeria, Morganella, Moraxella, Mycoplasma, Neisseria, Pasteurella, Peptococci, Peptostreptococci, Prevotella, Proteus Salmonella, Pseudomonas, Serratia, Shigella, Stenotrophomonas, Streptococcus, and Staphylococcus, in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), as claimed in any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.

18. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 8, for use in treating a bacterial infection in a warm-blooded animal, such as man.

19. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 8, for use in treating a bacterial infection caused by one or more pathogenic organism such as Acinetobacter baumanii, Aeromis hydrophila, Bacillus anthracis, Bacteroides fragilis, Bordatella pertussis, Burkholderia cepacia, Chlamyida pneumoniae, Citrobacter freundii, Clostridium difficile, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusobacterium necrophorum, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus somnus, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Salmonella typhi, Salmonella typhimurium, Serratia marcesens, Shigella flexneria, Shigella dysenteriae, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus intermedius, Staphylococcus saprophyticus, Stenotrophomonas maltophila, Streptococcus agalactiae, Streptococcus mutans, Streptococcus pneumoniae, and Streptococcus pyrogenes, in a warm-blooded animal such as man.

20. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 8, for use in treating infections such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intraabdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections, and urinary tract infections,in a warm-blooded animal such as man.

21. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 8, for use in treating a bacterial infection, wherein the bacteria is of a genus selected from Aeromonas, Acinetobacter, Bacillus, Bacteroides, Bordetella, Burkholderia, Chlamydophila, Citrobacter, Clostridium, Enterobacter, Enterococcus, Escherichia, Flavobacterium, Fusobacterium, Haemophilus, Klebsiella, Legionella, Listeria, Morganella, Moraxella, Mycoplasma, Neisseria, Pasteurella, Peptococci, Peptostreptococci, Prevotella, Proteus Salmonella, Pseudomonas, Serratia, Shigella, Stenotrophomonas, Streptococcus, and Staphylococcus, and Munnheimia, in a warmblooded animal such as man.

22. A pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 8, and at least one pharmaceutically acceptable carrier, diluent, or excipient.