Abstract:
Described are a series of 2-pyridone compounds as a potent and selective new class of type II topoisomerase inhibitors with broad-spectrum antimicrobial activity having the general formula (I); where R1, R2, X, and Y are defined herein Such compounds can be used in methods for treating an infection caused by a gram-positive pathogen, a gram-negative pathogen, or a drug-resistant strains thereof.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
       [0001]    This application claims the benefit of and claims priority from U.S. provisional patent application Ser. No. 61/386,721, filed Sep. 27, 2010, which is incorporated herein by reference in its entirety. 
     
    
     FIELD OF INVENTION 
       [0002]    The present invention relates to a new 2-pyridone compound series having broad-spectrum antibacterial activity and more particularly, potent activity against fluoroquinolone-resistant bacterial pathogens, particularly against multi-drug resistant community-acquired and nosocomial pathogens. 
       BACKGROUND OF INVENTION 
       [0003]    Drug-resistant bacterial infections and related morbidity and mortality are on the rise around the world. In particular the so-called “ESCAPE” pathogens ( Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa  and  Enterobacter  ssp) are the causative agents for the majority of hospital infections and effectively “escape” the effects of approved drugs (Clinical Infectious Diseases 2010; 50: 1081). 
         [0004]    Because of world-wide mortality due to uncontrolled severe infections is on the rise, the need for new antimicrobial compounds becomes greater every day. The limited number of targets for antibiotic action, development of multi-drug resistant strains and the ever shrinking number of active drugs have increased the health risks of the human race with respect to the number one killer of all people in the world today, bacterial infection. With the identification of New Delhi metallo-beta-lactamase-1 (NDM1), and highly drug resistant gonorrhoeal strains new antibiotics become more essential on a daily basis. 
         [0005]    New classes of antibiotics are being continuously developed, with limited success, in order to expand the armamentarium of treatment options against severe bacterial infections. For instance, second generation quinolones such as Ciprofloxacin are widely accepted for the treatment of bacterial infections of respiratory and urinary tract, skin and soft tissues. Such compounds have good pharmacokinetic profiles, potent activities against a wide range of Gram-positive and Gram-negative pathogens, and are widely used in both hospital and community settings. However, increasing frequency of bacterial resistance to quinolones, among other currently available antibiotics, has led to an urgent need for new analogs to overcome antibiotic resistance. 
         [0006]    Bacterial type II topoisomerases are key regulators of the replication, repair and decatenation of DNA in bacteria and are clinically validated targets for antibacterial agents, as demonstrated by the clinical and commercial success of quinolones for the treatment of bacterial infections. Nalidixic acid, introduced in 1962, is considered to be the predecessor of all members of the quinolone family, including the second (e.g. Ciprofloxacin), third (e.g. Levofloxacin) and fourth (e.g. Moxifloxacin) generations commonly known as fluoroquinolones. These molecules form a ternary complex consisting of the inhibitor, topoisomerase and DNA that disrupts DNA replication and repair as well as RNA transcription, a two-punch combination that leads to rapid bacterial cell death. Several compound- and DNA-bound enzyme structures have been solved, paving the way for a greater understanding of both the mechanism for DNA cleavage and the structural basis for inhibition of topoisomerases by antibacterial compounds. Recently, the X-ray crystal structures of the quinolone binding mode have appeared (Bax et al., 2010), generating opportunities for structural optimization and design of topoisomerase inhibitors. 
         [0007]    2-Pyridones are a class of antibiotics which inhibit type Ha bacterial topoisomerases and are chemically bioisosteres of quinolones. In 1994, Abbott reported that 2-pyridone analogs were efficacious against certain quinolone resistant microorganisms (34 th  Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC, paper F41), 1994; U.S. Pat. No. 5,789,591), specifically ABT-719, a 4-oxo-quinolizine possessing potent antibacterial activity against both Gram-positive and Gram-negative pathogens. See also Sato U.S. Pat. No. 6,525,066 and U.S. Pat. No. 7,223,773. 
         [0008]    The continuing development of natural and engineered resistance to antibiotics in use today necessitates the development of ever new classes of antibiotic compounds which are potent, safe and do not exhibit cross-resistance to existing classes of antibiotics. Furthermore, such compounds would have broad spectrum for empirical first-line treatment, have antibacterial activity via inhibition of bacterial type II topoisomerases, e.g. DNA gyrase (Topo II) and topoisomerase IV (Topo IV), and would preferably be orally bioavailable. 
       SUMMARY OF THE INVENTION 
       [0009]    The present invention provides a novel series of 2-pyridone compounds as a potent and selective new class of type II topoisomerase inhibitors with broad-spectrum antimicrobial activity. The present invention demonstrates for the first time a series of antibiotics having surprising and unexpected potent activity against fluoroquinolone-resistant bacterial pathogens, particularly against multi-drug resistant community-acquired and nosocomial pathogens, suggesting a new mechanism of action against a well-validated bacterial target, the DNA repair and replication system. Members of this compound series have demonstrated broad-spectrum antibacterial activity and favourable drug-like properties. 
         [0010]    The series possesses unique biological and physiochemical properties compared to other drugs in the clinic that should allow its use as a first line of defense antibiotic in the current clinical environment, particularly against target organisms such as MRSA and  S. pneumoniae . Not since the advent of aminoglycosides has a novel broad-spectrum antibiotic entered the clinic for empirical first-line treatment of drug-resistant bacterial infections. The present compounds are likely to serve in such a role in the future treatment of multidrug resistant infections. The 2-pyridone series of antibiotics of the present invention is very potent (MICs in the ng/mL range) against important nosocomial pathogens, including fluoroquinolone-resistant  Staphylococcus aureus  MRSA. 
         [0011]    The compounds of the present invention exhibit broad antibacterial activity via inhibition of bacterial type II topoisomerases, e.g. DNA gyrase (Topo II) and topoisomerase IV (Topo IV), and they are active against many bacterial strains that are resistant to quinolones and other more recently described topoisomerase inhibitors, and provides a potent and selective new class of type II topoisomerase inhibitors with broad-spectrum antimicrobial activity. The present compounds also exhibit potent inhibition of  Escherichia coli  DNA gyrase supercoiling with IC 50 ≦0.1 μM 
         [0012]    Furthermore, the inventive compounds were found to be bactericidal, stable (chemical, metabolic, plasma) with manageable protein binding data. Mammalian cytotoxicity was shown to be &gt;100 μM. Aqueous thermodynamic solubility ranges from, for example, 5 to 200 μM in PBS and SGF, but very importantly is &gt;100 μM in SIF hence contributing to the excellent absorption displayed by the compounds. In particular, the potassium salts of the various compounds herein have been found to have unexpectedly increased solubility in PBS, SGF, and/or SIF. These positive data allowed a selection of compounds to progress to PK studies in preparation of the efficacy studies. 
         [0013]    The inventive compounds are also very potent against  Staphylococcus aureus , including MRSA,  Streptococcus pneumoniae  and pyogenes,  Enterococcus faecium  and faecalis with MICs&lt;0.5 mg/L. Most compounds are also very potent against  Haemophilus influenzae, Moraxella  and Enterobacteriacae such as  Klebsiella, Proteus, Shigella  and others with MICs ranging between &lt;0.015 to 16 mg/L. Better coverage is seen against  Pseudomonas aeruginosa, Burkholderia cepacia, Acinetobacter baumannii  and  Escherichia coli  than levofloxacin. 
         [0014]    In addition, the inventive compounds are active against multidrug-resistant recent clinical isolates of the bacteria mentioned above. In particular, many of the compounds show activity against resistant strains, such as, but not limited to quinolone-resistant strains (e.g.,  Staphylococcus aureus, Pseudomonas aeruginosa  and  Acinetobacter baumanii ). No loss of activity is seen on  Staphylococcus aureus  strains with mutations in gyrB, Gr1A and Gr1B and show a low propensity of spontaneous resistance development. 
         [0015]    Finally, the inventive compounds have advantageous physicochemical characteristics. Excellent aqueous kinetic solubility could be achieved (≧10 mg/mL) with formation of potassium salt in place of the parent carboxylic acid. Overall, the compounds described herein may be prepared by efficient and scalable syntheses of less than 10 steps. 
         [0016]    In a first aspect, the invention provides methods for treating an infection comprising, providing to a patient infected by a gram-positive pathogen or gram-negative pathogen, such as a pathogen selected from the group consisting of  Acinetobacter baumannii, Bacillus anthracis, Brucella abortus, Burkholderia cepacia, Burkholderia mallei, Burkholderia pseudomallei, Burkholderia thailandensis, Citrobacter freundii, Corynebacterium jeikeium, Enterobacter  sp,  Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterococcus gallinarum, Escherichia coli, Francisella tularensis, Haemophilus influenza, Klebsiella aerogenes, Klebsiella pneumoniae, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, Neisseria meningitides, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens, Shigella  sp,  Staphylococcus aureus, Staphylococcus epidermis, Staphylococcus haemolyticus, Staphylococcus saprophyticus, Stenotrophomonas maltophilia, Streptococcus agalactiae, Streptococcus bovis, Streptococcus constellatus, Streptococcus mitis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus oralis, Streptococcus sanguis , Group C  Streptococcus, Yersinia pestis , and drug-resistant strains thereof, a therapeutically effective amount of a compound of the formula, 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein R 1 , R 2 , X, and Y are defined herein. 
         [0017]    In another aspect, the invention provides the use of a compound of the formula (I), as defined herein for the preparation of a medicament for treating an infection caused by a gram-positive pathogen or gram-negative pathogen, such as a pathogen selected from the group consisting of  Burkholderia mallei, Burkholderia pseudomallei, Burkholderia cepacia, Bacillus anthracis, Yersinia pestis, Francisella tularensis, Brucella abortus, Burkholderia thailandensis, Acinetobacter baumannii, Acinetobacter baumannii, Staphylococcus aureus, Staphylococcus epidermis, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Enterobacter cloacae, Pseudomonas aeruginosa, Klebsiella pneumoniae, Haemophilus influenza, Stenotrophomonas maltophilia, Streptococcus pneumoniae, Streptococcus pyogenes , Group C  Streptococcus , and drug-resistant strains thereof. 
         [0018]    In another aspect of the invention is provided a pharmaceutical composition comprising a 2-pyridone of formula (I) for prophylaxis or treatment of an infection induced by a pathogen in a subject that may be exposed to or is suffering from an infection, the composition conferring prophylaxis, reduction in contagion, treatment, amelioration or reduction of symptoms, reduction of mortality or survival in the subject after administration of the composition. 
         [0019]    The invention provides a useful 2-pyridone scaffold, structurally related but distinct to quinolones. It is hypothesised by the inventors that (a) 2-pyridones maintain activity on quinolone resistant strains because of the non-planar nature of the scaffold (vs. quinolones) induced by combinations of certain substituents; and (b) there are specific binding site residues and DNA structural elements which may be utilised to further enhance activity on quinolone resistant strains. 
         [0020]    In silico approaches have identified key structure guided hypotheses. 2-Pyridones maintain activity on quinolone-resistant strains because of the non-planar nature of the scaffold (as compared with quinolones) induced by combinations of certain substituents. Various substituents at the 9-position have been designed which optimise the ‘wedge-like’ effect of the compound to enhance its interaction with the binding site. There are specific binding site residues and DNA structural elements which may be utilised to further enhance activity on quinolone resistant strains. In silico design has been used to identify optimal receptor interactions from the 1- and 8-positions which may enhance compound binding to the ribose backbone and specific amino acids improving activity in the presence of known resistance mutations. 
         [0021]    Therefore, the present invention provides for 2-pyridone compounds with differing substituents at the 9-position designed to optimise the ‘wedge-like’ effect of the compound to enhance its interaction with the binding site. 
     
    
     DESCRIPTION OF THE INVENTION 
       [0022]    Accordingly, in the first aspect, infections caused by a pathogen selected from the group consisting of  Acinetobacter baumannii, Bacillus anthracis, Brucella abortus, Burkholderia cepacia, Burkholderia mallei, Burkholderia pseudomallei, Burkholderia thailandensis, Citrobacter freundii, Corynebacterium jeikeium, Enterobacter  sp,  Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterococcus gallinarum, Escherichia coli, Francisella tularensis, Haemophilus influenza, Klebsiella aerogenes, Klebsiella pneumoniae, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, Neisseria meningitides, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens, Shigella  sp,  Staphylococcus aureus, Staphylococcus epidermis, Staphylococcus haemolyticus, Staphylococcus saprophyticus, Stenotrophomonas maltophilia, Streptococcus agalactiae, Streptococcus bovis, Streptococcus constellatus, Streptococcus mitis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus oralis, Streptococcus sanguis , Group C  Streptococcus, Yersinia pestis , and drug-resistant strains thereof, can be treated by providing to a patient a therapeutically effective amount of a compound of the formula, 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    or a pharmaceutically acceptable salt thereof, wherein
   R 1  is hydrogen, halogen, cyano, C 1-8  alkyl, C 1-8  haloalkyl, heterocyclyl, —OR 11 , —N(R 11 ) 2 , or —C(O)N(R 11 ) 2 , wherein each R 11  is independently hydrogen, C 1-8  alkyl, or C 1-8  haloalkyl;   R 2  is a C 1-8  alkyl, C 1-8  haloalkyl, C 3-8 cycloalkyl, or heteroaryl, wherein the cycloalkyl and heteroaryl are optionally substituted with one to five groups that are each independently halogen, C 1-8  alkyl, —OR 21 , —N(R 21 ) 2 , or —C(O)OR 21 , wherein each R 21  is independently hydrogen or C 1-8  alkyl;   Y is heterocyclyl, aryl, or heteroaryl, each optionally substituted by one to five groups that are each independently halogen, C 1-8  alkyl, C 1-8  haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Y , or —C 1-8  alkyl-R Y , wherein R Y  is nitro, cyano, —OR Y1 , —SR Y1 , —N(R Y1 ) 2 , —C(O)R Y1 , —C(O)OR Y1 , —C(O)N(R Y1 ) 2 , —OC(O)R Y1 , —OC(O)OR Y1 , —OC(O)N(R Y1 ) 2 , —N(R Y1 )C(O)R Y1 , —N(R Y1 )C(O)OR Y1 , —N(R Y1 )C(O)N(R Y1 ) 2 , —S(O) 2 R Y1 , —S(O) 2 OR Y1 , —S(O) 2 N(R Y1 ) 2 , —OS(O) 2 R Y1 , —OS(O) 2 OR Y1 , —OS(O) 2 N(R Y1 ) 2 , —N(R Y1 )S(O) 2 R Y1 , —N(R Y1 )S(O) 2 OR Y1 , or —N(R Y1 )S(O) 2 N(R Y1 ) 2 , wherein each R Y1  is independently hydrogen, C 1-8  alkyl, or C 1-8  haloalkyl; and   X is hydrogen, halogen, cyano, C 1-8  alkyl, C 1-8 haloalkyl, —OR X , —N(R X ) 2 , —C(O)R X , —C(O)OR X , or —C(O)N(R X ) 2 , wherein each R X  is independently hydrogen, C 1-8  alkyl, or C 1-8 haloalkyl.   
 
         [0027]    In one embodiment of the compounds of formula (I), R 1  is hydrogen, halogen, or C 1-8  alkyl. In another embodiment, R 1  is hydrogen or C 1-8  alkyl. In another embodiment, R 1  is hydrogen or methyl. In another embodiment, R 1  is halogen or C 1-8  alkyl. In another embodiment, R 1  is C 1-8  alkyl. In another embodiment, R 1  is halogen. In another embodiment of the compounds of formula (I), R 1  is C 1-8  haloalkyl, —OR 11 , or —C(O)N(R 11 ) 2 . In another embodiment of the compounds of formula (I), R 1  is trifluoromethyl, methoxy, or —C(O)NH 2 . In certain embodiments, the compound for formula (I) is of one of the formulas, 
         [0000]    
       
                 
         
             
             
         
       
     
         [0028]    In one embodiment of the compounds of formula (I), (Ia)-(Ic), and any embodiment thereof, X is hydrogen or halogen. In another embodiment, X is hydrogen. In another embodiment, X is halogen. In another embodiment, X is fluoro. In another embodiment, X is hydrogen, halogen, C 1-8  alkyl, C 1-8  alkoxy, amino, C 1-8  alkylamino, or di(C 1-8  alkyl)amino. In another embodiment, X is —OR X , —N(R X ) 2 , —C(O)R X , —C(O)OR X , or —C(O)N(R X ) 2 . In another embodiment, X is —OR X  or —N(R X ) 2 . In another embodiment, X is —C(O)R X , —C(O)OR X , or —C(O)N(R X ) 2 . In another embodiment, X is C 1-8 haloalkyl (e.g., trifluoromethyl). 
         [0029]    In particular embodiments of the compounds of formula (I) and (Ia), R 1  and X are selected from one of the following combinations:
       (a) R 1  is hydrogen, halogen, or C 1-8  alkyl; and X is hydrogen or halogen.   (b) R 1  is hydrogen, halogen, or C 1-8  alkyl; and X is hydrogen.   (c) R 1  is hydrogen, halogen, or C 1-8  alkyl; and X is halogen.   (d) R 1  is hydrogen, halogen, or C 1-8  alkyl; and X is fluoro.   (e) R 1  is hydrogen or C 1-8  alkyl; and X is hydrogen or halogen.   (f) R 1  is hydrogen or C 1-8  alkyl; and X is hydrogen.   (g) R 1  is hydrogen or C 1-8  alkyl; and X is halogen.   (h) R 1  is hydrogen or C 1-8  alkyl; and X is fluoro.   (i) R 1  is hydrogen or methyl; and X is hydrogen or halogen.   (j) R 1  is hydrogen or methyl; and X is hydrogen.   (k) R 1  is hydrogen or methyl; and X is halogen.   (l) R 1  is hydrogen or methyl; and X is fluoro.   (m) R 1  is halogen or C 1-8  alkyl; and X is hydrogen or halogen.   (n) R 1  is halogen or C 1-8  alkyl; and X is hydrogen.   (o)R 1  is halogen or C 1-8  alkyl; and X is halogen.   (p) R 1  is halogen or C 1-8  alkyl; and X is fluoro.   (q) R 1  is C 1-8  alkyl; and X is hydrogen or halogen.   (r) R 1  is C 1-8  alkyl; and X is hydrogen.   (s) R 1  is C 1-8  alkyl; and X is halogen.   (t) R 1  is C 1-8  alkyl; and X is fluoro.       
 
         [0050]    In one embodiment of the compounds of formula (I), (Ia)-(Ic), and any embodiment thereof, Y is aryl optionally substituted by one to five groups that are each independently halogen, C 1-8  alkyl, C 1-8  haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Y , or —C 1-8  alkyl-R Y . 
         [0051]    In another embodiment of the compounds of formula (I), (Ia)-(Ic), and any embodiment thereof, Y is phenyl substituted with one group which is halogen, cyano, —OR Y1 , —SR Y1 , —N(R Y1 ) 2 , C 1-8  alkyl, —C 1-8  alkyl-N(R Y1 ) 2 , or —C 1-8  alkyl-OR Y1 , and optionally substituted by one to two groups that are each independently halogen, C 1-8  alkyl, C 1-8  haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Y , or —C 1-8  alkyl-R Y . 
         [0052]    In another embodiment of the compounds of formula (I), (Ia)-(Ic), and any embodiment thereof, Y is phenyl substituted with one group which is cyano, —OR Y1 , —N(R Y1 ) 2 , C 1-8  alkyl, or —C 1-8  alkyl-N(R Y1 ) 2 , and optionally substituted by one to two groups that are each independently halogen, C 1-8  alkyl, —R Y , or —C 1-8  alkyl-R Y . 
         [0053]    In another embodiment of the compounds of formula (I), (Ia)-(Ic), and any embodiment thereof, Y is phenyl substituted with one group which is —N(R Y1 ) 2  or —C 1-8  alkyl-N(R Y1 ) 2 , and optionally substituted by one to two groups that are each independently halogen, C 1-8  alkyl, —R Y , or —C 1-8  alkyl-R Y . 
         [0054]    In another embodiment of the compounds of formula (I), (Ia)-(Ic), and any embodiment thereof, Y is phenyl substituted with one group which is —NH 2  or —C 1-8  alkyl-NH 2 , and optionally substituted by one to two groups that are each independently halogen, C 1-8  alkyl, —R Y , or —C 1-8  alkyl-R Y . 
         [0055]    In another embodiment of the compounds of formula (I), (Ia)-(Ic), and any embodiment thereof, Y is phenyl substituted with one group which is —NH 2  or —CH 2 NH 2 , and optionally substituted by one to two groups that are each independently halogen, C 1-8  alkyl, —R Y , or —C 1-8  alkyl-R Y . 
         [0056]    In another embodiment of the compounds of formula (I), (Ia)-(Ic), and any embodiment thereof, Y is phenyl substituted with one group which is —NH 2  or —CH 2 NH 2 , and substituted by one to two groups that are each independently halogen, C 1-8  alkyl, —R Y , or —C 1-8  alkyl-R Y . 
         [0057]    In another embodiment of the compounds of formula (I), (Ia)-(Ic), and any embodiment thereof, Y is heteroaryl optionally substituted by one to five groups that are each independently halogen, C 1-8  alkyl, C 1-8  haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Y , or —C 1-8  alkyl-R Y . 
         [0058]    In another embodiment of the compounds of formula (I), (Ia)-(Ic), and any embodiment thereof, Y is a 5-membered or 6-membered heteroaryl optionally substituted by one to five groups that are each independently halogen, C 1-8  alkyl, C 1-8  haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Y , or —C 1-8  alkyl-R Y . 
         [0059]    In another embodiment of the compounds of formula (I), (Ia)-(Ic), and any embodiment thereof, Y is a 5-membered or 6-membered heteroaryl substituted with one group which is —N(R Y1 ) 2  or —C 1-8  alkyl-N(R Y1 ) 2 , and optionally substituted by one to two groups that are each independently halogen, C 1-8  alkyl, —R Y , or —C 1-8  alkyl-R Y . 
         [0060]    In another embodiment of the compounds of formula (I), (Ia)-(Ic), and any embodiment thereof, Y is pyridyl, furyl, or thienyl each optionally substituted with one group which is —N(R Y1 ) 2  or —C 1-8  alkyl-N(R Y1 ) 2 , and each optionally substituted by one to two groups that are each independently halogen, C 1-8  alkyl, —R Y , or —C 1-8  alkyl-R Y . 
         [0061]    In another embodiment of the compounds of formula (I), (Ia)-(Ic), and any embodiment thereof, Y is pyridyl, furyl, or thienyl each optionally substituted with one group which is —NH 2  or —CH 2 NH 2 , and each optionally substituted by one to two groups that are each independently halogen, C 1-8  alkyl, —R Y , or —C 1-8  alkyl-R Y . 
         [0062]    In another embodiment of the compounds of formula (I), (Ia)-(Ic), and any embodiment thereof, Y is a bicyclic heteroaryl optionally substituted by one to five groups that are each independently halogen, C 1-8  alkyl, C 1-8  haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Y , or —C 1-8  alkyl-R Y . 
         [0063]    In another embodiment of the compounds of formula (I), (Ia)-(Ic), and any embodiment thereof, Y is a benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, or benzotriazolyl, each optionally substituted by one to five groups that are each independently halogen, C 1-8  alkyl, C 1-8  haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Y , or —C 1-8  alkyl-R Y . 
         [0064]    In another embodiment of the compounds of formula (I), (Ia)-(Ic), and any embodiment thereof, Y is indazolyl optionally substituted by one to five groups that are each independently halogen, C 1-8  alkyl, C 1-8  haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Y , or —C 1-8  alkyl-R Y . 
         [0065]    In another embodiment of the compounds of formula (I), (Ia)-(Ic), and any embodiment thereof, Y is indazolyl. 
         [0066]    In one embodiment of the compounds of formula (I) and (Ib), and any embodiment thereof, R 2  is a C 1-8  alkyl, C 1-8  haloalkyl, or C 3-8 cycloalkyl. 
         [0067]    In one embodiment of the compounds of formula (I) and (Ib), and any embodiment thereof, R 2  is a C 1-8  alkyl (e.g., methyl). 
         [0068]    In one embodiment of the compounds of formula (I) and (Ib), and any embodiment thereof, R 2  is a C 1-8  haloalkyl (e.g., trifluoromethyl). 
         [0069]    In one embodiment of the compounds of formula (I) and (Ib), and any embodiment thereof, R 2  is C 3-8 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). 
         [0070]    In one embodiment of the compounds of formula (I) and (Ib), and any embodiment thereof, R 2  is C 3-8 cycloalkyl optionally substituted by one or two groups that are each independently halogen or C 1-8  alkyl (e.g., fluoro or methyl). 
         [0071]    In another embodiment of the compounds of formula (I) and (Ib), and any embodiment thereof, R 2  is heteroaryl, wherein the heteroaryl is optionally substituted with one to five groups that are each independently halogen, C 1-8  alkyl, —OR 21 , —N(R 21 ) 2 , or —C(O)OR 21 , wherein each R 21  is independently hydrogen or C 1-8  alkyl. 
         [0072]    In certain embodiments, the compound for use in the preceding method is selected from the group consisting of, 
         [0000]    
       
         
               
               
               
             
           
               
                   
               
               
                 Compounds 
                 Structure 
                 Name 
               
               
                   
               
             
             
               
                 Example 1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(3-fluoro-4-amino-phenyl)-1- cyclopropyl-7-fluoro-9-methyl-4- oxo-quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(3-fluoro-4-amino-phenyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(3-amino-phenyl)-1-cyclopropyl-9- methyl-4-oxo-quinolizine-3- carboxylic acid 
               
               
                   
               
               
                 Example 4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(3-amino-phenyl)-1-cyclopropyl-7- fluoro-9-methyl-4-oxo-quinolizine-3- carboxylic acid 
               
               
                   
               
               
                 Example 5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(4-amino-phenyl)-1-cyclopropyl-7- fluoro-9-methyl-4-oxo-quinolizine-3- carboxylic acid 
               
               
                   
               
               
                 Example 6 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(4-carbamoyl-phenyl)-1- cyclopropyl-7-fluoro-9-methyl-4- oxo-quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 7 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(2-fluoro-4-amino-phenyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 8 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(3-amino-4-fluoro-phenyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 9 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(3-amino-5-fluoro-phenyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 10 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(3-fluoro-phenyl)-1-cyclopropyl-9- methyl-4-oxo-quinolizine-3- carboxylic acid 
               
               
                   
               
               
                 Example 11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(3-chloro-4-amino-phenyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(3-methoxy-4-amino-phenyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(4-acetamido-phenyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(4-sulfonamido-phenyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(4-methylamino-phenyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 16 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(4-pyridyl)-1-cyclopropyl-9- methyl-4-oxo-quinolizine-3- carboxylic acid 
               
               
                   
               
               
                 Example 17 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(3-pyridyl)-1-cyclopropyl-9- methyl-4-oxo-quinolizine-3- carboxylic acid 
               
               
                   
               
               
                 Example 18 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(4-amino-phenyl)-1-cyclopropyl-9- methyl-4-oxo-quinolizine-3- carboxylic acid 
               
               
                   
               
               
                 Example 19 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(3-methyl-4-amino-phenyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 20 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(2-fluoro-4-pyridyl)-1-cyclopropyl- 9-methyl-4-oxo-quinolizine-3- carboxylic acid 
               
               
                   
               
               
                 Example 21 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(6-amino-3-pyridyl)-1-cyclopropyl- 9-methyl-4-oxo-quinolizine-3- carboxylic acid 
               
               
                   
               
               
                 Example 22 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(1H-indol-5-yl)-1-cyclopropyl-9- methyl-4-oxo-quinolizine-3- carboxylic acid 
               
               
                   
               
               
                 Example 23 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(1H-indazol-5-yl)-1-cyclopropyl-9- methyl-4-oxo-quinolizine-3- carboxylic acid 
               
               
                   
               
               
                 Example 24 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(4-ureido-phenyl)-1-cyclopropyl-9- methyl-4-oxo-quinolizine-3- carboxylic acid 
               
               
                   
               
               
                 Example 25 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(4-dimethylamino-phenyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 26 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-[(3S)-3-aminopyrrolidin-1-yl]-1- cyclopropyl-7-fluoro-9-methyl-4- oxo-quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 27 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-[(3S)-3-aminopyrrolidin-1-yl]-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 28 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(3,6-difluoro-4-amino-phenyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 29 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(3,5-dichloro-4-amino-phenyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 30 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(2-chloro-4-amino-5-methyl- phenyl)-1-cyclopropyl-9-methyl-4- oxo-quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 31 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(4-aminomethyl-phenyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 32 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(4-aminomethyl-phenyl)-1- cyclopropyl-7-fluoro-9-methyl-4- oxo-quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 33 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(4-toluyl)-1-cyclopropyl-9-methyl- 4-oxo-quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 34 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(piperazin-1-yl)-1-cyclopropyl-9- methyl-4-oxo-quinolizine-3- carboxylic acid 
               
               
                   
               
               
                 Example 35 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-[(3S)-3-amino-1-piperidyl]-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 36 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(4-carbamoyl-phenyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 37 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(4-carboxy-phenyl)-1-cyclopropyl- 9-methyl-4-oxo-quinolizine-3- carboxylic acid 
               
               
                   
               
               
                 Example 38 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(2,5-difluoro-4-amino-phenyl)-1- cyclopropyl-7-fluoro-9-methyl-4- oxo-quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 39 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(3,5-difluoro-4-amino-phenyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 40 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(3-fluoro-4-cyano-phenyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 41 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(4-carboxy-phenyl)-1-cyclopropyl- 7-fluoro-9-methyl-4-oxo-quinolizine- 3-carboxylic acid 
               
               
                   
               
               
                 Example 42 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(1,2,3,6-tetrahydro-pyridin-4-yl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 43 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(1H-pyrrol-3-yl)-1-cyclopropyl-9- methyl-4-oxo-quinolizine-3- carboxylic acid 
               
               
                   
               
               
                 Example 44 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(4-fluoro-phenyl)-1-cyclopropyl-9- methyl-4-oxo-quinolizine-3- carboxylic acid 
               
               
                   
               
               
                 Example 45 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(4-chloro-phenyl)-1-cyclopropyl-9- methyl-4-oxo-quinolizine-3- carboxylic acid 
               
               
                   
               
               
                 Example 46 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(4-hydroxy-phenyl)-1-cyclopropyl- 9-methyl-4-oxo-quinolizine-3- carboxylic acid 
               
               
                   
               
               
                 Example 47 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(4-methoxy-phenyl)-1-cyclopropyl- 9-methyl-4-oxo-quinolizine-3- carboxylic acid 
               
               
                   
               
               
                 Example 48 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(4-hydroxymethyl-phenyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 49 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(3-fluoro-4-aminomethyl-phenyl)- 1-cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 50 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(3-amino-2-oxo-3,4-dihydro-1H- quinolin-7-yl)-1-cyclopropyl-9- methyl-4-oxo-quinolizine-3- carboxylic acid 
               
               
                   
               
               
                 Example 51 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-[5-(aminomethyl)-2-furyl]-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid 
               
               
                   
               
               
                 Example 52 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 8-(4-cyano-phenyl)-1-cyclopropyl-9- methyl-4-oxo-quinolizine-3- carboxylic acid 
               
               
                   
               
               
                 and pharmaceutically acceptable salts thereof (e.g., a potassium salt thereof). 
               
             
          
         
       
     
         [0073]    In certain other embodiments, the compound for use in the preceding method is selected from the group consisting of,
   8-(3-fluoro-4-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(6-amino-3-pyridyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(1H-indazol-5-yl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(3,6-difluoro-4-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(4-hydroxy-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   
 
         [0079]    and pharmaceutically acceptable salts thereof (e.g., a potassium salt thereof). 
         [0080]    In an embodiment of any of the preceding embodiments, the pathogen can be selected from the group consisting of, (a)  Acinetobacter baumannii, Bacillus anthracis, Brucella abortus, Burkholderia cepacia, Burkholderia mallei, Burkholderia pseudomallei, Burkholderia thailandensis, Citrobacter freundii, Corynebacterium jeikeium, Enterobacter  sp,  Enterobacter cloacae, Enterococcus faecium, Enterococcus gallinarum, Francisella tularensis, Klebsiella aerogenes, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, Neisseria meningitides, Proteus mirabilis, Providencia stuartii, Serratia marcescens, Shigella  sp,  Staphylococcus haemolyticus, Staphylococcus saprophyticus, Stenotrophomonas maltophilia, Streptococcus agalactiae, Streptococcus bovis, Streptococcus constellatus, Streptococcus mitis, Streptococcus pyogenes, Streptococcus oralis, Streptococcus sanguis , Group C  Streptococcus , and  Yersinia pestis , (b) drug-resistant strains of any pathogen of part (a); and (c) and drug-resistant strains of  Staphylococcus aureus, Staphylococcus epidermis, Streptococcus pneumoniae, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa , and  Haemophilus influenza.    
         [0081]    In another embodiment of any of the preceding embodiments, the pathogen can be selected from the group consisting of  Acinetobacter baumannii, Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Haemophilus influenza, Stenotrophomonas maltophilia, Streptococcus pneumoniae , and drug-resistant strains thereof. 
         [0082]    In another embodiment of any of the preceding embodiments, the pathogen can be  Burkholderia mallei, Burkholderia pseudomallei, Bacillus anthracis, Francisella tularensis, Yersinia pestis , or  Brucella abortus.    
         [0083]    In another embodiment of any of the preceding embodiments, the pathogen is  Acinetobacter baumannii , or a drug-resistant strain thereof. 
         [0084]    In another embodiment of any of the preceding embodiments, the pathogen is  Burkholderia cepacia, Burkholderia mallei, Burkholderia pseudomallei, Burkholderia thailandensis , or a drug-resistant strain thereof. 
         [0085]    In another embodiment of any of the preceding embodiments, the pathogen is  Citrobacter freundii , or a drug-resistant strain thereof. 
         [0086]    In another embodiment of any of the preceding embodiments, the pathogen is  Corynebacterium jeikeium , or a drug-resistant strain thereof. 
         [0087]    In another embodiment of any of the preceding embodiments, the pathogen is  Enterobacter  sp,  Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium , or a drug-resistant strain thereof. 
         [0088]    In another embodiment of any of the preceding embodiments, the pathogen is  Enterococcus gallinarum , or a drug-resistant strain thereof. 
         [0089]    In another embodiment of any of the preceding embodiments, the pathogen is  Escherichia coli , or a drug-resistant strain thereof. 
         [0090]    In another embodiment of any of the preceding embodiments, the pathogen is  Haemophilus influenza , or a drug-resistant strain thereof. 
         [0091]    In another embodiment of any of the preceding embodiments, the pathogen is  Klebsiella aerogenes, Klebsiella pneumoniae , or a drug-resistant strain thereof. 
         [0092]    In another embodiment of any of the preceding embodiments, the pathogen is  Listeria monocytogenes , or a drug-resistant strain thereof. 
         [0093]    In another embodiment of any of the preceding embodiments, the pathogen is  Moraxella catarrhalis , or a drug-resistant strain thereof. 
         [0094]    In another embodiment of any of the preceding embodiments, the pathogen is  Morganella morganii , or a drug-resistant strain thereof. 
         [0095]    In another embodiment of any of the preceding embodiments, the pathogen is  Neisseria meningitides , or a drug-resistant strain thereof. 
         [0096]    In another embodiment of any of the preceding embodiments, the pathogen is  Proteus mirabilis , or a drug-resistant strain thereof. 
         [0097]    In another embodiment of any of the preceding embodiments, the pathogen is  Providencia stuartii , or a drug-resistant strain thereof. 
         [0098]    In another embodiment of any of the preceding embodiments, the pathogen is  Pseudomonas aeruginosa , or a drug-resistant strain thereof. 
         [0099]    In another embodiment of any of the preceding embodiments, the pathogen is  Serratia marcescens , or a drug-resistant strain thereof. 
         [0100]    In another embodiment of any of the preceding embodiments, the pathogen is  Shigella  sp, or a drug-resistant strain thereof. 
         [0101]    In another embodiment of any of the preceding embodiments, the pathogen is  Staphylococcus aureus, Staphylococcus epidermis, Staphylococcus haemolyticus, Staphylococcus saprophyticus , or a drug-resistant strain thereof. 
         [0102]    In another embodiment of any of the preceding embodiments, the pathogen is  Stenotrophomonas maltophilia , or a drug-resistant strain thereof. 
         [0103]    In another embodiment of any of the preceding embodiments, the pathogen is  Streptococcus agalactiae, Streptococcus bovis, Streptococcus constellatus, Streptococcus mitis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus oralis, Streptococcus sanguis , Group C  Streptococcus , or a drug-resistant strain thereof. 
         [0104]    In another embodiment of any of the preceding embodiments, the pathogen is a drug-resistant strain. 
         [0105]    In another embodiment of any of the preceding embodiments, the pathogen is  Staphylococcus aureus  ATCC 25923,  Staphylococcus aureus  ATCC 43300,  Staphylococcus aureus  BAA-1720,  Enterobacter faecium  ATCC 19434,  Enterobacter faecalis  ATCC 29212,  Streptococcus pneumoniae  ATCC 49619,  Escherichia coli  ATCC 25922,  Acinetobacter  baumannii ATCC 19606,  Pseudomonas aeruginosa  ATCC 27853  Klebsiella pneumoniae  ATCC 33495,  Haemophilus influenzae  ATCC 49247, or  Stenotrophomonas maltophilia  ATCC 17677. 
         [0106]    In another embodiment of any of the preceding embodiments, the pathogen is  Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus saprophyticus, Enterococcus faecalis, Enterococcus faecium, Enterococcus gallinarum, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus agalactiae , Group C  Streptococcus, Streptococcus mitis, Streptococcus constellatus, Streptococcus oralis, Streptococcus bovis, Streptococcus sanguis, Corynebacterium jeikeium, Listeria monocytogenes, Escherichia coli, Klebsiella aerogenes, Klebsiella pneumonia, Enterobacter  sp,  Serratia marcescens, Pseudomonas aeruginosa, Stenotrophomonas maltophila, Burkholderia cepacia, Proteus mirabilis, Shigella  sp,  Morganella morganii, Providencia stuartii, Neisseria meningitidis, Haemophilus influenza, Moraxella catarrhalis, Acinetobacter baumannii , or  Citrobacter freundii.    
         [0107]    In another embodiment of any of the preceding embodiments, the pathogen is  Staphylococcus aureus , EMRSA16  Staphylococcus aureus, Enterococcus faecali, Enterococcus faecium, Streptococcus pneumonia, Escherichia coli Pseudomonas aeruginosa, Providencia stuartii , or  Acinetobacter baumannii    
         [0108]    In another embodiment of any of the preceding embodiments, the pathogen is a class A or class B select biothreat agents as defined by the CDC (Centers for Disease Control and Prevention). 
         [0109]    In another embodiment of any of the preceding embodiments, the pathogen is  Bacillus anthracis  Ames strain,  Brucella abortus  ATCC 23448,  Burkholderia mallei  ATCC 23344,  Burkholderia pseudomallei  ATCC 23343,  Francisella tularensis  Schu S4, or  Yersinia pestis  CO92. 
         [0110]    In another embodiment, the pathogen is selected from the group consisting of  Burkholderia cepacia, Acinetobacter baumannii, Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Haemophilus influenza, Streptococcus pneumoniae, Streptococcus pyogenes , Group C  Streptococcus , and drug-resistant strains thereof; and the compound is
   8-(3-fluoro-4-amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(3-fluoro-4-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(4-amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(4-carbamoyl-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(4-pyridyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(6-amino-3-pyridyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(1H-indazol-5-yl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(3,6-difluoro-4-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(4-aminomethyl-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(3,5-difluoro-4-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(1,2,3,6-tetrahydro-pyridin-4-yl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(4-hydroxy-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   
 
         [0123]    or a pharmaceutically acceptable salt thereof (e.g., a potassium salt thereof). 
         [0124]    In another embodiment, the pathogen is selected from the group consisting of  Burkholderia mallei, Burkholderia pseudomallei, Bacillus anthracis, Yersinia pestis, Francisella tularensis , and  Brucella abortus , and the compound is
   8-(3-fluoro-4-amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(3-fluoro-4-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(3-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(3-amino-4-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(3-amino-5-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(4-pyridyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(2-fluoro-4-pyridyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(6-amino-3-pyridyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(1H-indazol-5-yl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(3,6-difluoro-4-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(4-aminomethyl-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(1,2,3,6-tetrahydro-pyridin-4-yl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(4-chloro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(4-hydroxy-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(4-hydroxymethyl-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   
 
         [0140]    or a pharmaceutically acceptable salt thereof (e.g., a potassium salt thereof). 
         [0141]    In another embodiment, the pathogen is selected from the group consisting of  Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, Streptococcus pyogenes , Group C  Streptococcus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Burkholderia cepacia, Haemophilus influenzae, Acinetobacter baumannii , and drug resistant strains thereof; and the compound is
   8-(3-fluoro-4-amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(3-fluoro-4-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(4-amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(4-carbamoyl-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(4-pyridyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(6-amino-3-pyridyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(1H-indazol-5-yl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(3,6-difluoro-4-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(4-aminomethyl-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(3,5-difluoro-4-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(1,2,3,6-tetrahydro-pyridin-4-yl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(4-hydroxy-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   
 
         [0154]    or a pharmaceutically acceptable salt thereof (e.g., a potassium salt thereof). 
         [0155]    In another embodiment, the pathogen is selected from the group consisting of  Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus saprophyticus, Enterococcus faecalis, Enterococcus faecium, Enterococcus gallinarum, Streptococcus pneumonia, Streptococcus pyogenes, Streptococcus agalactiae , Group C  Streptococcus, Streptococcus mitis, Streptococcus constellatus, Streptococcus oralis, Streptococcus bovis, Streptococcus sanguis, Corynebacterium jeikeium, Listeria monocytogenes, Escherichia coli, Klebsiella aerogenes, Klebsiella pneumoniae, Enterobacter  sp,  Serratia marcescens, Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Burkholderia cepacia, Proteus mirabilis, Shigella  sp,  Morganella morganii, Providencia stuartii, Neisseria meningitides, Haemophilus influenza, Moraxella catarrhalis, Acinetobacter baumannii, Citrobacter freundii , and drug resistant strains thereof; and the compound is
   8-(3-fluoro-4-amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(3-fluoro-4-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(4-amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(4-carbamoyl-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(4-pyridyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(6-amino-3-pyridyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(1H-indazol-5-yl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(3,6-difluoro-4-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(4-aminomethyl-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(3,5-difluoro-4-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(1,2,3,6-tetrahydro-pyridin-4-yl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(4-hydroxy-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   
 
         [0168]    or a pharmaceutically acceptable salt thereof (e.g., a potassium salt thereof). 
         [0169]    In another embodiment, the pathogen is selected from the group consisting of  Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Streptococcus pneumoniae, Streptococcus pyogenes , Group C  Streptococcus, Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Burkholderia cepacia, Haemophilus influenzae, Acinetobacter baumannii , and drug resistant strains thereof; and the compound is
   8-(4-aminomethyl-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(3,5-difluoro-4-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(1,2,3,6-tetrahydro-pyridin-4-yl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(4-hydroxy-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   
 
         [0174]    or a pharmaceutically acceptable salt thereof (e.g., a potassium salt thereof). 
         [0175]    In another embodiment, the pathogen is  Methicillin -resistant  Staphylococcus aureus  and the compound is
   8-(3-fluoro-4-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(6-amino-3-pyridyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(1H-indazol-5-yl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(3,6-difluoro-4-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   8-(4-hydroxy-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid;   
 
         [0181]    or a pharmaceutically acceptable salt thereof (e.g., a potassium salt thereof). 
         [0182]    In another aspect, the present disclosure provides compounds of the formula (II), 
         [0000]    
       
                 
         
             
             
         
       
     
         [0183]    or a pharmaceutically acceptable salt thereof, wherein 
         [0184]    R 1  is hydrogen, halogen, cyano, C 1-8  alkyl, C 1-8  haloalkyl, heterocyclyl, —OR 11 , —N(R 11 ) 2 , or —C(O)N(R 11 ) 2 , wherein each R 11  is independently hydrogen, C 1-8  alkyl, or C 1-8  haloalkyl; 
         [0185]    R 2  is a C 1-8  alkyl, C 1-8  haloalkyl, C 3-8 cycloalkyl, or heteroaryl, wherein the cycloalkyl and heteroaryl are optionally substituted with one to five groups that are each independently halogen, C 1-8  alkyl, —OR 21 , —N(R 21 ) 2 , or —C(O)OR 21 , wherein each R 21  is independently hydrogen or C 1-8  alkyl; 
         [0186]    Z is a bicyclic heteroaryl, optionally substituted by one to five groups that are each independently halogen, C 1-8  alkyl, C 1-8  haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Z , or —C 1-8  alkyl-R Z , wherein 
         [0187]    R Z  is nitro, cyano, —OR Z1 , —SR Z1 , —N(R Z1 ) 2 , —C(O)R Z1 , —C(O)OR Z1 , —C(O)N(R Z1 ) 2 , —OC(O)R Z1 , —OC(O)OR Z1 , —OC(O)N(R z1 ) 2 , —N(R Z1 )C(O)R Z1 , —N(R Z1 )C(O)OR Z1 , —N(R Z1 )C(O)N(R z1 ) 2 , —S(O) 2 R Z1 , —S(O) 2 OR Z1 , —S(O) 2 N(R z1 ) 2 , —OS(O) 2 R Z1 , —OS(O) 2 OR Z1 , —OS(O) 2 N(R z1 ) 2 , —N(R Z1 )S(O) 2 R Z1 , —N(R Z1 )S(O) 2 OR Z1 , or —N(R Z1 )S(O) 2 N(R Z1 ) 2 , wherein 
         [0188]    each R Z1  is independently hydrogen, C 1-8  alkyl, or C 1-8  haloalkyl; and 
         [0189]    X is hydrogen, halogen, cyano, C 1-8  alkyl, C 1-8 haloalkyl, —OR X , —N(R X ) 2 , —C(O)R X , —C(O)OR X , or —C(O)N(R X ) 2 , wherein each R X  is independently hydrogen, C 1-8  alkyl, or C 1-8 haloalkyl. 
         [0190]    In one embodiment of the compounds of formula (II), R 1  is hydrogen, halogen, or C 1-8  alkyl. In another embodiment, R 1  is hydrogen or C 1-8  alkyl. In another embodiment, R 1  is hydrogen or methyl. In another embodiment, R 1  is halogen or C 1-8  alkyl. In another embodiment, R 1  is C 1-8  alkyl. In another embodiment, R 1  is halogen. In another embodiment of the compounds of formula (II), R 1  is C 1-8  haloalkyl, —OR 11 , or —C(O)N(R 11 ) 2 . In another embodiment of the compounds of formula (II), R 1  is trifluoromethyl, methoxy, or —C(O)NH 2 . In certain embodiments, the compound for formula (II) is of one of the formulas, 
         [0000]    
       
                 
         
             
             
         
       
     
         [0191]    In one embodiment of the compounds of formula (II), (IIa)-(IIc), and any embodiment thereof, X is hydrogen or halogen. In another embodiment, X is hydrogen. In another embodiment, X is halogen. In another embodiment, X is fluoro. In another embodiment, X is hydrogen, halogen, C 1-8  alkyl, C 1-8  alkoxy, amino, C 1-8  alkylamino, or di(C 1-8  alkyl)amino. In another embodiment, X is —OR X , —N(R X ) 2 , —C(O)R X , —C(O)OR X , or —C(O)N(R X ) 2 . In another embodiment, X is —O(R X ) or —N(R X ) 2 . In another embodiment, X is —C(O)R X , —C(O)OR X , or —C(O)N(R X ) 2 . In another embodiment, X is C 1-8 haloalkyl (e.g., trifluoromethyl). 
         [0192]    In particular embodiments of the compounds of formula (II) and (IIa), R 1  and X are selected from one of the following combinations:
       (a) R 1  is hydrogen, halogen, or C 1-8  alkyl; and X is hydrogen or halogen.   (b) R 1  is hydrogen, halogen, or C 1-8  alkyl; and X is hydrogen.   (c) R 1  is hydrogen, halogen, or C 1-8  alkyl; and X is halogen.   (d) R 1  is hydrogen, halogen, or C 1-8  alkyl; and X is fluoro.   (e) R 1  is hydrogen or C 1-8  alkyl; and X is hydrogen or halogen.   (f) R 1  is hydrogen or C 1-8  alkyl; and X is hydrogen.   (g) R 1  is hydrogen or C 1-8  alkyl; and X is halogen.   (h) R 1  is hydrogen or C 1-8  alkyl; and X is fluoro.   (i) R 1  is hydrogen or methyl; and X is hydrogen or halogen.   (j) R 1  is hydrogen or methyl; and X is hydrogen.   (k) R 1  is hydrogen or methyl; and X is halogen.   (l) R 1  is hydrogen or methyl; and X is fluoro.   (m) R 1  is halogen or C 1-8  alkyl; and X is hydrogen or halogen.   (n) R 1  is halogen or C 1-8  alkyl; and X is hydrogen.   (o)R 1  is halogen or C 1-8  alkyl; and X is halogen.   (p) R 1  is halogen or C 1-8  alkyl; and X is fluoro.   (q) R 1  is C 1-8  alkyl; and X is hydrogen or halogen.   (r) R 1  is C 1-8  alkyl; and X is hydrogen.   (s) R 1  is C 1-8  alkyl; and X is halogen.   (t) R 1  is C 1-8  alkyl; and X is fluoro.       
 
         [0213]    In another embodiment of the compounds of formula (II), (IIa)-(IIc), and any embodiment thereof, Z is a benzofuranyl, benzothienyl, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzoisoxazolyl, benzothiazolyl, benzoisothiazolyl, or benzotriazolyl, each optionally substituted by one to five groups that are each independently halogen, C 1-8  alkyl, C 1-8  haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Z , or —C 1-8  alkyl-R Z . 
         [0214]    In another embodiment of the compounds of formula (II), (IIa)-(IIc), and any embodiment thereof, Z is indazolyl optionally substituted by one to five groups that are each independently halogen, C 1-8  alkyl, C 1-8  haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Z , or —C 1-8  alkyl-R Z . 
         [0215]    In another embodiment of the compounds of formula (II), (IIa)-(IIc), and any embodiment thereof, Z is indazolyl. 
         [0216]    In one embodiment of the compounds of formula (II) and (IIb), and any embodiment thereof, R 2  is a C 1-8  alkyl, C 1-8  haloalkyl, or C 3-8 cycloalkyl. 
         [0217]    In one embodiment of the compounds of formula (II) and (IIb), and any embodiment thereof, R 2  is a C 1-8  alkyl (e.g., methyl). 
         [0218]    In one embodiment of the compounds of formula (II) and (IIb), and any embodiment thereof, R 2  is a C 1-8  haloalkyl (e.g., trifluoromethyl). 
         [0219]    In one embodiment of the compounds of formula (II) and (IIb), and any embodiment thereof, R 2  is C 3-8 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). 
         [0220]    In one embodiment of the compounds of formula (II) and (IIb), and any embodiment thereof, R 2  is C 3-8 cycloalkyl optionally substituted by one or two groups that are each independently halogen or C 1-8  alkyl (e.g., fluoro or methyl). 
         [0221]    In another embodiment of the compounds of formula (II) and (IIb), and any embodiment thereof, R 2  is heteroaryl, wherein the heteroaryl is optionally substituted with one to five groups that are each independently halogen, C 1-8  alkyl, —OR 21 , —N(R 21 ) 2 , or —C(O)OR 21 , wherein each R 21  is independently hydrogen or C 1-8  alkyl. 
         [0222]    In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound of the formula (I) or (II), a pharmaceutically acceptable salt thereof, or any embodiment thereof, and a pharmaceutically acceptable carrier, excipient, or diluent. 
         [0223]    In another aspect, the present disclosure provides compound of the formula (I) or (II), a pharmaceutically acceptable salt thereof, or any of the preceding embodiments thereof, for treating an infection caused by a pathogen selected from the group consisting of  Burkholderia mallei, Burkholderia pseudomallei, Burkholderia cepacia, Bacillus anthracis, Yersinia pestis, Francisella tularensis, Brucella abortus, Burkholderia thailandensis, Acinetobacter baumannii, Acinetobacter baumannii, Staphylococcus aureus, Staphylococcus epidermis, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Enterobacter cloacae, Pseudomonas aeruginosa, Klebsiella pneumoniae,    Haemophilus influenza, Stenotrophomonas maltophilia, Streptococcus pneumoniae, Streptococcus pyogenes , Group C  Streptococcus , and drug-resistant strains thereof. 
         [0224]    In certain embodiments, the compound of formula (I) or (II) reduces the risk of contagion caused by an infection induced by a pathogen selected from the group consisting of  Burkholderia mallei, Burkholderia pseudomallei, Burkholderia cepacia, Bacillus anthracis, Yersinia pestis, Francisella tularensis, Brucella abortus, Burkholderia thailandensis, Acinetobacter baumannii, Acinetobacter baumannii, Staphylococcus aureus, Staphylococcus epidermis, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, Enterobacter cloacae, Pseudomonas aeruginosa, Klebsiella pneumoniae, Streptococcus pneumoniae, Streptococcus pyogenes , Group C  Streptococcus , and drug-resistant strains thereof, in an individual at risk of acquiring the infection by at least 5%, or at least 10%, or at least 15%, or at least 20%, or at least 30% or at least 40%, or at least 50%, or at least 60%, or at least 70% or at least 80%, or at least 90%, or more. 
         [0225]    In another aspect, the present disclosure provides methods for treating an infection comprising, providing to a subject infected by a pathogen selected from the group consisting of  Acinetobacter baumannii, Bacillus anthracis, Brucella abortus, Burkholderia cepacia, Burkholderia mallei, Burkholderia pseudomallei, Burkholderia thailandensis, Citrobacter freundii, Corynebacterium jeikeium, Enterobacter  sp,  Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterococcus gallinarum, Escherichia coli, Francisella tularensis, Haemophilus influenza, Klebsiella aerogenes, Klebsiella pneumoniae, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, Neisseria meningitides, Proteus mirabilis, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens, Shigella  sp,  Staphylococcus aureus, Staphylococcus epidermis, Staphylococcus haemolyticus, Staphylococcus saprophyticus, Stenotrophomonas maltophilia, Streptococcus agalactiae, Streptococcus bovis, Streptococcus constellatus, Streptococcus mitis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus oralis, Streptococcus sanguis , Group C  Streptococcus, Yersinia pestis , and drug-resistant strains thereof, a therapeutically effective amount of a compound selected from the group consisting of
   8-(3-fluoro-4-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid   8-(6-amino-3-pyridyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid   8-(1H-indazol-5-yl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid   8-(3,6-difluoro-4-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid   8-(4-hydroxy-phenyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid   
 
         [0231]    and pharmaceutically acceptable salts thereof (e.g., a potassium salt thereof), 
         [0000]    wherein the compound is provided to the subject as either (a) an oral formulation that, when given orally in a mouse model, has one or more of (i) peak serum concentration (C max )&gt;0.15 μg/mL; (ii) t max &lt;45 minutes; (iii) half-life (t 1/2 )≧1 hour; and/or (iv) oral bioavailability (F)&gt;40%; or (b) an intravenous formulation that, when given intravenously in a mouse model, has one or more of (i) an apparent volume of distribution (V d )&gt;5000 mL/kg; and/or (ii) half-life (t 1/2 )≧1 hour. 
       Treatment 
       [0232]    According to the present invention, treatment may be given either to a subject infected by the pathogen, or may be a subject at risk of acquiring such an infection. Generally, the subject is mammalian, such as a human or animal mammalian. 
         [0233]    The treatment may be ameliorating or curative. By curative, it is intended to mean survival from the infection which otherwise in the absence of the treatment causes the subject suffering from the infection to show increasing pathology or even morbidity. 
         [0234]    In another embodiment of the invention the treatment is prophylactic treatment. Thus, the pharmaceutical compositions described herein may be prepared for prophylactic treatment of an infection by a pathogen in an individual at risk of infection by the pathogen. 
         [0235]    In one embodiment of the invention, the pharmaceutical composition is for reducing the risk of contagion caused by the infection or in an individual at risk of acquiring an infection by the pathogen. In relation to epidemic or even pandemic infections causing a high mortality rate, even slight reductions in risk of contagion may be of major importance. 
         [0236]    In another embodiment, the pharmaceutical composition reduces the risk of contagion in a subject that has acquired the infection by at least 5%, preferably at least 10%, preferably at least 15%, more preferably at least 20%, or at least 30% or at least 40%, or at least 50%, or at least 60%, or at least 70% or at least 80%, or at least 90%, or more. 
         [0237]    The pharmaceutical compositions of the invention may also reduce the risk of contagion caused by an infection in an individual at risk of acquiring that infection by at least 5%, or at least 10%, or at least 15%, or at least 20%, or at least 30% or at least 40%, or at least 50%, or at least 60%, or at least 70% or at least 80%, or at least 90%, or more. 
         [0238]    Administration of the anti-infective pharmaceutical compositions according to the invention may be only once or administration may be repeated for a number of times. For example, the compositions may be given for a repeatedly with regular intervals, for example in the range of 1 to 5 times daily for in the range of 1 to 100 days, such as in the range of 1 to 50 days, for example in the range of 1 to 25 days, such as in the range of 10 to 16 days. The total daily dose of the compounds of this invention administered to a host in single or in divided doses can be in amounts, Single dose compositions may contain such amounts or submultiples thereof as make up the daily dose. 
         [0239]    The pharmaceutical compositions may be prepared for any suitable administration route, for example, topical, parenteral, oral, buccal, systemic, nasal, injection, transdermal, rectal, vaginal, etc., or a form suitable for administration by inhalation or insufflation. For example, the pharmaceutical compositions of the invention are prepared for oral administration or for intraperitoneal administration, such as for oral administration. Similarly, the pharmaceutical compositions of the invention may or may be used at the site of a wound on or in the body, for example as a result of surgery or injury. Equally, the pharmaceutical compositions of the invention may or may be used for an internal infection at the site of a prosthesis. 
         [0240]    Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the active compound suspended in diluents, such as water, saline or PEG 400; (b) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as liquids, solids, granules or gelatin; (c) suspensions in an appropriate liquid; and (d) suitable emulsions. Tablet forms can include one or more of lactose, sucrose, mannitol, sorbitol, calcium phosphates, corn starch, potato starch, microcrystalline cellulose, gelatin, colloidal silicon dioxide, talc, magnesium stearate, stearic acid, and other excipients, colorants, fillers, binders, diluents, buffering agents, moistening agents, preservatives, flavoring agents, dyes, disintegrating agents, and pharmaceutically compatible carriers. Lozenge forms can comprise the active ingredient in a flavor, e.g., sucrose, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia emulsions, gels, and the like containing, in addition to the active ingredient, carriers known in the art. 
         [0241]    A compound, as described above, alone or in combination with other suitable components, can be made into aerosol formulations (i.e., they can be “nebulized”) to be administered via inhalation. Aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. 
         [0242]    Suitable formulations for rectal administration include, for example, suppositories, which consist of the packaged compound with a suppository base. Suitable suppository bases include natural or synthetic triglycerides or paraffin hydrocarbons. In addition, it is also possible to use gelatin rectal capsules which consist of a combination of the compound of choice with a base, including, for example, liquid triglycerides, polyethylene glycols, and paraffin hydrocarbons. 
         [0243]    Formulations suitable for parenteral administration, such as, for example, by intraarticular (in the joints), intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. In the practice of this invention, compositions can be administered, for example, by intravenous infusion, orally, topically, intraperitoneally, intravesically or intrathecally. 
         [0244]    The pharmaceutical composition may be in unit dosage form. In such form the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. The composition can, if desired, also contain other compatible therapeutic agents, discussed in more detail, below. 
         [0245]    In therapeutic use, the compounds utilized in the methods of the invention may be administered to subjects at dosage levels suitable to achieve therapeutic benefit. By therapeutic benefit is meant that the administration of compound leads to a beneficial effect in the patient over time. 
         [0246]    Initial dosages suitable for administration to humans may be determined from in vitro assays or animal models. For example, an initial dosage may be formulated to achieve a serum concentration that includes the IC 50  of the particular compound being administered, as measured in an in vitro assay. Alternatively, an initial dosage for humans may be based upon dosages found to be effective in animal models of the disease. For example, thr dose may vary depending on the symptoms, age, body weight, etc. of the patient. Usually, they are administered to adults in a dose of 0.05 to 100 mg/kg/day, preferably 0.1 to 50 mg/kg/day, in the systemic administration. When they are used for the local treatment, the concentration of the active ingredient is 0.01 to 5%, preferably 0.1 to 3%. 
       DEFINITIONS 
       [0247]    The term “drug-resistant strain” as used herein means that the reference bacterial strain is either β-lactamase positive or resistant to one or more macrolide, beta-lactam, quinolone, carbapenem, aminoside, and/or glycopeptide antibiotic, including, but not limited to penicillin, methicillin, levofloxacin, ciprofloxacin, meropenem, imipenem, amikacin, tetracyclin, vancomycin, and polyoxin. 
         [0248]    As used herein, the term “individual” or “patient,” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans. 
         [0249]    As used herein, the phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response that is being sought in a tissue, system, animal, individual or human by a researcher, veterinarian, medical doctor or other clinician. 
         [0250]    As used herein, the phrase “pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is made with counterions understood in the art to be generally acceptable for pharmaceutical uses and which possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, piperidine, dimethylamine, diethylamine and the like. Also included are salts of amino acids such as arginates and the like, and salts of organic acids like glucuronic or galacturonic acids and the like (see, e.g., Berge et al, 1977, J. Pharm. Sci. 66:1-19). In certain embodiments of any of the preceding compounds, methods, and embodiments thereof, the compound is a potassium salt. 
         [0251]    Terms used herein may be preceded and/or followed by a single dash, “—”, or a double dash, “═”, to indicate the bond order of the bond between the named substituent and its parent moiety; a single dash indicates a single bond and a double dash indicates a double bond or a pair of single bonds in the case of a spiro-substituent. In the absence of a single or double dash it is understood that a single bond is formed between the substituent and its parent moiety; further, substituents are intended to be read “left to right” unless a dash indicates otherwise. For example, C 1 -C 6 alkoxycarbonyloxy and —OC(O)C 1 -C 6 alkyl indicate the same functionality; similarly arylalkyl, arylalkyl-, and -alkylaryl indicate the same functionality. 
         [0252]    Further, certain terms herein may be used as both monovalent and divalent linking radicals as would be familiar to those skilled in the art, and by their presentation linking between two other moieties. For example, an alkyl group can be both a monovalent radical or divalent radical; in the latter case, it would be apparent to one skilled in the art that an additional hydrogen atom is removed from a monovalent alkyl radical to provide a suitable divalent moiety. 
         [0253]    The term “alkyl” as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms, unless otherwise specified. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. When an “alkyl” group is a linking group between two other moieties, then it may also be a straight or branched chain; examples include, but are not limited to —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CHC(CH 3 )—, —CH 2 CH(CH 2 CH 3 )CH 2 —. 
         [0254]    The term “aryl,” as used herein, means a phenyl (i.e., monocyclic aryl), or a bicyclic ring system containing at least one phenyl ring or an aromatic bicyclic ring containing only carbon atoms in the aromatic bicyclic ring system. The bicyclic aryl can be azulenyl, naphthyl, or a phenyl fused to a monocyclic cycloalkyl, a monocyclic cycloalkenyl, or a monocyclic heterocyclyl. The bicyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the phenyl portion of the bicyclic system, or any carbon atom with the napthyl or azulenyl ring. The fused monocyclic cycloalkyl or monocyclic heterocyclyl portions of the bicyclic aryl are optionally substituted with one or two oxo and/or thia groups. Representative examples of the bicyclic aryls include, but are not limited to, azulenyl, naphthyl, dihydroinden-1-yl, dihydroinden-2-yl, dihydroinden-3-yl, dihydroinden-4-yl, 2,3-dihydroindol-4-yl, 2,3-dihydroindol-5-yl, 2,3-dihydroindol-6-yl, 2,3-dihydroindol-7-yl, inden-1-yl, inden-2-yl, inden-3-yl, inden-4-yl, dihydronaphthalen-2-yl, dihydronaphthalen-3-yl, dihydronaphthalen-4-yl, dihydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 2,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7-yl, benzo[d][1,3]dioxol-4-yl, and benzo[d][1,3]dioxol-5-yl. In certain embodiments, the bicyclic aryl is naphthyl or a phenyl ring fused to either a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, or a 5 or 6 membered monocyclic heterocyclyl, wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia. 
         [0255]    The term “cycloalkyl” as used herein, means a monocyclic or a bicyclic cycloalkyl ring system. Monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In certain embodiments, cycloalkyl groups are fully saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form —(CH 2 ) w —, where w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. Cycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thia. In certain embodiments, the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted by one or two groups which are independently oxo or thia. 
         [0256]    “Cycloalkenyl” as used herein refers to a monocyclic or a bicyclic cycloalkenyl ring system. Monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups are unsaturated (i.e., containing at least one annular carbon-carbon double bond), but not aromatic. Examples of monocyclic ring systems include cyclopentenyl and cyclohexenyl. Bicyclic cycloalkenyl rings are bridged monocyclic rings or a fused bicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkenyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form —(CH 2 ) w —, where w is 1, 2, or 3). Representative examples of bicyclic cycloalkenyls include, but are not limited to, norbornenyl and bicyclo[2.2.2]oct-2-enyl. Fused bicyclic cycloalkenyl ring systems contain a monocyclic cycloalkenyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The bridged or fused bicyclic cycloalkenyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkenyl ring. Cycloalkenyl groups are optionally substituted with one or two groups which are independently oxo or thia. 
         [0257]    The term “heteroaryl,” as used herein, means a monocyclic heteroaryl or a bicyclic ring system containing at least one heteroaromatic ring. The monocyclic heteroaryl can be a 5 or 6 membered ring. The 5 membered ring consists of two double bonds and one, two, three or four nitrogen atoms and optionally one oxygen or sulfur atom. The 6 membered ring consists of three double bonds and one, two, three or four nitrogen atoms. The 5 or 6 membered heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl. Representative examples of monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The fused cycloalkyl or heterocyclyl portion of the bicyclic heteroaryl group is optionally substituted with one or two groups which are independently oxo or thia. When the bicyclic heteroaryl contains a fused cycloalkyl, cycloalkenyl, or heterocyclyl ring, then the bicyclic heteroaryl group is connected to the parent molecular moiety through any carbon or nitrogen atom contained within the monocyclic heteroaryl portion of the bicyclic ring system. When the bicyclic heteroaryl is a monocyclic heteroaryl fused to a phenyl ring, then the bicyclic heteroaryl group is connected to the parent molecular moiety through any carbon atom or nitrogen atom within the bicyclic ring system. Representative examples of bicyclic heteroaryl include, but are not limited to, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinnolinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl, 5,6,7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5,6,7,8-tetrahydroquinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl, thienopyridinyl, 4,5,6,7-tetrahydrobenzo[c][1,2,5]oxadiazolyl, and 6,7-dihydrobenzo[c][1,2,5]oxadiazol-4(5H)-onyl. In certain embodiments, the fused bicyclic heteroaryl is a 5 or 6 membered monocyclic heteroaryl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia. 
         [0258]    The term “heterocyclyl” as used herein, means a monocyclic heterocycle or a bicyclic heterocycle. The monocyclic heterocycle is a 3, 4, 5, 6 or 7 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S where the ring is saturated or unsaturated, but not aromatic. The 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S. The 5 membered ring can contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle. Representative examples of monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclic heteroaryl. The bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system. Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, and octahydrobenzofuranyl. Heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5 or 6 membered monocyclic heterocyclyl ring fused to phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted by one or two groups which are independently oxo or thia. 
         [0259]    The term “oxo” as used herein means a ═O group. 
         [0260]    The term “saturated” as used herein means the referenced chemical structure does not contain any multiple carbon-carbon bonds. For example, a saturated cycloalkyl group as defined herein includes cyclohexyl, cyclopropyl, and the like. 
         [0261]    The term “thia” as used herein means a ═S group. 
         [0262]    The term “unsaturated” as used herein means the referenced chemical structure contains at least one multiple carbon-carbon bond, but is not aromatic. For example, a unsaturated cycloalkyl group as defined herein includes cyclohexenyl, cyclopentenyl, cyclohexadienyl, and the like. 
       EXAMPLES 
     Analytical Methods 
       [0263]    NMR spectra were recorded on a Bruker Avance-400 NMR or Bruker Avance-300 NMR or with samples in solution in deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD) or deuterated dimethyl sulfoxide (DMSO-d6). Chemical shifts and coupling constants are respectively expressed in part per million (ppm) and in Herz (Hz). Mass spectrometry (MS) analyses were performed on an Agilent MSD G1946D or a Waters TQD with electrospray ionization (ESI). High resolution mass spectrometry (High-Res MS) analyses were recorded on a Shimadzu IT-TOF apparatus. 
         [0264]    The following acronyms and abbreviations are used in the following examples: 
         [0000]    
       
         
               
               
               
             
           
               
                   
                   
               
             
             
               
                   
                 ACN 
                 Acetonitrile 
               
               
                   
                 Boc or BOC 
                 t-butoxycarbonyl 
               
               
                   
                 DMF 
                 N,N-dimethylformamide 
               
               
                   
                 DMSO 
                 Dimethylsulfoxide 
               
               
                   
                 ESI-MS 
                 electrospray ionization mass spectrometry 
               
               
                   
                 HPLC 
                 High-performance liquid chromatography 
               
               
                   
                 LCMS 
                 Liquid chromatography-mass spectrometry 
               
               
                   
                 MeOH 
                 methanol 
               
               
                   
                 nBuLi 
                 n-butyl lithium 
               
               
                   
                 NMR 
                 Nuclear magnetic resonance 
               
               
                   
                 Ph 
                 Phenyl 
               
               
                   
                 TFA 
                 Trifluoroacetic acid 
               
               
                   
                 THF 
                 Tetrahydrofuran 
               
               
                   
                   
               
             
          
         
       
     
       Synthetic Procedures and Analytical Data 
     Preparation of Scaffolds 
       [0265]    
       
                 
         
             
             
         
       
     
         [0266]    Scaffolds ethyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylate (Scaffold A) and methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylate (Scaffold B) were prepared synthetically. Scaffold ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-quinolizine-3-carboxylate (Scaffold C) was purchased from Beijing Louston Fine Chemical Co. Ltd., China. 
       Preparation of scaffold A ethyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylate 
     Preparation of 2-bromo-3-methyl-4-chloro-pyridine 
       [0267]    
       
                 
         
             
             
         
       
     
         [0268]    To a solution of 2,2,6,6-tetramethyl-pyridine (21.1 mL, 125 mmol) in freshly distilled THF (120 mL) at −78° C. was added nBuLi (50 mL, 125 mmol) in 30 min. The resulting mixture was stirred at −78° C. for 30 min and was added through a cannula over 30 min to a solution of 3-bromo-4-chloro-pyridine (20.0 g, 104 mmol) in freshly distilled THF (60 mL) that had been cooled to −78° C. prior to the addition. The reaction mixture was stirred at −78° C. for 30 min before iodomethane (7.78 mL, 125 mmol) was added over a period of 10 min. The reaction was stirred at −78° C. for 30 min and was allowed to warm up to room temperature prior to be quenched with aqueous NH 4 Cl (65 mL). The aqueous phase was extracted with ethyl acetate (2×150 mL). The organic phases were separated, dried, and concentrated. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 5:1) to afford the title compound as a yellow solid (10.6 g, 49%).  1 H NMR (CDCl 3 , 300 MHz) δ ppm: 8.10 (d, J=5.1 Hz, 1H), 7.27 (d, J=5.1 Hz, 1H), 2.51 (s, 3H). 
       Preparation of (3-methyl-4-chloro-pyridin-2-yl)-cyclopropyl-methanol 
       [0269]    
       
                 
         
             
             
         
       
     
         [0270]    A solution of 2-bromo-3-methyl-4-chloro-pyridine (10.6 g, 57.1 mmol) in freshly distilled THF (120 mL) was cooled down to 0° C. and treated with isopropyl magnesium chloride (45.7 mL, 2.0 M in THF, 91.5 mmol). The resulting mixture was stirred at room temperature for 3 h then cooled to −5° C. Cyclopropane carboxaldehyde (6.83 mL, 91.5 mmol) was added. The reaction mixture was stirred at room temperature for 1 h and quenched by adding water (100 mL), and extracted with ethyl acetate (2×150 mL). The organic phase was separated, dried, and concentrated. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 3:1) to afford the title compound as a yellow oil (7.01 g, 62%). ESI-MS m/z: 198 (M+H) + ;  1 H NMR (CDCl 3 , 300 MHz) δ ppm: 8.28 (d, J=5.4 Hz, 1H), 7.26 (d, J=5.4 Hz, 1H), 4.79 (d, J=5.4 Hz, 1H), 4.55 (br, s, 1H), 2.39 (s, 3H), 1.10-1.28 (m, 1H), 0.58-0.41 (m, 4H). 
       Preparation of (3-methyl-4-chloro-pyridin-2-yl)-cyclopropyl-methanone 
       [0271]    
       
                 
         
             
             
         
       
     
         [0272]    A solution of (3-methyl-4-chloro-pyridin-2-yl)-cyclopropyl-methanol (7.01 g, 35.5 mmol) in dichloromethane (80 mL) was treated with MnO 2  (30.8 g, 355 mmol) at room temperature overnight. The reaction mixture was filtered through a pad of Celite and the filtrate was concentrated to dryness, affording the title compound (6.82 g, 98%). ESI-MS m/z: 196 (M+H) + ;  1 H NMR (CDCl 3 , 300 MHz) δ ppm: 8.41 (d, J=5.4 Hz, 1H), 7.42 (d, J=5.4 Hz, 1H), 2.96-3.04 (m, 1H), 2.57 (s, 3H), 1.20-1.28 (m, 2H), 1.14-1.09 (m, 2H). 
       Preparation of 2-(1-cyclopropyl-2-methoxy-vinyl)-3-methyl-4-chloro-pyridine 
       [0273]    
       
                 
         
             
             
         
       
     
         [0274]    A solution of methoxymethyl triphenylphosphonium chloride (17.9 g, 52.3 mmol) in dry THF (80 mL) was treated with NaH (2.79 g, 69.8 mmol) at 0° C. for 3 h. To this mixture was added a solution of (3-methyl-4-chloro-pyridin-2-yl)-cyclopropyl-methanone (6.82 g, 34.9 mmol) in dry THF (20 mL). The reaction mixture was heated at 40° C. overnight. The reaction mixture was cooled down to room temperature and filtered. The filtrate was concentrated to dryness. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 3:1) to afford the title compound (6.41 g, 82%). ESI-MS m/z: 224 (M+H) + ;  1 H NMR (CDCl 3 , 300 MHz) δ ppm: 8.31 (d, J=5.4 Hz, 0.5; H), 8.23 (d, J=5.4 Hz, 0.5; H), 7.17 (d, J=5.4 Hz, 1H), 6.13-6.16 (m, 1H), 3.70 (s, 1.5; H), 3.56 (s, 1.5; H), 2.38 (s, 1.5; H), 2.31 (s, 1.5; H), 1.91-1.94 (m, 0.5; H), 1.63-1.65 (m, 0.5; H), 0.66-0.72 (m, 1H), 0.56-0.62 (m, 1H), 0.35-0.38 (m, 1H), 0.26-0.33 (m, 1H). 
       Preparation of 2-(3-methyl-4-chloro-pyridin-2-yl)-2-cyclopropyl-acetaldehyde 
       [0275]    
       
                 
         
             
             
         
       
     
         [0276]    A solution of 2-(1-cyclopropyl-2-methoxy-vinyl)-3-methyl-4-chloro-pyridine (6.41 g, 28.7 mmol) in acetic acid (50 mL) was treated with sulfuric acid (6.52 mL, 143 mmol) at room temperature overnight. The reaction mixture was neutralized with 2N NaOH to pH 8-9 extracted with ethyl acetate (2×100 mL). The organic phases were combined, dried, and concentrated. The residue was purified by flash silica column chromatography (hexane/ethyl acetate=2:1) to afford the title compound as a yellow solid (4.83 g, 80%). ESI-MS m/z: 210 (M+H) + ;  1 H NMR (CDCl 3 , 300 MHz) δ ppm: 9.89 (d, J=2.4 Hz, 1H), 8.35 (d, J=5.1 Hz, 1H), 7.26 (d, J=5.4 Hz, 1H), 3.26-3.28 (m, 1H), 2.35 (s, 3H), 1.53-1.59 (m, 1H), 0.55-0.79 (m, 2H), 0.25-0.39 (m, 2H). 
       Preparation of 2-[2-(3-methyl-4-chloro-pyridin-2-yl)-2-cyclopropyl-ethylidene]-malonic acid diethyl ester 
       [0277]    
       
                 
         
             
             
         
       
     
         [0278]    A mixture of (3-methyl-4-chloro-pyridin-2-yl)-cyclopropyl-acetaldehyde (4.83 g, 23.0 mmol), diethyl malonate (7.02 g, 43.8 mmol), piperidine (3.62 mL, 36.6 mmol), and acetic acid (4.19 mL, 73.2 mmol) in ethanol (100 mL) was heated to reflux overnight. The reaction mixture was concentrated to dryness. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 4:1) to afford the title compound as a yellow oil (5.76 g, 71%). ESI-MS m/z: 352 (M+H) + . 
       Preparation of ethyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0279]    
       
                 
         
             
             
         
       
     
         [0280]    A solution of 2-[2-(3-methyl-4-chloro-pyridin-2-yl)-2-cyclopropyl-ethylidene]-malonic acid diethyl ester (5.76 g, 16.4 mmol) in Dowtherm A (80 mL) was heated in a preheated oil bath at 230° C. for 15 min. The reaction mixture was cooled to room temperature and purified by flash silica column chromatography (hexane:ethyl acetate, 2:1 to 1:2) to afford the title compound as a yellow solid (3.76 g, 75%). ESI-MS m/z: 306 (M+H) + ;  1 H NMR (CDCl 3 , 300 MHz) δ ppm: 9.34 (d, J=7.8 Hz, 1H), 8.40 (s, 1H), 7.12 (d, J=7.8 Hz, 1H), 4.41 (q, 2H), 3.00 (s, 3H), 2.28-2.33 (m, 1H), 1.42 (t, 3H), 1.03-1.08 (m, 2H), 0.71-0.76 (m, 2H). 
       Preparation of scaffold B methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylate 
     Preparation of scaffold methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylate 
       [0281]    
       
                 
         
             
             
         
       
     
         [0282]    Piperidine (7 mL, 70.9 mmol) and acetic acid (5.5 mL, 95 mmol) were added to a solution of 2-(3-methyl-4-chloro-pyridin-2-yl)-2-cyclopropyl-acetaldehyde (4.98 g, 23.75 mmol) in absolute ethanol (200 mL). Dimethyl malonate (16.44 mL, 144 mmol) was added and the reaction mixture was stirred at 100° C. for 5 h (the reaction mixture turned into a red solution). The solvent was evaporated under reduced pressure. The resulting mixture was diluted with ether (100 mL) and washed with water (100 mL) and brine (50 mL). The organic layer was separated and dried over sodium sulfate. The mixture was evaporated to dryness. Dowtherm A (110 mL) was added. This reaction mixture was heated to 240° C. under microwave irradiation and stirred at this temperature for 0.5 h during which the reaction mixture turned into a black solution. The residue was purified by reversed phase flash chromatography using a 5%-100% acetonitrile gradient in water with 1% TFA yielding the cyclized methyl ester (4 g, 51.4%). ESI-MS m/z: 292 (M+H) + ;  1 H NMR (400 MHz, CDCl 3 ) δ ppm: 9.34 (d, J=7.8 Hz, 1H), 8.42 (s, 1H), 7.13 (d, J=7.8 Hz, 1H), 3.95 (s, 1H), 3.01 (s, 1H), 2.35-2.27 (m, 1H), 1.03-1.08 (m, 2H), 0.72-0.76 (m, 2H);  13 C NMR (100 MHz CDCl 3 ) δ ppm 166.6, 155.4, 148.4, 145.5, 142.3, 130.7, 129.0, 117.6, 115.6, 105.4, 52.3, 19.6, 17.0, 9.9 (2CH2). 
       Preparation of Examples 
       [0283]    Most of the examples were prepared according to the general procedures described below. The preparation of the other examples is otherwise reported specifically in the experimental section. 
         [0284]    General Procedure A: 
         [0285]    The quinolizine scaffold (1 eq.), boronate (1.3 eq.) and cesium carbonate (3 eq.) were added to a 3:1 mixture of 1,2-dimethoxyethane and water. The mixture was degassed with argon. 1,1′-Bis-diphenylphosphine ferrocene palladium(II) dichloride (0.1 eq.) was added and the mixture was heated at 90° C. under an argon atmosphere for 1 h. The reaction mixture was cooled. The mixture was diluted with CH 2 Cl 2  (3 mL) and water was added (3 mL). The layers were separated using a phase separator and the aqueous layer was extracted with CH 2 Cl 2  (2×5 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash silica column chromatography and dried in vacuo to afford the desired product. 
         [0286]    General Procedure B: 
         [0287]    The ester intermediate (1 eq.) was added to a solution of lithium hydroxide (2 eq.) in a 1:1 mixture of tetrahydrofuran and water. The reaction mixture was stirred for 18 h at 30° C. The mixture was acidified using 1M HCl in water. The precipitate was filtered off and dried in vacuo to afford the desired product. 
         [0288]    General Procedure C: 
         [0289]    The Boc-protected amine intermediate (1 eq.) was suspended in CH 2 Cl 2  and 1 M HCl in diethyl ether (20 eq.) was added. The reaction mixture was stirred for 16 h. The precipitate was filtered off and dried in vacuo to afford the desired product. 
         [0290]    General Procedure D: 
         [0291]    The free acid (1 eq.) was added to a solution of potassium hydroxide (1.1 eq.) in water and stirred for 1 h. The solution was lyophilized to obtain the desired product. 
       Example 1 
     Preparation of ethyl 8-(4-amino-3-fluoro-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0292]    
       
                 
         
             
             
         
       
     
         [0293]    Ethyl 8-(4-amino-3-fluoro-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (149 mg, 0.46 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (134 mg, 0.58 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (18 mg, 10%). ESI-MS m/z: 399 (M+H) + . 
       Preparation of EXAMPLE 1 8-(4-amino-3-fluoro-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0294]    
       
                 
         
             
             
         
       
     
         [0295]    8-(4-Amino-3-fluoro-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using ethyl 8-(4-amino-3-fluoro-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (24 mg, 0.06 mmol) to afford the title compound EXAMPLE 1 as a yellow solid (19 mg, 85%). ESI-MS m/z: 371 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 13.99 (br s, 1H), 9.32 (s, 1H), 8.22 (s, 1H), 7.3-6.8 (m, 3H), 5.73 (s, 2H), 2.84 (s, 3H), 2.6-2.5 (m, 1H), 1.04-1.08 (m, 2H), 0.76-0.80 (m, 2H). 
       Preparation of potassium 8-(4-amino-3-fluoro-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0296]    
       
                 
         
             
             
         
       
     
         [0297]    Potassium 8-(4-amino-3-fluorop-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure D using 8-(4-amino-3-fluoro-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid (250 mg, 0.68 mmol) and potassium hydroxide to afford the title compound K salt of EXAMPLE 1 as a yellow solid (276 mg, 90%). ESI-MS m/z: 371 (M−K +  H) + . 
       Example 2 
     Preparation of methyl 8-(4-amino-3-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0298]    
       
                 
         
             
             
         
       
     
         [0299]    Methyl 8-(4-amino-3-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (200 mg, 0.68 mmol) and 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (195 mg, 0.82 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (191 mg, 76%). ESI-MS m/z: 367 (M+H) + . 
       Preparation of EXAMPLE 2 8-(4-amino-3-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0300]    
       
                 
         
             
             
         
       
     
         [0301]    8-(4-Amino-3-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 8-(4-amino-3-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (191 mg, 0.52 mmol) to afford the title compound EXAMPLE 2 as a yellow solid (135 mg, 73%). ESI-MS m/z: 353 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 14.05 (br s, 1H), 9.55 (d, J=7.3 Hz, 1H), 8.21 (s, 1H), 7.57 (d, J=7.3 Hz, 1H), 7.16-7.34 (m, 2H), 6.92 (t, J=8.8 Hz, 1H), 5.74 (s, 2H), 2.89 (s, 3H), 2.50-2.70 (m, 1H), 1.02-1.05 (m, 2H), 0.73-0.80 (m, 2H). 
       Preparation of potassium 8-(4-amino-3-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0302]    
       
                 
         
             
             
         
       
     
         [0303]    Potassium 8-(4-amino-3-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure D using 8-(4-amino-3-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid (EXAMPLE 2) (260 mg, 0.74 mmol) to afford the title compound K salt of EXAMPLE 2 as a yellow solid (288 mg, 98%). ESI-MS m/z: 353 (M−K +  H) + . 
       Example 3 
     Preparation of methyl 8-(3-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0304]    
       
                 
         
             
             
         
       
     
         [0305]    Methyl 8-(3-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (195 mg, 0.66 mmol) and (3-aminophenyl)-boronic acid (119 mg, 0.87 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (91 mg, 39%). ESI-MS m/z: 349 (M+H) + . 
       Preparation of EXAMPLE 3 8-(3-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0306]    
       
                 
         
             
             
         
       
     
         [0307]    8-(3-Amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 8-(3-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (91 mg, 0.26 mmol) to afford the title compound EXAMPLE 3 as a yellow solid (62.4 mg, 72%). ESI-MS m/z: 335 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 14.20 (br s, 1H), 9.32 (d, J=7.3 Hz, 1H), 8.26 (s, 1H), 7.52 (d, J=7.3 Hz, 1H), 7.35-7.53 (m, 1H), 6.82-6.93 (m, 3H), 2.86 (s, 3H), 2.50-2.60 (m, 1H), 1.00-1.10 (m, 2H), 0.75-0.85 (m, 2H). 
       Example 4 
     Preparation of ethyl 8-(3-amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0308]    
       
                 
         
             
             
         
       
     
         [0309]    Ethyl 8-(3-amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (102.5 mg, 0.32 mmol) and (3-amino-phenyl)-boronic acid (54.8 mg, 0.40 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (30 mg, 25%). ESI-MS m/z: 381 (M+H) + . 
       Preparation of EXAMPLE 4 8-(3-amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0310]    
       
                 
         
             
             
         
       
     
         [0311]    8-(3-Amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using ethyl 8-(3-amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (140 mg, 0.37 mmol) to afford the title compound EXAMPLE 4 as a yellow solid (30 mg, 25%). ESI-MS m/z: 353 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.35 (d, J=5.8 Hz, 1H), 8.25 (s, 1H), 7.22 (t, J=7.6 Hz, 1H), 6.71 (dd, J=1.6 Hz and J=8.1 Hz, 1H), 6.57 (s, 1H), 6.51 (d, J=7.6 Hz, 1H), 5.40 (br s, 2H), 2.82 (s, 3H), 2.53-2.63 (m, 1H), 1.04-1.07 (m, 2H), 0.76-0.78 (m, 2H). 
       Example 5 
     Preparation of ethyl 8-(4-amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0312]    
       
                 
         
             
             
         
       
     
         [0313]    Ethyl 8-(4-amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.54 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (439 mg, 2.00 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (550 mg, 93%). ESI-MS m/z: 381 (M+H) + . 
       Preparation of EXAMPLE 5 8-(4-amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0314]    
       
                 
         
             
             
         
       
     
         [0315]    8-(4-Amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using ethyl 8-(4-amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (550 mg, 1.45 mmol) to afford the title compound EXAMPLE 5 as a yellow solid (435 mg, 85%). ESI-MS m/z: 353 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 13.95-14.02 (m, 1H), 9.32 (d, J=5.8 Hz, 1H), 8.21 (s, 1H), 7.21 (d, J=6.8 Hz, 2H), 6.79 (d, J=8.3 Hz, 2H), 2.85 (s, 3H), 2.50-2.60 (m, 1H), 1.05-1.07 (m, 2H), 0.76-0.78 (m, 2H). 
       Preparation of potassium 8-(4-amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0316]    
       
                 
         
             
             
         
       
     
         [0317]    Potassium 8-(4-amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure D using 8-(4-amino-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid (460 mg, 0.74 mmol) to afford the title compound K salt of EXAMPLE 5 as a yellow solid (510 mg, 100%). ESI-MS m/z: 353 (M−K +  H) + . 
       Example 6 
     Preparation of ethyl 8-(4-carbamoyl-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0318]    
       
                 
         
             
             
         
       
     
         [0319]    Ethyl 8-(4-carbamoyl-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.54 mmol) and (4-carbamoyl-phenyl)-boronic acid (305.7 mg, 1.85 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (540 mg, 85%). ESI-MS m/z: 409 (M+H) + , 453 (M+HCOO) − . 
       Preparation of EXAMPLE 6 8-(4-carbamoyl-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0320]    
       
                 
         
             
             
         
       
     
         [0321]    8-(4-Carbamoyl-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using ethyl 8-(4-carbamoyl-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (540 mg, 1.32 mmol) and reacted for 10 days at 30° C. to afford the title compound EXAMPLE 6 as a yellow solid: (360 mg, 71%). ESI-MS m/z: 381 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 13.94 (s, 1H), 9.42 (d, J=5.6 Hz, 1H), 8.28 (s, 1H), 8.16 (s, 1H), 8.08 (d, J=8.1 Hz, 2H), 7.57-7.60 (m, 3H), 2.80 (s, 3H), 2.50-2.60 (m, 1H), 1.06-1.08 (m, 2H), 0.76-0.80 (m, 2H). 
       Preparation of potassium 8-(4-carbamoyl-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0322]    
       
                 
         
             
             
         
       
     
         [0323]    Potassium 8-(4-carbamoyl-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure D using 8-(4-carbamoyl-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid (310 mg, 0.82 mmol) to afford the title compound K salt of EXAMPLE 6 as a yellow solid (345 mg, 100%). ESI-MS m/z: 381 (M−K +  H) + . 
       Example 7 
     Preparation of methyl 8-(4-amino-2-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0324]    
       
                 
         
             
             
         
       
     
         [0325]    Methyl 8-(4-amino-2-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (122 mg, 0.51 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (87 mg, 64%). ESI-MS m/z: 367 (M+H) + . 
       Preparation of EXAMPLE 7 8-(4-amino-2-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0326]    
       
                 
         
             
             
         
       
     
         [0327]    8-(4-Amino-2-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 8-(4-amino-2-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (87 mg, 0.24 mmol) to afford the title compound EXAMPLE 7 as a yellow solid (50 mg, 59%). ESI-MS m/z: 353 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.27 (d, J=7.3 Hz, 1H), 8.27 (s, 1H), 7.48 (s, 1H), 7.18 (t, J=8.6 Hz, 1H), 6.57 (dd, J=8.3 Hz, J=1.8 Hz, 1H), 6.49 (dd, J=13.4 Hz, J=1.8 Hz, 1H), 5.92 (s, 2H), 2.80 (s, 3H), 2.40-2.60 (m, 1H), 1.03-1.06 (m, 2H), 0.70-0.72 (m, 2H). 
       Example 8 
     Preparation of methyl 8-(3-amino-4-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0328]    
       
                 
         
             
             
         
       
     
         [0329]    Methyl 8-(3-amino-4-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (122 mg, 0.51 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (128 mg, 98%). ESI-MS m/z: 367 (M+H) + . 
       Preparation of EXAMPLE 8 8-(3-amino-4-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0330]    
       
                 
         
             
             
         
       
     
         [0331]    8-(3-Amino-4-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 8-(3-amino-4-fluorophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (123 mg, 0.35 mmol) to afford the title compound EXAMPLE 8 as a yellow solid (EXAMPLE 8) (60 mg, 49%). ESI-MS m/z: 353 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.31 (d, J=7.3 Hz, 1H), 8.26 (s, 1H), 7.50 (d, J=7.3 Hz, 1H), 7.18 (dd, J=8.3 Hz, J=11.4 Hz, 1H), 6.89 (dd, J=2.0 Hz, J=8.6 Hz, 1H), 6.63-6.67 (m, 1H), 5.44 (s, 2H), 2.85 (s, 3H), 2.40-2.54 (m, 1H), 1.04-1.07 (m, 2H), 0.76-0.78 (m, 2H). 
       Example 9 
     Preparation of methyl 8-(3-amino-5-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0332]    
       
                 
         
             
             
         
       
     
         [0333]    Methyl 8-(3-amino-5-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 3-amino-5-fluoro-phenyl-boronic acid (80 mg, 0.51 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (108 mg, 81%). ESI-MS m/z: 367 (M+H) + . 
       Preparation of EXAMPLE 9 8-(3-amino-5-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0334]    
       
                 
         
             
             
         
       
     
         [0335]    8-(3-Amino-5-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 8-(3-amino-5-fluorophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (108 mg, 0.29 mmol) to afford the title compound EXAMPLE 9 as a yellow solid (69 mg, 67%). ESI-MS m/z: 353 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.22 (d, J=7.3 Hz, 1H), 8.48 (s, 1H), 7.19 (d, J=7.6 Hz, 1H), 6.36-6.44 (m, 3H), 6.68 (s, 2H), 2.81 (s, 3H), 2.40-2.50 (m, 1H), 1.02-1.04 (m, 2H), 0.70-0.72 (m, 2H). 
       Example 10 
     Preparation of methyl 1-cyclopropyl-8-(3-fluoro-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0336]    
       
                 
         
             
             
         
       
     
         [0337]    Methyl 1-cyclopropyl-8-(3-fluoro-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 3-fluoro-phenyl-boronic acid (71 mg, 0.51 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (96 mg, 77%). ESI-MS m/z: 352 (M+H) + . 
       Preparation of EXAMPLE 10 1-cyclopropyl-8-(3-fluoro-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0338]    
       
                 
         
             
             
         
       
     
         [0339]    1-Cyclopropyl-8-(3-fluoro-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 1-cyclopropyl-8-(3-fluoro-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (96 mg, 0.27 mmol) to afford the title compound EXAMPLE 10 as a yellow solid (21 mg, 23%). ESI-MS m/z: 338 (M+H) + ; 1H NMR (400 MHz, DMSO-d6) δ ppm: 9.34 (d, J=7.3 Hz, 1H), 8.28 (s, 1H), 7.57-7.65 (m, 2H), 7.39-7.47 (m, 3H), 2.86 (s, 3H), 2.40-2.50 (m, 1H), 1.07-1.09 (m, 2H), 0.80-0.82 (m, 2H). 
       Example 11 
     Preparation of methyl 8-(4-amino-3-chloro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0340]    
       
                 
         
             
             
         
       
     
         [0341]    Methyl 8-(4-amino-3-chloro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (76 mg, 0.26 mmol) and 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (78 mg, 0.31 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (63 mg, 62%). ESI-MS m/z: 387 (M+H) + . 
       Preparation of EXAMPLE 11 8-(4-amino-3-chloro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0342]    
       
                 
         
             
             
         
       
     
         [0343]    8-(4-Amino-3-chloro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 8-(4-amino-3-chloro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (63 mg, 0.16 mmol) to afford the title compound EXAMPLE 11 as a yellow solid (37 mg, 62%). ESI-MS m/z: 369 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.21 (d, J=7.3 Hz, 1H), 8.38 (s, 1H), 7.43 (s, 1H), 7.30 (s, 1H), 7.26 (d, J=14.5 Hz, 1H), 6.94 (d, J=8.3 Hz, 1H), 5.82 (s, 2H), 2.85 (s, 3H), 2.40-2.50 (m, 1H), 1.04-1.06 (m, 2H), 0.72-0.74 (m, 2H). 
       Example 12 
     Preparation of methyl 8-(4-amino-3-methoxy-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0344]    
       
                 
         
             
             
         
       
     
         [0345]    Methyl 8-(4-amino-3-methoxy-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (76 mg, 0.26 mmol) and 2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (78 mg, 0.31 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (41 mg, 40%). ESI-MS m/z: 379 (M+H) + . 
       Preparation of EXAMPLE 12 8-(4-amino-3-methoxy-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0346]    
       
                 
         
             
             
         
       
     
         [0347]    8-(4-Amino-3-methoxy-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 8-(4-amino-3-methoxy-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (41 mg, 0.11 mmol) to afford the title compound EXAMPLE 12 as a yellow solid (29 mg, 92%). ESI-MS m/z: 365 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.27 (d, J=7.3 Hz, 1H), 8.19 (s, 1H), 7.43 (d, J=7.3 Hz, 1H), 7.03 (s, 1H), 6.99 (dd, J=1.8 Hz, J=8.1 Hz, 1H), 6.80 (d, J=8.1 Hz, 1H), 5.38 (s, 2H), 3.86 (s, 3H), 2.92 (s, 3H), 2.40-2.54 (m, 1H), 1.06-1.10 (m, 2H), 0.76-0.80 (m, 2H). 
       Example 13 
     Preparation of methyl 8-(4-acetamido-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0348]    
       
                 
         
             
             
         
       
     
         [0349]    Methyl 8-(4-acetamido-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (77 mg, 0.26 mmol) and (4-acetamido-phenyl)-boronic acid (56 mg, 0.31 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (93 mg, 90%). ESI-MS m/z: 391 (M+H) + . 
       Preparation of EXAMPLE 13 8-(4-acetamido-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0350]    
       
                 
         
             
             
         
       
     
         [0351]    8-(4-Acetamido-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure: using methyl 8-(4-acetamido-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (93 mg, 0.24 mmol) to afford the title compound EXAMPLE 13 as a yellow solid (45 mg, 50%). ESI-MS m/z: 377 (M+H) + ; 1H NMR (400 MHz, DMSO-d6) δ ppm: 10.20 (s, 1H), 9.32 (d, J=7.3 Hz, 1H), 8.25 (s, 1H), 7.79 (d, J=8.4 Hz, 2H), 7.58 (d, J=7.3 Hz, 1H), 7.53 (d, J=8.1 Hz, 2H), 2.88 (s, 3H), 2.40-2.54 (m, 1H), 2.10 (s, 3H), 1.07-1.09 (m, 2H), 0.77-0.79 (m, 2H). 
       Example 14 
     Preparation of methyl 1-cyclopropyl-9-methyl-8-(4-(methylsulfonamido)-phenyl)-4-oxo-4H-quinolizine-3-carboxylate 
       [0352]    
       
                 
         
             
             
         
       
     
         [0353]    Methyl 1-cyclopropyl-9-methyl-8-(4-(methylsulfonamido)-phenyl)-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (74 mg, 0.25 mmol) and N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)-methane-sulfonamide (96 mg, 0.32 mmol). Compound precipitated from solution and was filtered off and dried in vacuo to afford the title compound as a yellow solid (83 mg, 77%). ESI-MS m/z: 427 (M+H) + . 
       Preparation of EXAMPLE 14 1-cyclopropyl-9-methyl-8-(4-(methylsulfonamido)-phenyl)-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0354]    
       
                 
         
             
             
         
       
     
         [0355]    1-Cyclopropyl-9-methyl-8-(4-(methylsulfonamido)-phenyl)-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 1-cyclopropyl-9-methyl-8-(4-(methylsulfonamido)-phenyl)-4-oxo-4H-quinolizine-3-carboxylate (83 mg, 0.20 mmol) to afford the title compound EXAMPLE 14 as a yellow solid (53 mg, 64%). ESI-MS m/z: 413 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 10.1 (s, 1H), 9.33 (d, J=7.3 Hz, 1H), 8.26 (s, 1H), 7.55-7.58 (m, 3H), 7.39 (d, J=8.6 Hz, 2H), 3.11 (s, 3H), 2.88 (s, 3H), 2.40-2.55 (m, 1H), 1.06-1.09 (m, 2H), 0.78-0.80 (m, 2H). 
       Example 15 
     Preparation of methyl 1-cyclopropyl-9-methyl-8-(4-(methylamino)-phenyl)-4-oxo-4H-quinolizine-3-carboxylate 
       [0356]    
       
                 
         
             
             
         
       
     
         [0357]    Methyl 1-cyclopropyl-9-methyl-8-(4-(methylamino)-phenyl)-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (74 mg, 0.25 mmol) and N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (71 mg, 0.31 mmol). 
         [0358]    Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (81 mg, 81%). ESI-MS m/z: 363 (M+H) + . 
       Preparation of EXAMPLE 15 1-cyclopropyl-9-methyl-8-(4-(methylamino)-phenyl)-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0359]    
       
                 
         
             
             
         
       
     
         [0360]    1-Cyclopropyl-9-methyl-8-(4-(methylamino)-phenyl)-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 1-cyclopropyl-9-methyl-8-(4-(methylamino)-phenyl)-4-oxo-4H-quinolizine-3-carboxylate (81 mg, 0.22 mmol) to afford the title compound EXAMPLE 15 as a yellow solid (55 mg, 72%). ESI-MS m/z: 349 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.27 (d, J=7.3 Hz, 1H), 8.20 (s, 1H), 9.59 (d, J=7.3 Hz, 1H), 7.39 (d, J=8.6 Hz, 2H), 6.70 (d, J=8.6 Hz, 2H), 6.28 (d, J=5.1 Hz, 1H), 2.90 (s, 3H), 2.76 (d, J=4.8 Hz, 3H), 2.40-2.52 (m, 1H), 1.06-1.08 (m, 2H), 0.75-0.77 (m, 2H). 
       Example 16 
     Preparation of methyl 1-cyclopropyl-9-methyl-4-oxo-8-(pyridin-4-yl)-4H-quinolizine-3-carboxylate 
       [0361]    
       
                 
         
             
             
         
       
     
         [0362]    Methyl 1-cyclopropyl-9-methyl-4-oxo-8-(pyridin-4-yl)-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.71 mmol) and pyridin-4-yl-boronic acid (253 mg, 2.05 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (400 mg, 69%). ESI-MS m/z: 373 (M+K) + , 357 (M+Na) + , 335 (M+H) + . 
       Preparation of EXAMPLE 16 1-cyclopropyl-9-methyl-4-oxo-8-(pyridin-4-yl)-4H-quinolizine-3-carboxylic acid 
       [0363]    
       
                 
         
             
             
         
       
     
         [0364]    1-Cyclopropyl-9-methyl-4-oxo-8-(pyridin-4-yl)-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 1-cyclopropyl-9-methyl-4-oxo-8-(pyridin-4-yl)-4H-quinolizine-3-carboxylate (400 mg, 1.20 mmol) to afford the title compound EXAMPLE 16 as a yellow solid (262 mg, 68%). ESI-MS m/z: 321 (M+H) + ; 1H NMR (400 MHz, DMSO-d6) δ ppm: 14.05 (s, 1H), 9.36 (d, J=7.3 Hz, 1H), 8.79 (d, J=5.8 Hz, 2H), 8.30 (s, 1H), 7.55-7.59 (m, 3H), 2.83 s, (3H), 2.50-2.60 (m, 1H), 1.05-1.10 (m, 2H), 0.79-0.84 (m, 2H). 
       Preparation of potassium 1-cyclopropyl-9-methyl-4-oxo-8-(pyridin-4-yl)-4H-quinolizine-3-carboxylate 
       [0365]    
       
                 
         
             
             
         
       
     
         [0366]    Potassium 1-cyclopropyl-9-methyl-4-oxo-8-(pyridin-4-yl)-4H-quinolizine-3-carboxylate was prepared according to General Procedure D using 1-cyclopropyl-9-methyl-4-oxo-8-(pyridin-4-yl)-4H-quinolizine-3-carboxylic acid (EXAMPLE 16) (250 mg, 0.78 mmol) to afford the K salt of title compound EXAMPLE 16 as a yellow solid (290 mg, 100%). ESI-MS m/z: 321 (M−K +  H) + ;  1 H NMR (400 MHz, CD 3 OD) δ ppm: 9.43 (d, J=7.3 Hz, 1H), 8.72 (d, J=5.8 Hz, 2H), 8.62 (s, 1H), 7.58 (d, J=5.8 Hz, 2H), 7.20 (d, J=3.6 Hz, 2H), 2.87 (s, 3H), 2.46-2.53 (m, 1H), 0.80-1.10 (m, 2H), 0.84-0.86 (m, 2H). 
       Example 17 
     Preparation of methyl 1-cyclopropyl-9-methyl-4-oxo-8-(pyridin-3-yl)-4H-quinolizine-3-carboxylate 
       [0367]    
       
                 
         
             
             
         
       
     
         [0368]    Methyl 1-cyclopropyl-9-methyl-4-oxo-8-(pyridin-3-yl)-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and pyridin-3-ylboronic acid (63 mg, 0.51 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (100 mg, 87%). ESI-MS m/z: 335 (M+H) + . 
       Preparation of EXAMPLE 17 1-cyclopropyl-9-methyl-4-oxo-8-(pyridin-3-yl)-4H-quinolizine-3-carboxylic acid 
       [0369]    
       
                 
         
             
             
         
       
     
         [0370]    1-Cyclopropyl-9-methyl-4-oxo-8-(pyridin-3-yl)-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 1-cyclopropyl-9-methyl-4-oxo-8-(pyridin-3-yl)-4H-quinolizine-3-carboxylate (100 mg, 0.30 mmol) to afford the title compound EXAMPLE 17 as a yellow solid (84 mg, 87%). ESI-MS m/z: 321 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.35 (d, J=7.3 Hz, 1H), 8.73-8.78 (s, 2H), 8.28 (s, 1H), 8.02-8.05 (m, 1H), 7.61-7.65 (m, 2H), 2.86 (s, 3H), 2.40-2.54 (m, 1H), 1.06-1.10 (m, 2H), 0.80-0.83 (m, 2H). 
       Example 18 
     Preparation of methyl 8-(4-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0371]    
       
                 
         
             
             
         
       
     
         [0372]    Methyl 8-(4-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (150 mg, 0.51 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (135 mg, 0.62 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (25 mg, 14%). ESI-MS m/z: 349 (M+H) + . 
       Preparation of EXAMPLE 18 8-(4-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0373]    
       
                 
         
             
             
         
       
     
         [0374]    8-(4-Amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 8-(4-amino-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (25 mg, 0.07 mmol) to afford the title compound EXAMPLE 18 as a yellow solid (18 mg, 77%). ESI-MS m/z: 335 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 14.11 (s, 1H), 9.24 (d, J=7.1 Hz, 1H), 8.22 (s, 1H), 7.53 (s, 1H), 7.30 (d, J=8.1 Hz, 2H), 6.72 (d, J=8.4 Hz, 2H), 5.67 (s, 2H), 2.89 (s, 3H), 2.40-2.50 (m, 1H), 1.05-1.07 (m, 2H), 0.73-0.75 (m, 2H). 
       Example 19 
     Preparation of 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline 
       [0375]    
       
                 
         
             
             
         
       
     
         [0376]    Potassium acetate (317 mg, 3.22 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (300 mg, 1.18 mmol) and 4-bromo-2-methyl-aniline (200 mg, 1.08 mmol) were dissolved in dimethylsulfoxide (3 mL). The reaction mixture was degassed using argon. 1,1′-Bis-diphenylphosphine ferrocene palladium(II) dichloride (24 mg, 0.03 mmol) was added and the reaction mixture was heated at 80° C. for 5 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (20 mL). The organic layer was washed with saturated sodium bicarbonate (20 mL) and brine (20 mL). The organic layer was dried with sodium sulfate, filtered and purified by flash silica column chromatography (heptane:ethyl acetate, 0-40%) to obtain a crude mixture of starting material and product. The mixture was purified using reversed phase column chromatography to obtain the title compound as a clear oil (50 mg, 21%). ESI-MS m/z: 234 (M+H) + . 
       Preparation of methyl 8-(4-amino-3-methyl-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0377]    
       
                 
         
             
             
         
       
     
         [0378]    Methyl 8-(4-amino-3-methyl-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (50 mg, 0.17 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (52 mg, 0.22 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (31 mg, 50%). ESI-MS m/z: 363 (M+H) + . 
       Preparation of EXAMPLE 19 8-(4-amino-3-methyl-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0379]    
       
                 
         
             
             
         
       
     
         [0380]    8-(4-Amino-3-methyl-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 8-(4-amino-3-methyl-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (31 mg, 0.09 mmol) to afford the title compound EXAMPLE 19 as a yellow solid (19 mg, 60%). ESI-MS m/z: 349 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 13.99 (s, 1H), 9.16-9.25 (m, 1H), 8.21-8.34 (m, 1H), 7.52-7.54 (m, 2H), 7.16-7.20 (m, 1H), 6.76 (d, J=8.1 Hz, 1H), 5.43 (s, 2H), 2.99 (s, 3H), 2.89 (s, 3H), 2.40-2.50 (m, 1H), 1.03-1.07 (m, 2H), 0.70-0.75 (m, 2H). 
       Example 20 
     Preparation of methyl 1-cyclopropyl-8-(2-fluoro-pyridin-4-yl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0381]    
       
                 
         
             
             
         
       
     
         [0382]    Methyl 1-cyclopropyl-8-(2-fluoro-pyridin-4-yl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 2-fluoro-pyridin-4-yl-boronic acid (72 mg, 0.51 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (107 mg, 89%). ESI-MS m/z: 353 (M+H) + . 
       Preparation of EXAMPLE 20 1-cyclopropyl-8-(2-fluoro-pyridin-4-yl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0383]    
       
                 
         
             
             
         
       
     
         [0384]    1-Cyclopropyl-8-(2-fluoro-pyridin-4-yl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 1-cyclopropyl-8-(2-fluoro-pyridin-4-yl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (107 mg, 0.30 mmol) to afford the title compound EXAMPLE 20 as a yellow solid (53 mg, 52%). ESI-MS m/z: 339 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.21-9.31 (m, 1H), 8.52 (s, 1H), 8.39-8.47 (m, 1H,), 7.20-7.60 (m, 3H), 2.80 (s, 3H), 2.50-2.60 (m, 1H), 0.98-1.13 (m, 2H), 0.71-0.81 (m, 2H). 
       Example 21 
     Preparation of methyl 8-(6-amino-pyridin-3-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0385]    
       
                 
         
             
             
         
       
     
         [0386]    Methyl 8-(6-amino-pyridin-3-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-2-amine (113 mg, 0.51 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (135 mg, 100%). ESI-MS m/z: 350 (M+H) + . 
       Preparation of EXAMPLE 21 8-(6-amino-pyridin-3-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0387]    
       
                 
         
             
             
         
       
     
         [0388]    8-(6-Amino-pyridin-3-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 8-(6-amino-pyridin-3-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (61 mg, 0.17 mmol) to afford the title compound EXAMPLE 21 as a yellow solid (34 mg, 60%). ESI-MS m/z: 336 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.20 (d, J=7.6 Hz, 1H), 8.47 (s, 1H), 8.33 (s, 1H), 8.12 (s, 1H), 7.60 (dd, J=2.3 Hz, J=8.6 Hz, 1H), 8.29 (d, J=6.6 Hz, 1H), 6.59 (d, J=8.8 Hz, 1H), 6.39 (s, 2H), 2.84 (s, 3H), 2.50-2.60 (m, 1H), 1.23 (s, 2H), 1.03-1.07 (m, 4H) 0.70-0.72 (m, 2H). 
       Preparation of potassium 8-(6-amino-pyridin-3-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0389]    
       
                 
         
             
             
         
       
     
         [0390]    Potassium 8-(6-amino-pyridin-3-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure D using 8-(6-amino-pyridin-3-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid (EXAMPLE 21) (510 mg, 1.52 mmol) to afford the K salt of the title compound as a yellow solid (564 mg, 99%). ESI-MS m/z: 336 (M−K +  H) + . 
       Example 22 
     Preparation of methyl 1-cyclopropyl-8-(1H-indol-5-yl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0391]    
       
                 
         
             
             
         
       
     
         [0392]    Methyl 1-cyclopropyl-8-(1H-indol-5-yl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 1H-indol-5-yl-boronic acid (83 mg, 0.51 mmol) to afford the title compound as a yellow solid (60 mg, 47%). ESI-MS m/z: 373 (M+H) + . 
       Preparation of EXAMPLE 22 1-cyclopropyl-8-(1H-indol-5-yl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0393]    
       
                 
         
             
             
         
       
     
         [0394]    1-Cyclopropyl-8-(1H-indol-5-yl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 1-cyclopropyl-8-(1H-indol-5-yl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (60 mg, 0.16 mmol) to afford the title compound EXAMPLE 22 as a yellow solid (20 mg, 35%). ESI-MS m/z: 359 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 11.35 (s, 1H), 9.24 (d, J=7.0 Hz, 1H), 8.48 (s, 1H), 7.70 (s, 1H), 7.50-7.60 (m, 2H), 7.46 (s, 1H), 7.31 (d, J=7.6 Hz, 1H), 7.22 (d, J=7.8 Hz, 1H), 6.54 (s, 1H), 2.84 (s, 3H), 2.50-2.60 (m, 1H), 1.00-1.08 (m, 2H), 0.72-0.76 (m, 2H). 
       Example 23 
     Preparation of methyl 1-cyclopropyl-8-(1H-indazol-5-yl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0395]    
       
                 
         
             
             
         
       
     
         [0396]    Methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol), cesium carbonate (335 mg, 1.03 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (92 mg, 0.38 mmol) were added to a mixture of 1,2-dimethoxyethane (3 mL) and water (1 mL). The mixture was degassed with argon. 1,1′-Bis-(diphenylphosphino)-ferrocene) palladium dichloride (28 mg, 0.03 mmol) was added. The reaction mixture was heated at 150° C. under argon atmosphere for 0.25 h. The reaction mixture was cooled. The mixture was diluted with CH 2 Cl 2  (3 mL) and water was added (3 mL). The layers were separated using a phase separator and the aqueous layer was extracted with CH 2 Cl 2  (2×5 mL). The combined organic layers were concentrated in vacuo. The crude product was purified by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 9:1) and dried in vacuo to afford the title compound as a yellow solid (93 mg, 72%). ESI-MS m/z: 374 (M+H) + . 
       Preparation of EXAMPLE 23 1-cyclopropyl-8-(1H-indazol-5-yl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0397]    
       
                 
         
             
             
         
       
     
         [0398]    1-Cyclopropyl-8-(1H-indazol-5-yl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 1-cyclopropyl-8-(1H-indazol-5-yl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (555 mg, 1.49 mmol) to afford the title compound EXAMPLE 23 as a yellow solid (200 mg, 37%). ESI-MS m/z: 360 (M+H) + ; ([M−H] − =358.2; 100%);  1 H NMR (400 MHz, DMSO-d6) δ ppm: 14.13 (s, 1H), 13.35 (s, 1H), 9.36 (d, J=7.3 Hz, 1H), 8.25 (d, J=15.9 Hz, 2H), 8.01 (s, 1H), 7.74 (d, J=8.6 Hz, 1H), 7.67 (d, J=7.6 Hz, 1H), 7.54 (d, J=9.6 Hz, 1H), 2.90 (s, 3H), 2.40-2.60 (m, 1H), 1.07-1.11 (m, 2H), 0.79-0.82 (m, 2H). 
       Preparation of potassium 1-cyclopropyl-8-(1H-indazol-5-yl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0399]    
       
                 
         
             
             
         
       
     
         [0400]    Potassium 1-cyclopropyl-8-(1H-indazol-5-yl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure D using 1-cyclopropyl-8-(1H-indazol-5-yl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid (180 mg, 0.50 mmol) to afford the K salt of EXAMPLE 23 as a yellow solid (195 mg, 98%). ESI-MS m/z: 360 (M−K +  H) + . 
       Example 24 
     Preparation of methyl 1-cyclopropyl-9-methyl-4-oxo-8-(4-ureido-phenyl)-4H-quinolizine-3-carboxylate 
       [0401]    
       
                 
         
             
             
         
       
     
         [0402]    Methyl 1-cyclopropyl-9-methyl-4-oxo-8-(4-ureido-phenyl)-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (75 mg, 0.26 mmol) and 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)-urea (84 mg, 0.32 mmol). Compound precipitated from solution and was filtered off and dried in vacuo to afford the title compound as a yellow solid (29 mg, 26%). ESI-MS m/z: 392 (M+H) + . 
       Preparation of EXAMPLE 24 1-cyclopropyl-9-methyl-4-oxo-8-(4-ureido-phenyl)-4H-quinolizine-3-carboxylic acid 
       [0403]    
       
                 
         
             
             
         
       
     
         [0404]    1-Cyclopropyl-9-methyl-4-oxo-8-(4-ureido-phenyl)-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 1-cyclopropyl-9-methyl-4-oxo-8-(4-ureido-phenyl)-4H-quinolizine-3-carboxylate (28 mg, 0.07 mmol) to afford the title compound EXAMPLE 24 as a yellow solid (15 mg, 58%). ESI-MS m/z: 378 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 14.10 (s, 1H), 9.30 (d, J=7.6 Hz, 1H), 9.09 (s, 1H), 8.23 (s, 1H), 7.57-7.63 (m, 3H), 7.46 (d, J=8.6 Hz, 2H), 6.04 (s, 2H), 2.89 (s, 3H), 2.40-2.55 (m, 1H), 1.06-1.08 (m, 2H,), 0.76-0.78 (m, 2H). 
       Example 25 
     Preparation of methyl 1-cyclopropyl-8-(4-(dimethylamino)-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0405]    
       
                 
         
             
             
         
       
     
         [0406]    Methyl 1-cyclopropyl-8-(4-(dimethylamino)-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (77 mg, 0.26 mmol) and (4-(dimethylamino)-phenyl)-boronic acid (56 mg, 0.34 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (39 mg, 31%). ESI-MS m/z: 377 (M+H) + . 
       Preparation of EXAMPLE 25 1-cyclopropyl-8-(4-(dimethylamino)-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0407]    
       
                 
         
             
             
         
       
     
         [0408]    1-Cyclopropyl-8-(4-(dimethylamino)-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 1-cyclopropyl-8-(4-(dimethylamino)-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (34 mg, 0.09 mmol) to afford the title compound EXAMPLE 25 as a yellow solid (5.1 mg, 15%). ESI-MS m/z: 363 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.10-9.20 (m, 1H), 8.44 (s, 1H), 7.20-7.40 (m, 3H), 6.80-6.85 (m, 2H), 2.88 (s, 6H), 2.82 (s, 3H), 2.50-2.60 (m, 1H), 0.98-1.05 (m, 1H), 0.65-0.70 (m, 1H). 
       Example 26 
     Preparation of methyl 8-(3-S-((tert-butoxycarbonyl)-amino)-pyrrolidin-1-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0409]    
       
                 
         
             
             
         
       
     
         [0410]    Methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol), tert-butyl-pyrrolidin-3-S-yl-carbamate (313 mg, 1.68 mmol) and triethylamine (0.5 mL, 3.6 mmol) were added to 2-propanol (20 mL). The reaction mixture was heated at 130° C. and stirred for 6 h. The reaction mixture was cooled and evaporated to dryness. The crude product was purified by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 9:1) and dried in vacuo to afford the title compound as a yellow foam (70 mg, 46%). ESI-MS m/z: 442 (M+H) + . 
       Preparation of EXAMPLE 26 8-(3-S-amino-pyrrolidin-1-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0411]    
       
                 
         
             
             
         
       
     
         [0412]    8-(3-S-amino-pyrrolidin-1-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 8-(3-S-((tert-butoxycarbonyl)-amino)-pyrrolidin-1-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (76 mg, 0.17 mmol) to afford a yellow residue. The residue was treated according to General Procedure C and purified using preparative LCMS to afford the title compound EXAMPLE 26 as a yellow solid (5.5 mg, 10% over 2 steps). ESI-MS m/z: 328 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.03 (d, J=10.8 Hz, 1H), 7.90 (s, 1H), 5.41 (s, 1H), 3.90-4.00 (m, 1H), 3.80-3.90 (m, 1H), 3.65-3.80 (m, 1H), 3.50-3.60 (m, 1H), 3.30-3.40 (m, 2H), 2.58 (s, 3H), 2.40-2.60 (m, 1H), 2.26-2.30 (m, 1H), 2.01-2.06 (m, 1H), 1.72-1.76 (m, 1H), 0.95-0.98 (m, 2H), 0.57-0.60 (m, 2H). 
       Example 27 
     Preparation of methyl 8-(3-S-((tert-butoxycarbonyl)-amino)-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0413]    
       
                 
         
             
             
         
       
     
         [0414]    Ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol), (S)-tert-butyl-pyrrolidin-3-ylcarbamate (313 mg, 1.68 mmol) and triethylamine (0.5 mL, 3.6 mmol) were added to 2-propanol (20 mL). The reaction mixture was heated at 130° C. and stirred for 6 h. The reaction mixture was cooled and evaporated to dryness. The crude product was purified by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 9:1) and dried in vacuo to afford the title compound as a yellow foam (70 mg, 46%). ESI-MS m/z: 442 (M+H) + . 
       Preparation of EXAMPLE 27 8-(3-S-amino-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0415]    
       
                 
         
             
             
         
       
     
         [0416]    8-(3-S-Amino-pyrrolidin-1-yl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using (85 mg, 0.18 mmol) followed by hydrolysis according to General Procedure C. Purification using preparative LCMS afforded the title compound EXAMPLE 27 as a yellow solid (20.5 mg, 33% over 2 steps). ESI-MS m/z: 346 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.02 (d, J=8.1 Hz, 1H), 7.82 (s, 1H,), 7.21 (d, J=8.1 Hz, 1H), 5.68 (s, 1H), 3.70-3.90 (m, 2H), 3.59-3.61 (m, 2H), 3.24-3.29 (m, 2H), 2.60 (s, 3H), 2.40-2.60 (m, 1H), 2.23-2.29 (m, 1H), 2.00-2.10 (m, 1H), 1.70-1.85 (m, 1H), 0.95-0.98 (m, 2H), 0.57-0.59 (m, 2H). 
       Example 28 
     Preparation of 2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline 
       [0417]    
       
                 
         
             
             
         
       
     
         [0418]    Potassium acetate (7.08 g, 72 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (7.94 g, 31 mmol) and 4-bromo-2,5-difluoro-aniline (5 g, 24 mmol) were dissolved in 1,2-dimethoxyethane (60 mL), followed by the addition of 1′-Bis-diphenylphosphine ferrocene palladium(II) dichloride (2.1 g, 2.6 mmol). The reaction mixture was heated at 90° C. for 16 h. The reaction mixture was evaporated to dryness in vacuo. The mixture was coated onto hydromatrix and purified by flash silica column chromatography (heptane:ethyl acetate, 3:1). The product was dried in vacuo and crystallized from CH 2 Cl 2  and heptane to give the title compound as a white solid (3.5 g, 57%). ESI-MS m/z: 297 (M+MeCN+H) + , 256.2 (M+H) + ;  1 H NMR (400 MHz, CDCl 3 ) δ ppm: 7.30 (dd, J=5.0 Hz and J=11.1 Hz, 1H), 6.41 (q, J=6.8 Hz, 1H), 4.06 (br s, 1H), 1.33 (s, 12H). 
       Preparation of methyl 8-(4-amino-2,5-difluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0419]    
       
                 
         
             
             
         
       
     
         [0420]    Methyl 8-(4-amino-2,5-difluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.71 mmol) and 2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (667 mg, 2.06 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (500 mg, 75%). ESI-MS m/z: 407 (M+Na) + . 
       Preparation of EXAMPLE 28 8-(4-amino-2,5-difluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0421]    
       
                 
         
             
             
         
       
     
         [0422]    8-(4-Amino-2,5-difluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 8-(4-amino-2,5-difluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (1 g, 2.6 mmol) to afford the title compound EXAMPLE 28 as a yellow solid (639 mg, 66%). ESI-MS m/z: 371 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 13.97 (s, 1H), 9.32 (d, J=5.5 Hz, 1H), 8.24 (s, 1H), 7.21 (d, J=12.1 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.92 (t, J=8.7 Hz, 1H), 6.00 (s, 2H), 2.85 (s, 3H), 2.40-2.60 (m, 1H), 1.06-1.08 (m, 2H), 0.77-0.79 (m, 2H). 
       Preparation of potassium 8-(4-amino-2,5-difluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0423]    
       
                 
         
             
             
         
       
     
         [0424]    Potassium 8-(4-amino-2,5-difluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure D using 8-(4-amino-2,5-difluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid (290 mg, 0.78 mmol) to afford the K salt of EXAMPLE 28 as a yellow solid (287 mg, 90%). ESI-MS m/z: 371 (M−K +  H) + . 
       Example 29 
     Preparation of ethyl 1-cyclopropyl-8-(4-amino-3,5-dichloro-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0425]    
       
                 
         
             
             
         
       
     
         [0426]    A mixture of 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (120 mg, 0.400 mmol), 2,6-dichloro-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-aniline (138 mg, 0.48 mmol), (Ph 3 P) 2 PdCl 2  (28 mg, 0.040 mmol), and Na 2 CO 3  (190 mg in 0.8 mL of water, 1.80 mmol) in THF (5 mL) was degassed 3 times under N 2  and heated to 80° C. overnight. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2×20 mL). The organic phase was separated, dried, and concentrated. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 2:3) to afford the title compound as a yellow solid (140 mg, 81%). ESI-MS m/z: 431 (M+H) + . 
       Preparation of EXAMPLE 29 1-cyclopropyl-8-(4-amino-3,5-dichloro-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0427]    
       
                 
         
             
             
         
       
     
         [0428]    A solution of ethyl 1-cyclopropyl-8-(4-amino-3,5-dichloro-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (140 mg, 0.326 mmol) in THF (6 mL) and water (2 mL) was treated with LiOH (55 mg, 1.31 mmol). The reaction was heated to 60° C. overnight and acidified with 1N HCl to pH 4. The precipitate was dissolved with ethyl acetate (50 mL) and washed with brine (2×20 mL). The organic phase was separated, dried, and concentrated. The precipitate was filtered to afford the title compound EXAMPLE 29 as yellow solid (90 mg, 69%). ESI-MS m/z: 403 (M+H) + ;  1 H NMR (300 MHz, DMSO-d6) δ ppm: 9.30 (d, J=7.5 Hz, 1H), 8.25 (s, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.57 (s, 2H), 6.12 (s, 2H), 2.92 (s, 3H), 2.54-2.51 (m, 1H), 1.13-1.10 (m, 2H), 0.84-0.83 (m, 2H). 
       Example 30 
     Preparation of ethyl 1-cyclopropyl-8-(4-amino-2-chloro-5-methyl-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0429]    
       
                 
         
             
             
         
       
     
         [0430]    A mixture of ethyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (120 mg, 0.4 mmol), 3-chloro-6-methyl-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxa-borolan-2-yl)-aniline (128 mg, 0.48 mmol), (Ph 3 P) 2 PdCl 2  (28 mg, 0.040 mmol), and Na 2 CO 3  (190 mg in 0.8 mL of water, 1.80 mmol) in THF (5 mL) was degassed 3 times under N 2  and heated to 80° C. overnight. The reaction mixture was diluted with ethyl acetate (20 mL), and washed with water (20 mL). The organic phase was separated, dried, and concentrated. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 1:3) to afford the title compound as a yellow solid (70 mg, 43%). ESI-MS m/z: 411 (M+H) + . 
       Preparation of EXAMPLE 30 1-cyclopropyl-8-(4-amino-2-chloro-5-methyl-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0431]    
       
                 
         
             
             
         
       
     
         [0432]    A solution of ethyl 1-cyclopropyl-8-(4-amino-2-chloro-5-methyl-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (70 mg, 0.171 mmol) in THF (6 mL) and water (2 mL) was treated with LiOH (29 mg, 0.690 mmol). The reaction was heated to 60° C. overnight and acidified with 1N HCl to pH 4. The precipitate was dissolved with ethyl acetate (50 mL) and washed with brine (2×20 mL). The organic phase was separated, dried, and concentrated. The precipitate was filtered to afford the title compound EXAMPLE 30 as yellow solid (51 mg, 78%). ESI-MS m/z: 383 (M+H) + ;  1 H NMR (300 MHz, DMSO-d6) δ ppm: 9.28 (d, J=7.5 Hz, 1H), 8.24 (s, 1H), 7.43 (d, J=7.5 Hz, 1H), 6.99 (s, 1H), 6.81 (s, 1H), 5.55 (s, 2H), 2.75 (s, 3H), 2.54-2.52 (m, 1H), 2.07 (s, 3H), 1.03-1.01 (m, 2H), 0.74-0.70 (m, 2H). 
       Example 31 
     Preparation of methyl 8-(4-(((tert-butoxycarbonyl)-amino)-methyl)-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0433]    
       
                 
         
             
             
         
       
     
         [0434]    Methyl 8-(4-(((tert-butoxycarbonyl)-amino)-methyl)-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.71 mmol) and (4-(((tert-butoxycarbonyl)-amino)-methyl)-phenyl)-boronic acid (516 mg, 2.06 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (850 mg, 100%). ESI-MS m/z: 485 (M+Na) + , 463 (M+H) + . 
       Preparation of 8-(4-(((tert-butoxycarbonyl)-amino)-methyl)-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0435]    
       
                 
         
             
             
         
       
     
         [0436]    8-(4-(((tert-Butoxycarbonyl)-amino)-methyl)-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 8-(4-(((tert-butoxycarbonyl)-amino)-methyl)-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (1050 mg, 2.3 mmol) to afford the title compound as a yellow solid (950 mg, 93%). ESI-MS m/z: 449 (M+H) + . 
       Preparation of EXAMPLE 31 8-(4-(aminomethyl)-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0437]    
       
                 
         
             
             
         
       
     
         [0438]    8-(4-(Aminomethyl)-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure C using 8-(4-(((tert-butoxycarbonyl)-amino)-methyl)-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid (540 mg, 1.20 mmol) to afford the title compound EXAMPLE 31 as a yellow solid (360 mg, 86%). ESI-MS m/z: 349 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 14.07 (s, 1H), 9.35 (d, J=7.3 Hz, 1H), 8.64 (s, 2H), 8.27 (s, 1H), 7.73 (d, J=7.8 Hz, 2H), 7.56-7.63 (m, 3H), 4.13 (s, 2H), 2.86 (s, 3H), 2.40-2.60 (m, 1H), 1.07-1.09 (m, 2H), 0.78-0.80 (m, 2H). 
       Preparation of potassium 8-(4-(amino-methyl)-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0439]    
       
                 
         
             
             
         
       
     
         [0440]    Potassium 8-(4-(amino-methyl)-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure D using 8-(4-(amino-methyl)-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid (200 mg, 0.52 mmol) to afford the K salt of EXAMPLE 31 as a yellow solid (153 mg, 76%). ESI-MS m/z: 349 (M−K +  H) + . 
       Example 32 
     Preparation of ethyl 8-(4-(((tert-butoxycarbonyl)-amino)-methyl)-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0441]    
       
                 
         
             
             
         
       
     
         [0442]    Ethyl 8-(4-(((tert-butoxycarbonyl)-amino)-methyl)-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.31 mmol) and (4-(((tert-butoxycarbonyl)-amino)-methyl)-phenyl)-boronic acid (101 mg, 0.40 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (167 mg, 100%). ESI-MS m/z: 495 (M+Na) + . 
       Preparation of 8-(4-(((tert-butoxycarbonyl)-amino)-methyl)-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0443]    
       
                 
         
             
             
         
       
     
         [0444]    8-(4-(((tert-Butoxycarbonyl)-amino)-methyl)-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using ethyl 8-(4-(((tert-butoxycarbonyl)-amino)-methyl)-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (167 mg, 0.34 mmol) to afford the title compound as a yellow solid (150 mg, 95%). ESI-MS m/z: 467 (M+H) + . 
       Preparation of EXAMPLE 32 8-(4-amino-methyl-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0445]    
       
                 
         
             
             
         
       
     
         [0446]    8-(4-Amino-methyl-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure C using 8-(4-(((tert-butoxycarbonyl)-amino)-methyl)-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid (150 mg, 0.32 mmol) to afford the title compound EXAMPLE 32 as a yellow solid (137 mg, 100%). ESI-MS m/z: 367 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 13.9 (br s, 1H), 9.41 (d, J=7.3 Hz, 1H), 8.50 (br s, 2H), 8.28 (s, 1H), 7.72 (d, J=7.8 Hz, 2H), 7.56 (d, J=7.8 Hz 2H), 4.16 (s, 2H), 2.79 (s, 3H), 2.40-2.60 (m, 1H), 1.05-1.09 (m, 2H), 0.79-0.82 (m, 2H). 
       Preparation of potassium 8-(4-amino-methyl)-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0447]    
       
                 
         
             
             
         
       
     
         [0448]    Potassium 8-(4-amino-methyl)-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure D 8-(4-aminomethyl-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid (65 mg, 0.16 mmol) to afford the K salt of EXAMPLE 32 as a yellow solid (79 mg, 100%). ESI-MS m/z: 367 (M−K +  H)) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 13.9 (br s, 1H), 9.40 (d, J=7.3 Hz, 1H), 8.43 (br s, 2H), 8.28 (s, 1H), 7.72 (d, J=7.8 Hz, 2H), 7.56 (d, J=7.8 Hz, 2H), 4.16 (s, 2H), 2.79 (s, 3H), 2.50-2.55 (m, 1H), 1.05-1.09 (m, 2H), 0.79-0.82 (m, 2H). 
       Example 33 
     Preparation of ethyl 1-cyclopropyl-8-(4-methyl-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0449]    
       
                 
         
             
             
         
       
     
         [0450]    A mixture of 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (120 mg, 0.400 mmol), 4-methyl-phenyl boronic acid (65 mg, 0.48 mmol), (Ph 3 P) 2 PdCl 2  (28 mg, 0.040 mmol), and Na 2 CO 3  (190 mg in 0.8 mL of water, 1.80 mmol) in THF (5 mL) was degassed 3 times under N 2  and heated to 80° C. overnight. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with water (2×20 mL). The organic phase was separated, dried, and concentrated. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 1:2) to afford the title compound as a yellow solid (90 mg, 62%). ESI-MS m/z: 362 (M+H) + . 
       Preparation of EXAMPLE 33 1-cyclopropyl-8-(4-methyl-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0451]    
       
                 
         
             
             
         
       
     
         [0452]    A solution of ethyl 1-cyclopropyl-8-(4-methylphenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (90 mg, 0.249 mmol) in THF (6 mL) and water (2 mL) was treated with LiOH (43 mg, 1.02 mmol). The reaction was heated to 60° C. for 2 h and acidified with 1N HCl to pH 4. The precipitate was dissolved with ethyl acetate (20 mL) and washed with brine (20 mL). The organic phase was separated, dried, and concentrated. The precipitate was filtered to afford the title compound EXAMPLE 33 as a yellow solid (65 mg, 78%). ESI-MS m/z: 334 (M+H) + ;  1 H NMR (300 MHz, DMSO-d6) δ ppm: 9.31 (d, J=7.2Hz, 1H), 8.24 (s, 1H), 7.54 (d, J=7.2 Hz, 1H), 7.44 (d, J=7.2 Hz, 2H), 7.38 (d, J=7.2 Hz, 2H), 2.84 (s, 3H), 2.54-2.52 (m, 1H), 2.39 (s, 3H), 1.06-1.03 (m, 2H), 0.77-0.75 (m, 2H). 
       Example 34 
     Preparation of 1-cyclopropyl-9-methyl-4-oxo-8-piperazin-1-yl-quinolizine-3-carboxylic acid 
       [0453]    
       
                 
         
             
             
         
       
     
         [0454]    A mixture of methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (200 mg, 0.69 mmol), N-(tert-butoxycarbonyl)-piperazine (256 mg, 1.38 mmol) and NaHCO 3  (259 mg, 14.64 mmol) in ACN (8.6 mL) was heated in a microwave at 120° C. for 20 min. DMF (2 mL) was added to the mixture and the reaction was heated in a microwave at 120° C. for 20 min. Then the reaction was heated in a microwave at 130° C. for 30 min twice. The reaction mixture was diluted with ethyl acetate (30 mL), and washed with water (30 mL). After extraction of the aqueous phase with ethyl acetate (2×30 mL), the organic phases were combined washed with brine, dried with magnesium sulfate, filtrated, and concentrated. The residue was dissolved in TFA (1 mL) and agitated for 1 hour prior to evaporation of the solvent. The residue was dissolved in THF (1 mL) and an aqueous 4M NaOH solution (0.79 mL) and heated in a microwave at 120° C. for 10 min. More aqueous 4M NaOH solution (0.5 mL) was added and the reaction was heated in a microwave at 120° C. for 10 min. The mixture was evaporated and the residue purified by preparative HPLC. The title compound EXAMPLE 34 was obtained after lyophilization (28 mg, 12.5%). High-Res MS: calculated 328.1656 (M+H) + , found 328.1642 (M+H) + . 
       Example 35 
     Preparation of 8-[(3S)-3-amino-1-piperidyl]-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid 
       [0455]    
       
                 
         
             
             
         
       
     
         [0456]    A mixture of methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (300 mg, 1 mmol), 3-S—N-(tert-butoxycarbonyl)-amino)-piperidine (413 mg, 2 mmol) and NaHCO 3  (390 mg, 14.64 mmol) in ACN (13 mL) was heated in a microwave at 120° C. for 20 min, and twice at 130° C. for 30 min. The reaction mixture was diluted with ethyl acetate (30 mL), and washed with water (30 mL). After extraction of the aqueous phase with ethyl acetate (2×30 mL), the organic phases were combined washed with brine, dried with magnesium sulfate, filtrated, and concentrated. The residue was dissolved in TFA (1 mL) and agitated for 1 hour prior to evaporation of the solvent. The residue was dissolved in THF (1 mL) and an aqueous 4M NaOH solution (1.4 mL) and heated in a microwave at 100° C. for 10 min and at 120° C. for 10 min. The mixture was evaporated and the residue purified by preparative HPLC. The title compound EXAMPLE 35 was obtained after lyophilization (65 mg, 19%). High-Res MS: calculated m/z 342.1812 (M+H) + , found m/z 342.1787 (M+H) + . 
       Example 36 
     Preparation of methyl 8-(4-cyano-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0457]    
       
                 
         
             
             
         
       
     
         [0458]    Methyl 8-(4-cyano-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (123 mg, 0.42 mmol) and 4-cyano-phenyl-boronic acid (132 mg, 0.90 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (142 mg, 94%). ESI-MS m/z: 359 (M+H) + . 
       Preparation of EXAMPLE 36 8-(4-carbamoyl-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0459]    
       
                 
         
             
             
         
       
     
         [0460]    8-(4-Carbamoyl-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 8-(4-cyano-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (123 mg, 0.35 mmol) and purified by preparative LCMS to afford the title compound EXAMPLE 36 as a yellow solid (9.1 mg, 7%). ESI-MS m/z: 363 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.25 (d, J=7.3 Hz, 1H), 8.24 (s, 1H), 8.12 (s, 1H), 8.04 (d, J=8.1 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.50 (s, 1H), 7.35 (d, J=7.1 Hz, 1H), 2.81 (s, 3H), 2.50-2.60 (m, 1H), 1.02-1.10 (m, 2H), 0.71-0.79 (m, 2H). 
       Example 37 
     Preparation of EXAMPLE 37 8-(4-carboxy-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0461]    
       
                 
         
             
             
         
       
     
         [0462]    8-(4-Carboxy-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 8-(4-cyano-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (123 mg, 0.35 mmol). Preparative LC-MS purification afforded the title compound EXAMPLE 37 as a yellow solid (9.3 mg, 7%). ESI-MS m/z: 364 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 9.36 (d, J=7.3 Hz, 1H), 8.50 (br s, 1H), 8.08 (d, J=8.1 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.32 (br s, 1H), 2.86 (s, 3H), 2.46-2.55 (m, 1H), 1.02-1.12 (m, 1H), 0.78-0.82 (m, 1H). 
       Example 38 
     Preparation of ethyl 8-(4-amino-2,5-difluoro-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0463]    
       
                 
         
             
             
         
       
     
         [0464]    Ethyl 8-chloro-1-cyclopropyl-7-gluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.32 mmol), 2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (667 mg, 2.06 mmol), tricyclohexylphosphine (105 mg, 0.41 mmol) and cesium fluoride (482 mg, 3.2 mmol) were added to acetonitrile (5 mL). The reaction mixture was degassed with argon. Palladium(II) acetate (24 mg, 0.11 mmol) was added. The reaction mixture was heated at 85° C. for 2 h. The reaction mixture was cooled and evaporated in vacuo. Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (100 mg, 35%). ESI-MS m/z: 403 (M+H) + . 
       Preparation of EXAMPLE 38 8-(4-amino-2,5-difluoro-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0465]    
       
                 
         
             
             
         
       
     
         [0466]    8-(4-Amino-2,5-difluoro-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using ethyl 8-(4-amino-2,5-difluoro-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.24 mmol). The compound was purified using preparative LCMS and dried in vacuo to afford the title compound EXAMPLE 38 as a yellow solid (11 mg, 12%). ESI-MS m/z: 389 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 14.0 (br s, 1H), 9.30 (d, J=4.3 Hz, 1H), 8.26 (s, 1H), 7.25 (q, J=6.6 Hz, 1H), 6.72 (t, J=7.6 Hz, 1H), 6.02 (s, 2H), 2.84 (s, 3H), 2.50-2.60 (m, 1H), 0.98-1.12 (m, 2H), 0.63-0.83 (m, 2H). 
       Example 39 
     Preparation of 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline 
       [0467]    
       
                 
         
             
             
         
       
     
         [0468]    Potassium acetate (7.08 g, 72 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (6.7 g, 26 mmol) and 4-bromo-2,6-difluoroaniline (5 g, 24 mmol) were dissolved in dimethylsulfoxide (30 mL), followed by the addition of 1′-Bis-diphenylphosphine ferrocene palladium(II) dichloride (0.53 g, 0.7 mmol). The reaction mixture was heated at 80° C. for 16 h. The reaction mixture was diluted in ethyl acetate (150 mL) and washed with saturated sodium bicarbonate and brine (2×100 mL). The organic layer was collected, dried over sodium sulfate and dried in vacuo. Purification by flash silica column chromatography (hexane:ethyl acetate, 3:2) afforded the title compound as a white solid (4.5 g, 73%). ESI-MS m/z: 297 (M+MeCN+H) + , 256 (M+H) + ;  1 H NMR (400 MHz, CDCl 3 ) δ ppm: 7.20-7.30 (m, 2H), 3.93 (br s, 2H), 1.32 (s, 12H). 
       Preparation of methyl 8-(4-amino-3,6-difluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0469]    
       
                 
         
             
             
         
       
     
         [0470]    Methyl 8-(4-amino-3,6-difluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.71 mmol) and 2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-aniline (667 mg, 2.06 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (1140 mg, 86%). ESI-MS m/z: 423 (M+K) + , 407 (M+Na) + , 385 (M+H) + . 
       Preparation of EXAMPLE 39 8-(4-amino-3,5-difluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0471]    
       
                 
         
             
             
         
       
     
         [0472]    8-(4-Amino-3,5-difluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 8-(4-amino-3,6-difluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (1140 mg, 3.0 mmol) to afford the title compound EXAMPLE 39 as a yellow solid (916 mg, 97%). ESI-MS m/z: 371 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 14.08 (s, 1H), 9.26 (d, J=7.3 Hz, 1H), 8.22 (s, 1H), 7.59 (d, J=7.6 Hz, 1H), 7.25 (d, J=7.3 Hz, 2H), 5.80 (s, 2H), 2.89-2.91 (m, 3H), 2.40-2.60 (m, 1H), 1.07-1.09 (m, 2H), 0.77-0.79 (m, 2H). 
       Preparation of potassium 8-(4-amino-3,5-difluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0473]    
       
                 
         
             
             
         
       
     
         [0474]    Potassium 8-(4-amino-3,5-difluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure D using 8-(4-amino-3,5-difluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid (300 mg, 0.81 mmol) to afford the title compound as a yellow solid (335 mg, 100%). ESI-MS m/z: 371 (M−K +  H) + . 
       Example 40 
     Preparation of methyl 8-(4-cyano-3-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0475]    
       
                 
         
             
             
         
       
     
         [0476]    Methyl 8-(4-cyano-3-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and 4-cyano-3-fluoro-phenyl-boronic acid (85 mg, 0.51 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (135 mg, 98%). ESI-MS m/z: 377 (M+H) + . 
       Preparation of EXAMPLE 40 8-(4-cyano-3-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0477]    
       
                 
         
             
             
         
       
     
         [0478]    8-(4-Cyano-3-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using me methyl 8-(4-cyano-3-fluoro-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (135 mg, 0.36 mmol) to afford the title compound EXAMPLE 40 as a yellow solid (37 mg, 28%). ESI-MS m/z: 363 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 14.0 (br s, 1H), 9.30 (d, J=7.3 Hz, 1H), 8.33 (s, 1H), 8.15 (t, J=7.6 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.59-7.61 (m, 1H), 7.38-7.52 (m, 1H), 2.82 (s, 3H), 2.40-2.60 (m, 1H), 1.00-1.18 (m, 2H), 0.73-0.92 (m, 2H). 
       Example 41 
     Preparation of ethyl 8-(4-cyano-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0479]    
       
                 
         
             
             
         
       
     
         [0480]    Ethyl 8-(4-cyano-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using ethyl 8-chloro-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (151 mg, 0.47 mmol) and 4-cyano-phenyl-boronic acid (82 mg, 0.56 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH, 1:0 to 9:1) afforded the title compound as a yellow solid (189 mg, 100%). ESI-MS m/z: 391 (M+H) + . 
       Preparation of EXAMPLE 41 8-(4-carboxy-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0481]    
       
                 
         
             
             
         
       
     
         [0482]    8-(4-Carboxy-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 8-(4-cyano-phenyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (123 mg, 0.35 mmol). Preparative LC-MS purification afforded the title compound EXAMPLE 41 as a yellow solid (12 mg, 7%). ESI-MS m/z: 382 (M+H) + ;  1 H NMR (400 MHz, CD 3 OD) δ ppm 9.40 (br s, 1H), 8.50 (br s, 1H), 8.11 (d, J=8.1 Hz, 2H), 7.40 (d, J=8.1 Hz, 2H), 2.83 (s, 3H), 2.43-2.55 (m, 1H), 0.99-1.15 (m, 2H), 0.82-0.86 (m, 2H). 
       Example 42 
     Preparation of methyl 8-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0483]    
       
                 
         
             
             
         
       
     
         [0484]    Methyl 8-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.71 mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (467.0 mg, 1.51 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 9:1) afforded the title compound as a brown oil (830 mg, 100%). ESI-MS m/z: 461 (M+Na) + , 439 (M+H) + . 
       Preparation of 8-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0485]    
       
                 
         
             
             
         
       
     
         [0486]    8-(1-(tert-Butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 8-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (830 mg, 1.89 mmol) to afford the title compound as a brown oil (628 mg, 78%). ESI-MS m/z: 425 (M+H) + . 
       Preparation of EXAMPLE 42 1-cyclopropyl-9-methyl-4-oxo-8-(1,2,3,6-tetrahydropyridin-4-yl)-4H-quinolizine-3-carboxylic acid 
       [0487]    
       
                 
         
             
             
         
       
     
         [0488]    1-Cyclopropyl-9-methyl-4-oxo-8-(1,2,3,6-tetrahydropyridin-4-yl)-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure C using 8-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid and purified by preparative LCMS to afford the title compound EXAMPLE 42 as a yellow solid (164 mg, 47%). ESI-MS m/z: 325 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 14.05 (s, 1H), 9.32 (d, J=7.3 Hz, 1H), 8.25 (s, 1H), 7.41 (d, J=7.3 Hz, 1H), 5.91 (s, 1H), 3.79 (s, 2H), 3.39-3.41 (m, 2H), 2.93 (s, 3H), 2.54-2.59 (s, 2H), 2.40-2.60 (m, 1H), 1.03-1.11 (m, 2H), 0.73-0.77 (m, 2H). 
       Example 43 
     Preparation of methyl 8-(1-(tert-butoxycarbonyl)-1H-pyrrol-3-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0489]    
       
                 
         
             
             
         
       
     
         [0490]    Methyl 8-(1-(tert-butoxycarbonyl)-1H-pyrrol-3-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrole-1-carboxylate (151.0 mg, 0.51 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 94:6) afforded the title compound as a yellow solid (89 mg, 61%). ESI-MS m/z: 423 (M+H) + . 
       Preparation of EXAMPLE 43 1-cyclopropyl-9-methyl-4-oxo-8-(1H-pyrrol-3-yl)-4H-quinolizine-3-carboxylic acid 
       [0491]    
       
                 
         
             
             
         
       
     
         [0492]    1-cyclopropyl-9-methyl-4-oxo-8-(1H-pyrrol-3-yl)-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 8-(1-(tert-butoxycarbonyl)-1H-pyrrol-3-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (89 mg, 0.22 mmol) followed by BOC removal according to General Procedure C. Purification by preparative LCMS afforded the title compound EXAMPLE 43 as a yellow solid (22 mg, 7% over 2 steps). ESI-MS m/z: 309 (M+H) + ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 14.14 (s, 1H), 11.58 (s, 1H), 9.18 (d, J=7.6 Hz, 1H), 8.14 (s, 1H), 7.78 (d, J=7.6 Hz, 1H), 7.53 (s, 1H), 7.01 (s, 1H), 6.64 (s, 1H), 3.04 (s, 3H), 2.50-2.60 (m, 1H), 1.03-1.12 (m, 2H), 0.68-0.72 (m, 2H). 
       Example 44 
     Preparation of ethyl 1-cyclopropyl-8-(4-fluoro-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0493]    
       
                 
         
             
             
         
       
     
         [0494]    A mixture of ethyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (120 mg, 0.400 mmol), 4-fluoro-phenyl boronic acid (67 mg, 0.48 mmol), (Ph 3 P) 2 PdCl 2  (28 mg, 0.040 mmol), and Na 2 CO 3  (190 mg in 0.8 mL of water, 1.80 mmol) in THF (5 mL) was degassed 3 times under N 2  and heated to 80° C. overnight. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with water (2×20 mL). The organic phase was separated, dried, and concentrated. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 1:2) to afford the title compound as a yellow solid (120 mg, 82%). ESI-MS m/z: 366 (M+H) + . 
       Preparation of EXAMPLE 44 1-cyclopropyl-8-(4-fluoro-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0495]    
       
                 
         
             
             
         
       
     
         [0496]    A solution of ethyl 1-cyclopropyl-8-(4-fluoro-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (120 mg, 0.329 mmol) in THF (6 mL) and water (2 mL) was treated with LiOH (55 mg, 1.31 mmol). The reaction was heated to 60° C. for 2 h and acidified with 1N HCl to pH 4. The precipitate was dissolved with ethyl acetate (50 mL) and washed with brine (2×20 mL). The organic phase was separated, dried, and concentrated. The precipitate was filtered to afford the title compound EXAMPLE 44 as a yellow solid (110 mg, 99%). ESI-MS m/z: 338 (M+H) + ;  1 H NMR (300 MHz, DMSO-d6) δ ppm: 9.37 (d, J=7.5 Hz, 1H), 8.30 (s, 1H), 7.70-7.61 (m, 3H), 7.51-7.45 (m, 2H), 2.89 (s, 3H), 2.53-2.51 (m, 1H), 1.13-1.10 (m, 2H), 0.83-0.82 (m, 2H). 
       Example 45 
     Preparation of ethyl 1-cyclopropyl-8-(4-chloro-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0497]    
       
                 
         
             
             
         
       
     
         [0498]    A mixture of 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (120 mg, 0.400 mmol), 4-chloro-phenyl boronic acid (75 mg, 0.48 mmol), (Ph 3 P) 2 PdCl 2  (28 mg, 0.040 mmol), and Na 2 CO 3  (190 mg in 0.8 mL of water, 1.80 mmol) in THF (5 mL) was degassed 3 times under N 2  and heated to 80° C. overnight. The reaction mixture was diluted with ethyl acetate (50 mL), and washed with water (2×20 mL). The organic phase was separated, dried, and concentrated. The residue was purified by flash silica column chromatography (hexane:ethyl, acetate 2:3) to afford the title compound as a yellow solid (95 mg, 62%). ESI-MS m/z: 382 (M+H) + . 
       Preparation of EXAMPLE 45 1-cyclopropyl-8-(4-chloro-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0499]    
       
                 
         
             
             
         
       
     
         [0500]    A solution of ethyl 1-cyclopropyl-8-(4-chloro-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (95 mg, 0.249 mmol) in THF (6 mL) and water (2 mL) was treated with LiOH (43 mg, 1.02 mmol). The reaction was heated to 60° C. for 4 h and acidified with 1N HCl to pH 4. The precipitate was dissolved with ethyl acetate (50 mL) and washed with brine (2×20 mL). The organic phase was separated, dried, and concentrated. The precipitate was filtered to afford the title compound EXAMPLE 45 as yellow solid (49 mg, 56%). ESI-MS m/z: 354 (M+H) + ;  1 H NMR (300 MHz, DMSO-d6) δ ppm: 9.34 (d, J=7.2 Hz, 1H), 8.27 (s, 1H), 7.68-7.56 (m, 5H), 2.84 (s, 3H), 2.55-2.52 (m, 1H), 2.39 (s, 3H), 1.08-1.05 (m, 2H), 0.80-0.78 (m, 2H). 
       Example 46 
     Preparation of methyl 1-cyclopropyl-8-(4-hydroxy-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0501]    
       
                 
         
             
             
         
       
     
         [0502]    Methyl 1-cyclopropyl-8-(4-hydroxy-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A using methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (500 mg, 1.71 mmol) and 4-hydroxy-phenyl-boronic acid (283 mg, 2.06 mmol). Purification by flash silica column chromatography (CH 2 Cl 2 :MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (610 mg, 100%). ESI-MS m/z: 388 (M+K) + , 372 (M+Na) + , 350 (M+H) + . 
       Preparation of EXAMPLE 46 1-cyclopropyl-8-(4-hydroxy-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0503]    
       
                 
         
             
             
         
       
     
         [0504]    1-Cyclopropyl-8-(4-hydroxy-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid was prepared according to General Procedure B using methyl 1-cyclopropyl-8-(4-hydroxy-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (610 mg, 1.74 mmol) to afford the title compound EXAMPLE 46 as a yellow solid (383 mg, 65%). ESI-MS m/z: 336 (M+H) + , 334.20 (M−H) − ;  1 H NMR (400 MHz, DMSO-d6) δ ppm: 14.12 (s, 1H), 10.00 (s, 1H), 9.30 (d, J=7.3 Hz, 1H), 8.23 (s, 1H,), 7.57 (d, J=7.6 Hz, 1H), 7.43 (d, J=8.6 Hz, 2H), 6.96 (d, J=8.6 Hz, 2H), 2.88 (s, 3H), 2.40-2.60 (m, 1H), 1.05-1.08 (m, 2H), 0.76-0.78 (m, 2H). 
       Preparation of potassium 1-cyclopropyl-8-(4-hydroxy-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0505]    
       
                 
         
             
             
         
       
     
         [0506]    Potassium 1-cyclopropyl-8-(4-hydroxy-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure D using 1-cyclopropyl-8-(4-hydroxy-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid (370 mg, 0.81 mmol) to afford the K salt of EXAMPLE 46 as a yellow solid (429 mg, 100%). ESI-MS m/z: 336 (M−K +  H) + , 334 (M−K−H) − . 
       Example 47 
     Preparation of 1-cyclopropyl-8-(4-methoxy-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester 
       [0507]    
       
                 
         
             
             
         
       
     
         [0508]    A mixture of 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (120 mg, 0.400 mmol), 4-methoxy-phenyl boronic acid (73 mg, 0.48 mmol), (Ph 3 P) 2 PdCl 2  (28 mg, 0.040 mmol), and Na 2 CO 3  (190 mg in 0.8 mL of water, 1.80 mmol) in THF (5 mL) was degassed 3 times under N 2  and heated to 80° C. overnight. The reaction mixture was diluted with ethyl acetate, and washed with water. The organic phase was separated, dried, and concentrated. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 1:2) to afford the title compound as a yellow solid (68 mg, 45%). ESI-MS m/z: 378 (M+H) + . 
       Preparation of EXAMPLE 47 1-cyclopropyl-8-(4-methoxy-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0509]    
       
                 
         
             
             
         
       
     
         [0510]    A solution of 1-cyclopropyl-8-(4-methoxy-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (68 mg, 0.180 mmol) in THF (6 mL) and water (2 mL) was treated with LiOH (33 mg, 0.78 mmol). The reaction was heated to 60° C. overnight and acidified with 1N HCl to pH 4. The precipitate was dissolved with ethyl acetate (50 mL) and washed with brine (2×20 mL). The organic phase was separated, dried, and concentrated. The precipitate was filtered to afford the title compound EXAMPLE 47 as yellow solid (22 mg, 35%). ESI-MS m/z: 350 (M+H) + ;  1 H NMR (300 MHz, DMSO-d6) δ ppm: 9.30 (d, J=7.5 Hz, 1H), 8.23 (s, 1H), 7.57 (d, J=7.5 Hz, 1H), 7.52 (d, J=8.4 Hz, 2H), 7.12 (d, J=7.5 Hz, 2H), 3.84 (s, 3H), 2.86 (s, 3H), 2.53-2.51 (m, 1H), 1.06-1.04 (m, 2H), 0.78-0.75 (m, 2H). 
       Example 48 
     Preparation of 1-cyclopropyl-8-(4-hydroxy-methyl-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester 
       [0511]    
       
                 
         
             
             
         
       
     
         [0512]    A mixture of 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (120 mg, 0.400 mmol), 4-hydroxy-methyl-phenyl boronic acid (73 mg, 0.48 mmol), (Ph 3 P) 2 PdCl 2  (28 mg, 0.040 mmol), and Na 2 CO 3  (190 mg in 0.8 mL of water, 1.80 mmol) in THF (5 mL) was degassed 3 times under N 2  and heated to 80° C. overnight. The reaction mixture was diluted with ethyl acetate (50 mL) and washed with water (2×20 mL). The organic phase was separated, dried, and concentrated. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 1:3 to pure ethyl acetate) to afford the title compound as a yellow solid (60 mg, 40%). ESI-MS m/z: 378 (M+H) + . 
       Preparation of EXAMPLE 48 1-cyclopropyl-8-(4-hydroxy-methyl-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0513]    
       
                 
         
             
             
         
       
     
         [0514]    A solution of 1-cyclopropyl-8-(4-hydroxy-methyl-phenyl)-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid ethyl ester (60 mg, 0.159 mmol) in THF (6 mL) and water (2 mL) was treated with LiOH (27 mg, 0.642 mmol). The reaction was heated to 60° C. overnight and acidified with 1N HCl to pH 4. The precipitate was dissolved with ethyl acetate (50 mL) and washed with brine (2×20 mL). The organic phase was separated, dried, and concentrated. The precipitate was filtered to afford the title compound EXAMPLE 48 as yellow solid (21 mg, 38%). ESI-MS m/z: 350 (M+H) + ;  1 H NMR (300 MHz, DMSO-d6) δ ppm: 9.38 (d, J=7.2 Hz, 1H), 8.30 (s, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.59-7.56 (m, 4H), 5.41 (t, 1H), 4.64 (d, J=5.7 Hz, 2H), 2.91 (s, 3H), 2.54-2.51 (m, 1H), 1.13-1.10 (m, 2H), 0.83-0.81 (m, 2H). 
       Example 49 
     Preparation of tert-butyl 4-bromo-2-fluorobenzyl-carbamate 
       [0515]    
       
                 
         
             
             
         
       
     
         [0516]    To a solution of (4-bromo-2-fluorophenyl) methanamine (2.5 g, 12 mmol) in CH 2 Cl 2  (50 mL) at 0° C. was added di-tert-butyl dicarbonate (4.01 g, 18 mmol) and triethylamine (2.6 mL, 18 mmol). The mixture was allowed to warm to room temperature and stirred for 2 h. Water was added (50 mL) and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash silica column chromatography (heptane:ethyl acetate) (1:0 to 4:1) to afford the title compound as a colorless oil. (2.7 g, 71%).  1 H NMR (400 MHz, DMSO-d6) δ ppm 7.21-7.26 (m, 3H), 4.90 (br s, H), 4.27-4.33 (m, 2H), 1.44 (s, 9H). 
       Preparation of tert-butyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzylcarbamate 
       [0517]    
       
                 
         
             
             
         
       
     
         [0518]    A mixture of tert-butyl 4-bromo-2-fluorobenzyl-carbamate (1.3 g, 4.3 mmol), bis(pinacolato)-diboron (1.6 g, 6.4 mmol), sodium acetate (1.1 g, 13 mmol) in dimethylsulfoxide (dry) (4 mL) was degassed with argon. 1,1′-Bis(diphenylphosphino)-ferrocene palladium(II) dichloride (0.156 g, 0.214 mmol) was added and the mixture was heated at 90° C. for 3 h. After cooling, the reaction mixture was partitioned between ethyl acetate (50 mL) and water (50 mL). The layers were separated and the organic layer was washed with water (50 mL), brine, dried over sodium sulfate and concentrated to give a red/brown crude product. The material was purified by flash silica column chromatography (heptane:ethyl acetate) (1:0 to 4:1) to afford the title compound as a colorless oil (980 mg, 65%).  1 H NMR (400 MHz, DMSO-d6) δ ppm 7.53 (d, J=7.6 Hz, 1H), 7.45 (d, J=10.4 Hz, 1H), 7.31-7.35 (m, 1H), 4.91 (br s, H), 4.36-4.40 (m, 2H), 1.44 (s, 9H), 1.34 (s, 12H). 
       Preparation of methyl 8-(4-((tert-butoxycarbonylamino)-methyl)-3-fluorophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0519]    
       
                 
         
             
             
         
       
     
         [0520]    Methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (46 mg, 0.158 mmol) was dissolved in toluene (500 μL), ethanol (96%) (237 μL) and aqueous sodium carbonate 2M (237 μL, 0.473 mmol). tert-Butyl 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (97 mg, 0.21 mmol) was added. The mixture was degassed with argon and 1,1′-bis(diphenylphosphino)-ferrocene palladium(II) dichloride (11.5 mg, 0.016 mmol) was added. The mixture was heated at 90° C. for 4 h. After cooling, the mixture was diluted with CH 2 Cl 2  (3 mL) and water (3 mL). The layers were separated and the aqueous layer was extracted with CH 2 Cl 2  (3×2 mL). The organic layer was concentrated in vacuo. The crude product was purified with flash silica column chromatography (heptane:ethyl acetate) (1:1 to 1:2) to afford the title compound as a yellow solid (24 mg, 32%). ESI-MS m/z: 481 (M+H) + . 
       Preparation of 8-(4-((tert-butoxycarbonylamino)methyl)-3-fluorophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0521]    
       
                 
         
             
             
         
       
     
         [0522]    Methyl 8-(4-((tert-butoxycarbonylamino)methyl)-3-fluorophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (24 mg, 0.050 mmol) was dissolved in methanol (2 mL) and 1M aqueous sodium hydroxide (0.5 mL, 0.5 mmol) was added. The mixture was stirred at 50° C. for 2 h. After cooling, the methanol was removed in vacuo and the residue was dissolved in water (5 mL) and neutralized with 1M HCl (˜0.5 mL). The precipitate formed was extracted with CH 2 Cl 2  (3×4 mL). The organic layer was concentrated to afford the title compound as a yellow solid (20 mg, 86%). ESI-MS m/z: 3467 (M+H) + . 
       Preparation of EXAMPLE 49 8-(4-(aminomethyl)-3-fluorophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride 
       [0523]    
       
                 
         
             
             
         
       
     
         [0524]    8-(4-((tert-Butoxycarbonylamino)methyl)-3-fluorophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid (24 mg, 0.051 mmol) was dissolved in acetonitrile (4 mL). HCl 4M in dioxane (1 mL, 4 mmol) was added. The mixture was stirred for 4 h and a suspension was formed affording after filtration the title compound EXAMPLE 49 as a yellow solid (17.7 mg, 86%). ESI-MS m/z: 453 (M+H) + . 
       Example 50 
     Preparation of tert-butyl 7-bromo-1-hydroxy-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl-carbamate 
       [0525]    
       
                 
         
             
             
         
       
     
         [0526]    To a suspension of 3-amino-7-bromo-1-hydroxy-3,4-dihydroquinolin-2(1H)-one hydrochloride (203 mg, 0.692 mmol) in CH 2 Cl 2  (10 mL) was added di-tert-butyl dicarbonate (226 mg, 1.04 mmol) and triethylamine (0.482 mL, 3.46 mmol). The suspension was stirred at room temperature for 16 h. Water (20 mL) was added to the clear solution and the layers were separated. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash silica column chromatography (heptane:ethyl acetate) (1:0 to 7:3) to afford the title compound as a white solid (102 mg, 41%). ESI-MS m/z: 303, 301 (M−tBu+H) + . 
       Preparation of tert-butyl 2-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate 
       [0527]    
       
                 
         
             
             
         
       
     
         [0528]    Sodium acetate (20.7 mg, 0.252 mmol) and bis(pinacolato)diboron (32.0 mg, 0.126 mmol) were placed as solids in a flask under argon. tert-Butyl 7-bromo-1-hydroxy-2-oxo-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (30 mg, 0.084 mmol) in dimethylsulfoxide (dry) (1 mL) was added and the mixture was degassed with argon. trans-Bis(triphenylphosphine)-palladium(II) dichloride (5.9 mg, 8.4 mmol) was added and the reaction mixture was heated at 40° C. for 2 h. After cooling the reaction mixture was concentrated and purified by flash silica column chromatography (heptane:ethyl acetate) (95:5 to 3:2) to afford the title compound as a white solid (13.5 mg, 41%).  1 H NMR (400 MHz, DMSO-d6) δ ppm 7.78 (s, 1H), 7.46 (d, J=7.6 Hz, 1H), 7.21 (d, J=7.6 Hz, 1H), 5.60 (br s, 1H), (4.34 (br s, 1H), 3.48-3.53 (m, 1H), 2.81-2.89 (m, 2H), 1.47 (s, 9H), 1.34 (s, 12H). 
       Preparation of methyl 8-(3-(tert-butoxycarbonylamino)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate 
       [0529]    
       
                 
         
             
             
         
       
     
         [0530]    Methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (45 mg, 0.15 mmol) was dissolved in toluene (330 μL), ethanol (96%) (243 μL) and 2M aqueous sodium carbonate solution (231 μL, 0.463 mmol). tert-Butyl 2-oxo-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4-tetrahydroquinolin-3-ylcarbamate (78 mg, 0.20 mmol) was added and the mixture was degassed with argon. 1,1′-Bis(diphenylphosphino)-ferrocene palladium(II) dichloride (11.3 mg, 0.015 mmol) was added and the mixture was heated at 80° C. under an argon atmosphere for 16 h. After cooling, the mixture was diluted with CH 2 Cl 2  (3 mL) and water (3 mL) and the layers were separated. The aqueous layer was extracted with CH 2 Cl 2  (3×2 mL). The combined organic layers were concentrated and the yellow crude product was purified with flash silica column chromatography (heptane/ethyl acetate) (1:0 to 0:1) to afford the title compound as a yellow solid (43 mg, 53%). ESI-MS m/z: 518 (M+H) + . 
       Preparation of 8-(3-(tert-butoxycarbonylamino)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid 
       [0531]    
       
                 
         
             
             
         
       
     
         [0532]    Methyl 8-(3-(tert-butoxycarbonylamino)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (43 mg, 0.083 mmol) was dissolved in methanol (2 mL) and sodium hydroxide 1M solution in water (0.5 mL, 0.5 mmol) was added. The mixture was stirred at 50° C. for 2 h. After cooling, the methanol was removed in vacuo. The residue was dissolved in water (5 mL) and then neutralized with 1M HCl (˜0.5 mL). The precipitate formed was stirred at room temperature overnight. The mixture was extracted with CH 2 Cl 2  (3×4 mL). The organic layers were concentrated to afford the title compound as a yellow solid (29 mg, 69%). ESI-MS m/z: 504 (M+H) + . 
       Preparation of EXAMPLE 50 8-(3-amino-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid hydrochloride 
       [0533]    
       
                 
         
             
             
         
       
     
         [0534]    8-(3-(tert-Butoxycarbonylamino)-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylic acid (29 mg, 0.046 mmol) was dissolved in acetonitrile (4 mL). HCl 4M in dioxane (1 mL, 4 mmol) was added. The mixture was stirred for 4 h and a suspension was formed. The solvents were evaporated and the crude was triturated with diethyl ether (4 mL) to afford the title compound EXAMPLE 50 as a yellow solid (20 mg, 98%). ESI-MS m/z: 404 (M+H) + . 
       Preparation of potassium salts of EXAMPLES 51 and 52 
       [0535]    
       
                 
         
             
             
         
       
     
         [0000]    Similarly the potassium salts of EXAMPLES 51 and 52 can be obtained via the application of general procedures A, B, C, and D described earlier. 
       Biological Example 1 
       [0536]    All examples were tested against a select panel of bacterial pathogens. MICs were determined as described in the latest CLSI guidelines—Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard—Eighth Edition. In brief, a standardized bacterial inoculum containing 5×10 5  cfu/mL of each strain was exposed to series of 2-fold dilutions of each test compound in 100 μL of Mueller-Hinton Broth (MHB) in 96-well plates. After incubation at 37° C. for 16-20 hours in a humidified incubator, plates were scored visually to determine the lowest test concentration that inhibited visible growth, which corresponds to the Minimum Inhibitory Concentration or MIC. Results are shown for representative gram-positive and gram-negative bacteria in Tables 1 and 2, respectively. Each of the potassium salts tested in Tables 1 and 2 were prepared in situ by titration of a solution of the corresponding free acid with potassium hydroxide. 
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 MICs (μg/mL) against Gram positive bacteria 
               
             
          
           
               
                   
                   
                 
                   S. aureus 
                 
                   
                   
                   
                   
               
               
                   
                 
                   S. aureus 
                 
                 ATCC 43300 
                 
                   S. aureus 
                 
                 
                   E. faecium 
                 
                 
                   E. faecalis 
                 
                 
                   S. pneumonia 
                 
               
               
                 Compounds 
                 ATCC 25923 
                 (MRSA, FQ-S) 
                 BAA-1720 (MRSA, FQ-R) 
                 ATCC 19434 
                 ATCC 29212 
                 ATCC 49619 
               
               
                   
               
             
          
           
               
                 Example 1 K salt 
                 ≦0.004 
                 ≦0.004 
                 0.125 
                 0.25 
                 0.008 
                 0.016 
               
               
                 Example 2 K salt 
                 ≦0.004 
                 0.004 
                 0.125 
                 0.25 
                 0.016 
                 0.032 
               
               
                 Example 3 K salt 
                 0.016 
                 0.016 
                 0.5 
                 1 
                 0.064 
                 0.25 
               
               
                 Example 4 K salt 
                 0.016 
                 0.016 
                 0.25 
                 1 
                 0.032 
                 0.125 
               
               
                 Example 5 K salt 
                 0.008 
                 0.008 
                 0.25 
                 0.5 
                 0.016-0.032 
                 0.032 
               
               
                 Example 6 K salt 
                 0.008-0.016 
                 0.008 
                 1 
                 1 
                 0.016 
                 0.032 
               
               
                 Example 7 K salt 
                 0.008 
                 0.008 
                 0.25 
                 0.5 
                 0.032 
                 0.032-0.064 
               
               
                 Example 8 K salt 
                 0.008 
                 0.008 
                 0.25 
                 0.5 
                 0.032 
                 0.125 
               
               
                 Example 9 K salt 
                 0.008 
                 0.008 
                 0.25 
                 0.5 
                 0.032 
                 0.064 
               
               
                 Example 10 K salt 
                 0.008 
                 0.008 
                 0.5 
                 0.5 
                 0.032 
                 0.125 
               
               
                 Example 11 K salt 
                 ≦0.004 
                 ≦0.004 
                 0.125 
                 0.25 
                 0.016 
                 0.032 
               
               
                 Example 12 K salt 
                 0.016-0.032 
                 0.016 
                 0.5-1 
                 1 
                 0.064 
                 0.25 
               
               
                 Example 13 K salt 
                 0.008-0.016 
                 0.008 
                 0.25 
                 0.5 
                 0.016 
                 0.032 
               
               
                 Example 14 K salt 
                 0.016 
                 0.016 
                 0.5 
                 8 
                 0.064 
                 0.125 
               
               
                 Example 15 K salt 
                 0.016 
                 0.016 
                 1 
                 &gt;8 
                 0.032 
                 0.064 
               
               
                 Example 16 K salt 
                 0.016 
                 0.016 
                 0.5-1 
                 1 
                 0.064 
                 0.125 
               
               
                 Example 17 K salt 
                 0.016 
                 0.016 
                 1 
                 1 
                 0.064 
                 0.125 
               
               
                 Example 18 K salt 
                 0.008 
                 0.008 
                 0.25 
                 0.25 
                 0.032 
                 0.064 
               
               
                 Example 19 K salt 
                 0.016 
                 0.016 
                 0.25 
                 1 
                 0.032 
                 0.064-0.125 
               
               
                 Example 20 K salt 
                 0.032 
                 0.016 
                 1 
                 1 
                 0.125 
                 0.25 
               
               
                 Example 21 K salt 
                 0.008 
                 0.008 
                 0.25 
                 0.5 
                 0.032 
                 0.032 
               
               
                 Example 22 K salt 
                 0.008 
                 0.016 
                 0.5 
                 4 
                 0.032 
                 0.125 
               
               
                 Example 23 K salt 
                 ≦0.004 
                 ≦0.004 
                 0.125 
                 0.25 
                 0.008 
                 0.064 
               
               
                 Example 24 K salt 
                 0.032-0.064 
                 0.032 
                 &gt;8 
                 0.5 
                 0.032 
                 0.032 
               
               
                 Example 25 K salt 
                 0.064 
                 0.064 
                 1 
                 8 
                 0.125 
                 0.25 
               
               
                 Example 26 K salt 
                 0.032 
                 0.032 
                 1 
                 1 
                 0.125 
                 0.064 
               
               
                 Example 27 K salt 
                 1 
                 0.5 
                 8 
                 &gt;8 
                 4 
                 2 
               
               
                 Example 28 K salt 
                 ≦0.004 
                 ≦0.004 
                 0.064 
                 0.25 
                 0.016 
                 0.032 
               
               
                 Example 29 K salt 
                 ≦0.004 
                 0.008 
                 0.125 
                 0.5 
                 0.008-0.016 
                 0.064 
               
               
                 Example 30 K salt 
                 0.064 
                 0.032 
                 1 
                 2 
                 0.064 
                 0.25 
               
               
                 Example 31 K salt 
                 0.064 
                 0.032 
                 1 
                 2 
                 0.25 
                 0.125 
               
               
                 Example 32 K salt 
                 0.064 
                 0.064 
                 1 
                 2 
                 0.125 
                 0.125 
               
               
                 Example 33 K salt 
                 0.016-0.032 
                 0.016 
                 0.5 
                 0.5-1 
                 0.064 
                 0.25 
               
               
                 Example 34 K salt 
                 0.5 
                 0.5 
                 &gt;8 
                 &gt;8 
                 4 
                 2 
               
               
                 Example 35 K salt 
                 0.032 
                 0.032 
                 0.5 
                 2 
                 0.125 
                 0.032 
               
               
                 Example 36 K salt 
                 0.016-0.032 
                 0.016 
                 0.5 
                 0.5 
                 0.032 
                 0.064 
               
               
                 Example 37 K salt 
                 2 
                 0.125 
                 8 
                 &gt;8 
                 0.5 
                 1 
               
               
                 Example 38 K salt 
                 ≦0.004 
                 ≦0.004 
                 0.064 
                 &gt;8 
                 0.008-0.016 
                 0.016 
               
               
                 Example 39 K salt 
                 ≦0.004 
                 ≦0.004 
                 0.125 
                 0.25 
                 0.016 
                 0.032 
               
               
                 Example 40 K salt 
                 0.016 
                 0.016 
                 0.5-1 
                 2 
                 0.064 
                 0.125 
               
               
                 Example 41 K salt 
                 2 
                 0.25 
                 &gt;8 
                 &gt;8 
                 0.25 
                 0.5-1   
               
               
                 Example 42 
                 0.5 
                 0.5 
                 &gt;8 
                 &gt;8 
                 4 
                 2 
               
               
                 Example 43 K salt 
                 0.016-0.032 
                 0.032 
                 2 
                 4 
                 0.125 
                 0.5 
               
               
                 Example 44 K salt 
                 0.016 
                 0.016 
                 0.5 
                 0.5 
                 0.064 
                 0.25 
               
               
                 Example 45 K salt 
                 0.016-0.032 
                 0.016 
                 0.5 
                 0.5-1 
                 0.064 
                 0.25 
               
               
                 Example 46 K salt 
                 ≦0.004 
                 ≦0.004 
                 0.125 
                 0.25 
                 0.016 
                 0.032 
               
               
                 Example 47 K salt 
                 0.016 
                 0.016 
                 0.5-1 
                 1 
                 0.032-0.064 
                 0.25 
               
               
                 Example 48 K salt 
                 0.008-0.016 
                 0.008 
                 0.5 
                 1 
                 0.032-0.064 
                 0.125 
               
               
                 Ciprofloxacin 
                 0.25 
                 0.25 
                 &gt;8 
                 8 
                 1 
                 0.5 
               
               
                 Levofloxacin 
                 0.25 
                 0.125 
                 &gt;8 
                 8 
                 1 
                 0.5 
               
               
                 Moxyfloxacin 
                 0.064 
                 0.064 
                 4 
                 4 
                 0.25 
                 0.125 
               
               
                   
               
             
          
         
       
     
         [0000]    
       
         
               
             
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 MICs (μg/mL) against Gram negative bacteria 
               
             
          
           
               
                   
                 
                   E. coli 
                 
                 
                   A. baumannii 
                 
                 
                   P. aeruginosa 
                 
                 
                   K. pneumoniae 
                 
                 
                   H. influenzae 
                 
                 
                   S. maltophilia 
                 
               
               
                 Compounds 
                 ATCC 25922 
                 B. ATCC 19606 
                 ATCC 27853 
                 ATCC 33495 
                 ATCC 49247 
                 ATCC 17677 
               
               
                   
               
             
          
           
               
                 Example 1 K salt 
                 0.032-0.064 
                 0.064 
                 2 
                 0.125 
                 ≦0.004 
                 0.125 
               
               
                 Example 2 K salt 
                 0.032 
                 0.125 
                 1 
                 0.125 
                 ≦0.004 
                 0.125 
               
               
                 Example 3 K salt 
                 0.064-0.125 
                 0.25 
                 2 
                 0.25 
                 0.016 
                 0.25 
               
               
                 Example 4 K salt 
                 0.125 
                 0.125 
                 8 
                 0.25 
                 0.008 
                 0.25 
               
               
                 Example 5 K salt 
                 0.064 
                 0.064 
                 2 
                 0.125-0.25 
                 ≦0.004 
                 0.125 
               
               
                 Example 6 K salt 
                 0.125 
                 0.5 
                 8 
                 0.5 
                 ≦0.004 
                 0.5 
               
               
                 Example 7 K salt 
                 0.064 
                 0.125 
                 4 
                 0.125-0.25 
                 0.008 
                 0.25 
               
               
                 Example 8 K salt 
                 0.032-0.064 
                  0.064-0.125 
                 2 
                 0.125 
                 0.064 
                 0.125 
               
               
                 Example 9 K salt 
                 0.064 
                 0.125 
                 2 
                 0.125-0.25 
                 0.008 
                 0.25 
               
               
                 Example 10 K salt 
                 0.125 
                 0.25 
                 2 
                 0.25 
                 0.008 
                 0.25-0.5 
               
               
                 Example 11 K salt 
                 0.064 
                 0.064 
                 2 
                 0.125 
                 ≦0.004 
                 0.125 
               
               
                 Example 12 K salt 
                 0.25 
                 0.25-0.5 
                 8 
                 0.5 
                 0.032 
                 0.5 
               
               
                 Example 13 K salt 
                 0.125 
                 0.5 
                 8 
                 0.5 
                 0.016 
                 0.5 
               
               
                 Example 14 K salt 
                 0.25 
                 0.5-1  
                 &gt;8 
                 1 
                 0.016 
                 1 
               
               
                 Example 15 K salt 
                 0.125 
                 0.5-1  
                 &gt;8 
                 1 
                 0.016-0.032 
                 0.5 
               
               
                 Example 16 K salt 
                 0.032 
                 0.125 
                 2 
                 0.125 
                 ≦0.004 
                 0.125 
               
               
                 Example 17 K salt 
                 0.064 
                 0.125-0.25 
                 2-4 
                 0.125 
                 ≦0.004 
                 0.25 
               
               
                 Example 18 K salt 
                 0.032 
                 0.064 
                 1 
                 0.064-0.25 
                 0.008 
                 0.125 
               
               
                 Example 19 K salt 
                 0.064-0.125 
                 0.125-0.25 
                 2 
                 0.25 
                 0.008 
                 0.25 
               
               
                 Example 20 K salt 
                 0.064 
                 0.25 
                 2-4 
                 0.125-0.25 
                 ≦0.004 
                 0.25 
               
               
                 Example 21 K salt 
                 0.016-0.032 
                  0.064-0.125 
                 1-2 
                 0.064 
                 ≦0.004 
                 0.125 
               
               
                 Example 22 K salt 
                 0.125 
                 0.25 
                 4 
                 0.25 
                 0.016 
                 0.5 
               
               
                 Example 23 K salt 
                 0.032 
                 0.125 
                 2 
                 0.125 
                 ≦0.004 
                 0.064 
               
               
                 Example 24 K salt 
                 0.125-0.25 
                 4 
                 8 
                 0.5 
                 0.016 
                 &gt;8 
               
               
                 Example 25 K salt 
                 0.5 
                 1 
                 &gt;8 
                 1 
                 0.064 
                 1 
               
               
                 Example 26 K salt 
                 ≦0.004 
                 0.064 
                 0.125 
                 0.016 
                 ≦0.004 
                 0.064 
               
               
                 Example 27 K salt 
                 0.064-0.125 
                 2 
                 2 
                 0.25 
                 0.125 
                 2 
               
               
                 Example 28 K salt 
                 0.032-0.064 
                 0.125 
                 2 
                 0.25-0.5 
                 ≦0.004 
                 0.125 
               
               
                 Example 29 K salt 
                 0.25 
                 0.25 
                 4 
                 0.5-1  
                 0.008-0.016 
                 0.25 
               
               
                 Example 30 K salt 
                 1 
                 1-2 
                 &gt;8 
                  2-4 
                 0.064 
                 4 
               
               
                 Example 31 K salt 
                 0.032 
                 0.25 
                 1 
                 0.125-0.25 
                 0.016 
                 0.125 
               
               
                 Example 32 K salt 
                 0.032 
                 0.25 
                 1 
                 0.064.125 
                 0.008 
                 0.125 
               
               
                 Example 33 K salt 
                 0.25 
                 0.5 
                 2 
                 0.5-1  
                 0.016-0.032 
                 0.5 
               
               
                 Example 34 K salt 
                 0.064 
                 1 
                 1 
                 0.125-0.5  
                 0.064 
                 1 
               
               
                 Example 35 K salt 
                 0.032 
                 0.25 
                 0.5 
                 0.125-0.5  
                 0.008-0.016 
                 0.125 
               
               
                 Example 36 K salt 
                 0.125 
                 0.5 
                 8 
                 0.25 
                 0.008 
                 0.125 
               
               
                 Example 37 K salt 
                 &gt;8 
                 &gt;8 
                 &gt;8 
                 &gt;8 
                 0.064 
                 &gt;8 
               
               
                 Example 38 K salt 
                 0.064-0.125 
                 0.125 
                 &gt;8 
                 1-2 
                 ≦0.004 
                 0.25 
               
               
                 Example 39 K salt 
                 0.064 
                 0.064 
                 2 
                 0.125 
                 ≦0.004 
                 0.064 
               
               
                 Example 40 K salt 
                 0.125-0.25 
                 0.25 
                 &gt;8 
                 0.5-1  
                 0.016 
                 0.25 
               
               
                 Example 41 K salt 
                 &gt;8 
                 &gt;8 
                 &gt;8 
                 &gt;8 
                 0.032 
                 &gt;8 
               
               
                 Example 42 
                 0.064 
                 2 
                 1 
                 0.125 
                 0.064 
                 1 
               
               
                 Example 43 K salt 
                 0.064-0.125 
                 0.25 
                 4 
                 0.125 
                 0.008 
                 0.25 
               
               
                 Example 44 K salt 
                 0.125 
                 0.125-0.25 
                 2 
                 0.25 
                 0.008 
                 0.25 
               
               
                 Example 45 K salt 
                 0.25 
                 0.25 
                 2 
                 0.5-1 
                 0.016 
                 0.25 
               
               
                 Example 46 K salt 
                 0.032 
                 0.064 
                 1-2 
                 0.064 
                 ≦0.004 
                 0.125 
               
               
                 Example 47 K salt 
                 0.25 
                 0.5 
                 4 
                  1-2 
                 0.032 
                 0.5 
               
               
                 Example 48 K salt 
                 0.064 
                 0.125 
                 2 
                 0.25 
                 ≦0.004 
                 0.25 
               
               
                 Ciprofloxacin 
                 0.008 
                 1 
                 0.25 
                 0.032 
                 0.016 
                 0.5 
               
               
                 Levofloxacin 
                 0.016 
                 0.25 
                 1 
                 0.032 
                 0.016 
                 0.25 
               
               
                 Moxyfloxacin 
                 0.032 
                 0.5 
                 2 
                 0.125 
                 0.032 
                 0.125 
               
               
                   
               
             
          
         
       
     
       Biological Example 2 
       [0537]    A select number of examples were tested against a broader panel of bacterial pathogens including clinical isolates and quinolone-resistant strains. MICs were determined as described in the latest CLSI guidelines—Methods for Dilution Antimicrobial 
         [0538]    Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard—Eighth Edition. In brief, a standardized bacterial inoculum containing 5×10 5  cfu/mL of each strain was exposed to series of 2-fold dilutions of each test compound in 100 μL of Mueller-Hinton Broth (MHB) in 96-well plates. After incubation at 37° C. for 16-20 hours in a humidified incubator, plates were scored visually to determine the lowest test concentration that inhibited visible growth, which corresponds to the Minimum Inhibitory Concentration or MIC. Results are shown for a selection of various representative bacteria from the Quotient Bioresearch (Cambridgeshire, UK) collection in Tables 3 and 4. The potassium salts of Tables 3 and 4 were prepared synthetically as described in General Procedure D (supra). 
         [0000]    
       
         
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                 TABLE 3 
               
               
                   
               
               
                   
                   
                 
                   Staphylococcus 
                 
                 
                   Enterococcus 
                 
                 
                   Enterococcus 
                 
                 
                   Streptococcus 
                 
                 
                   Streptococcus 
                 
                 Group C 
               
               
                   
                   
                 
                   aureus 
                 
                 
                   faecalis 
                 
                 
                   faecium 
                 
                 
                   pneumonia 
                 
                 
                   pyogenes 
                 
                 
                   Streptococcus 
                 
               
               
                 Cmpd ID 
                 MIC Range (μg/mL) 
                 (16 strains) 
                 (5 strains) 
                 (3 strains) 
                 (5 strains) 
                 (4 strains) 
                 (4 strains) 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 Example 1 
                 Low 
                 ≦0.015 
                 0.12 
                 1 
                 0.5 
                 0.5 
                 0.12 
               
               
                 K salt 
                 Median 
                 0.5 
                 0.12 
                 2 
                 0.5 
                 0.5 
                 0.25 
               
               
                   
                 High 
                 0.5 
                 4 
                 8 
                 0.5 
                 1 
                 0.5 
               
               
                 Example 2 
                 Low 
                 ≦0.015 
                 ≦0.015 
                 0.12 
                 0.06 
                 0.06 
                 0.03 
               
               
                 K salt 
                 Median 
                 0.06 
                 0.03 
                 0.5 
                 0.12 
                 0.09 
                 0.06 
               
               
                   
                 High 
                 0.25 
                 1 
                 2 
                 0.12 
                 0.12 
                 0.12 
               
               
                 Example 5 
                 Low 
                 ≦0.015 
                 0.03 
                 0.25 
                 0.12 
                 0.12 
                 0.06 
               
               
                 K salt 
                 Median 
                 0.12 
                 0.06 
                 1 
                 0.12 
                 0.12 
                 0.06 
               
               
                   
                 High 
                 0.25 
                 1 
                 4 
                 0.25 
                 0.5 
                 0.12 
               
               
                 Example 6 
                 Low 
                 0.03 
                 0.12 
                 1 
                 0.25 
                 0.12 
                 0.06 
               
               
                 K salt 
                 Median 
                 0.5 
                 0.25 
                 2 
                 0.25 
                 0.12 
                 0.12 
               
               
                   
                 High 
                 1 
                 4 
                 8 
                 0.25 
                 0.25 
                 0.12 
               
               
                 Example 16 
                 Low 
                 ≦0.015 
                 0.25 
                 1 
                 0.5 
                 0.25 
                 0.25 
               
               
                 K salt 
                 Median 
                 1 
                 0.25 
                 8 
                 0.5 
                 0.375 
                 0.25 
               
               
                   
                 High 
                 1 
                 8 
                 16 
                 1 
                 1 
                 0.5 
               
               
                 Example 21 
                 Low 
                 ≦0.015 
                 0.03 
                 0.25 
                 0.06 
                 0.06 
                 0.03 
               
               
                 K salt 
                 Median 
                 0.25 
                 0.12 
                 1 
                 0.06 
                 0.06 
                 0.03 
               
               
                   
                 High 
                 0.5 
                 2 
                 4 
                 0.12 
                 0.12 
                 0.06 
               
               
                 Example 23 
                 Low 
                 ≦0.015 
                 ≦0.015 
                 0.06 
                 ≦0.015 
                 ≦0.015 
                 ≦0.015 
               
               
                 K salt 
                 Median 
                 0.03 
                 ≦0.015 
                 0.25 
                 0.03 
                 0.03 
                 ≦0.015 
               
               
                   
                 High 
                 0.12 
                 0.25 
                 0.5 
                 0.03 
                 0.03 
                 0.03 
               
               
                 Example 28 
                 Low 
                 ≦0.015 
                 ≦0.015 
                 0.12 
                 0.03 
                 0.03 
                 0.03 
               
               
                 K salt 
                 Median 
                 0.06 
                 0.25 
                 0.25 
                 0.06 
                 0.06 
                 0.045 
               
               
                   
                 High 
                 0.12 
                 0.5 
                 1 
                 0.06 
                 0.06 
                 0.06 
               
               
                 Example 31 
                 Low 
                 ≦0.015 
                 0.06 
                 0.5 
                 0.06 
                 0.06 
                 0.06 
               
               
                 K salt 
                 Median 
                 0.5 
                 0.12 
                 4 
                 0.12 
                 0.09 
                 0.09 
               
               
                   
                 High 
                 2 
                 4 
                 8 
                 0.25 
                 0.25 
                 0.12 
               
               
                 Example 39 
                 Low 
                 ≦0.015 
                 ≦0.015 
                 0.12 
                 0.12 
                 0.06 
                 0.03 
               
               
                 K salt 
                 Median 
                 0.06 
                 0.03 
                 0.5 
                 0.12 
                 0.12 
                 0.09 
               
               
                   
                 High 
                 0.12 
                 0.5 
                 1 
                 0.25 
                 0.25 
                 0.12 
               
               
                 Example 42 
                 Low 
                 0.5 
                 4 
                 16 
                 4 
                 2 
                 2 
               
               
                   
                 Median 
                 16.25 
                 4 
                 &gt;32 
                 4 
                 3 
                 2 
               
               
                   
                 High 
                 32 
                 32 
                 &gt;32 
                 8 
                 8 
                 4 
               
               
                 Example 46 
                 Low 
                 ≦0.015 
                 ≦0.015 
                 0.12 
                 0.06 
                 0.03 
                 0.03 
               
               
                 K salt 
                 Median 
                 0.06 
                 0.03 
                 0.5 
                 0.06 
                 0.06 
                 0.045 
               
               
                   
                 High 
                 0.12 
                 0.5 
                 1 
                 0.12 
                 0.12 
                 0.06 
               
               
                 Levofloxacin 
                 Low 
                 0.12 
                 1 
                 2 
                 0.5 
                 0.5 
                 0.5 
               
               
                   
                 Median 
                 0.25 
                 2 
                 ≧16 
                 1 
                 0.75 
                 0.75 
               
               
                   
                 High 
                 ≧16 
                 ≧16 
                 ≧16 
                 2 
                 2 
                 1 
               
               
                   
               
             
          
         
       
     
         [0000]                                                                                  TABLE 4                         Escherichia       Klebsiella       Pseudomonas       Burkholderia       Haemophilus       Acinetobacter                   coli       pneumonia       aeruginosa       cepacia       influenza       baumannii         Cmpd ID   MIC Range (μg/mL)   (6 strains)   (4 strains)   (12 strains)   (5 strains)   (5 strains)   (12 strains)                                Example 1   Low   0.06   0.5   2   0.5   ≦0.015   0.25       K salt   Median   &gt;32   16   16   1   ≦0.015   20           High   &gt;32   &gt;32   32   2   0.03   &gt;32       Example 2   Low   ≦0.015   0.12   0.5   0.06   ≦0.015   0.06       K salt   Median   16   10   4   0.12   ≦0.015   6           High   16   16   16   0.25   ≦0.015   16       Example 5   Low   0.03   0.12   1   0.12   ≦0.015   0.06       K salt   Median   8   10   4   0.25   ≦0.015   6           High   16   16   16   0.5   ≦0.015   16       Example 6   Low   0.25   1   8   1   0.03   1       K salt   Median   &gt;32   &gt;32   &gt;32   2   0.03   &gt;32           High   &gt;32   &gt;32   &gt;32   4   0.06   &gt;32       Example 16   Low   0.03   0.12   2   0.25   ≦0.015   0.12       K salt   Median   &gt;32   16   16   0.25   ≦0.015   16           High   &gt;32   &gt;32   &gt;32   0.5   ≦0.015   &gt;32       Example 21   Low   ≦0.015   0.06   0.5   0.12   ≦0.015   0.03       K salt   Median   16   9   8   0.25   ≦0.015   4           High   32   32   32   0.25   ≦0.015   16       Example 23   Low   ≦0.015   0.06   0.25   ≦0.015   ≦0.015   0.03       K salt   Median   4   5   2   0.06   ≦0.015   3           High   16   16   16   0.25   ≦0.015   8       Example 28   Low   0.03   0.12   1   0.12   ≦0.015   0.06       K salt   Median   16   18   6   0.25   ≦0.015   8           High   32   &gt;32   &gt;32   0.5   ≦0.015   16       Example 31   Low   ≦0.015   0.03   0.5   0.12   ≦0.015   0.03       K salt   Median   8   9   8   0.5   ≦0.015   8           High   32   32   &gt;32   1   ≦0.015   &gt;32       Example 39   Low   ≦0.015   0.12   0.5   0.06   ≦0.015   0.06       K salt   Median   12   9   4   0.25   ≦0.015   4           High   16   32   16   0.5   ≦0.015   16       Example 42   Low   0.06   0.12   1   2   0.03   0.25           Median   32   8   32   2   0.06   &gt;32           High   &gt;32   &gt;32   &gt;32   2   0.06   &gt;32       Example 46   Low   ≦0.015   0.06   0.25   0.06   ≦0.015   0.03       K salt   Median   12   18   4   0.12   ≦0.015   4           High   32   &gt;32   &gt;32   0.12   ≦0.015   16       Levofloxacin   Low   0.015   0.03   1   1   0.008   0.12           Median   ≧16   2   ≧16   2   0.015   ≧16           High   ≧16   2   ≧16   2   0.015   ≧16                    
Gram positive strains in Tables 3 and 4 were as follow: The lab ID is the strain catalogue number of the strains of the Quotient Bioresearch (Cambridgeshire, UK) collection.
 
         [0000]                                Strains ID   Gram positive strains information                   GP1     Staphylococcus aureus  ATCC 29213 - antibiotic-susceptible type strain       GP3     Staphylococcus aureus  ATCC 43300 - methicillin-resistant type strain       GP4     Staphylococcus aureus  - methicillin-resistant clinical isolate       GP5     Staphylococcus aureus  - multi-drug-resistant clinical isolate       GP6     Staphylococcus aureus  - teicoplanin-intermediate clinical isolate       GP31   MU50  Staphylococcus aureus  (MRSA) - VISA type strain       GP32   EMRSA3  Staphylococcus aureus  (MRSA) - SSCmec type 1       GP33   EMRSA16  Staphylococcus aureus  (MRSA) - SSCmec type 2       GP34   EMRSA1  Staphylococcus aureus  (MRSA) - SSCmec type 3       GP35   EMRSA15  Staphylococcus aureus  (MRSA) - SSCmec type 4       GP36   HT2001254  Staphylococcus aureus  (MRSA) - PVL positive       GP79     Staphylococcus aureus  - levofloxacin-resistant clinical isolate, amino acid           changes GrlA &amp; GyrA       GP80     Staphylococcus aureus  - levofloxacin-resistant clinical isolate, amino acid           changes GrlA &amp; GyrA       GP81     Staphylococcus aureus  - levofloxacin-resistant clinical isolate, amino acid           changes GrlA &amp; GyrA       GP82     Staphylococcus aureus  - levofloxacin-resistant clinical isolate, amino acid           changes GrlA, GrlB &amp; GyrA       GP83     Staphylococcus aureus  - levofloxacin-resistant clinical isolate, amino acid           changes GrlA, GrlB &amp; GyrA       GP7     Staphylococcus epidermidis  - antibiotic susceptible clinical isolate       GP8     Staphylococcus epidermidis  - methicillin-resistant clinical isolate       GP9     Staphylococcus haemolyticus  - antibiotic susceptible clinical isolate       GP10     Staphylococcus saprophyticus  - antibiotic susceptible clinical isolate       GP11     Enterococcus faecalis  - ATCC 29212 antibiotic-susceptible type strain       GP64     Enterococcus faecalis  - vancomycin-susceptible clinical isolate       GP56     Enterococcus faecalis  - vancomycin-resistant (VanA) clinical isolate       GP14     Enterococcus faecalis  - vancomycin-resistant (VanB) clinical isolate       GP58     Enterococcus faecalis  - high-level gentamicin-resistant clinical isolate       GP16     Enterococcus faecium  - vancomycin-susceptible clinical isolate       GP17     Enterococcus faecium  - vancomycin-resistant (VanA) clinical isolate       GP18     Enterococcus faecium  - vancomycin-resistant (VanB) clinical isolate       GP19     Enterococcus gallinarum  - vancomycin-resistant (VanC) clinical isolate       GP20     Streptococcus pneumoniae  - ATCC 49619 antibiotic-susceptible type strain       GP21     Streptococcus pneumoniae  - penicillin-susceptible clinical isolate       GP22     Streptococcus pneumoniae  - penicillin-intermediate clinical isolate       GP23     Streptococcus pneumoniae  - penicillin-resistant clinical isolate       GP24     Streptococcus pneumoniae  - multi-drug resistant clinical isolate       GP59     Streptococcus pyogenes  - antibiotic-susceptible clinical isolate       GP61     Streptococcus pyogenes  - ATCC 19615       GP26     Streptococcus pyogenes  - Macrolide (MLS) resistant clinical isolate       GP60     Streptococcus pyogenes  - Macrolide (M-type) resistance clinical isolate       GP37     Streptococcus agalactiae  - antibiotic-susceptible clinical isolate       GP38     Streptococcus agalactiae  - macrolide-resistant clinical isolate       GP39   Group C  Streptococcus  - antibiotic-susceptible clinical isolate       GP55   Group C  Streptococcus  - macrolide-resistant clinical isolate       GP41   Group G  Streptococcus  - antibiotic-susceptible clinical isolate       GP42   Group G  Streptococcus  - macrolide-resistant clinical isolate       GP43     Streptococcus mitis  - antibiotic-susceptible clinical isolate       GP44     Streptococcus mitis  - macrolide-resistant clinical isolate       GP62     Streptococcus constellatus  - antibiotic-susceptible clinical isolate       GP63     Streptococcus constellatus  - macrolide-resistant clinical isolate       GP47     Streptococcus oralis  - antibiotic-susceptible clinical isolate       GP48     Streptococcus oralis  - macrolide-resistant clinical isolate       GP49     Streptococcus bovis  - antibiotic-susceptible clinical isolate       GP50     Streptococcus bovis  - macrolide-resistant clinical isolate       GP51     Streptococcus sanguis  - antibiotic-susceptible clinical isolate       GP52     Streptococcus sanguis  - macrolide-resistant clinical isolate       GP28     Corynebacterium jeikeium  - antibiotic-susceptible clinical isolate       GP29     Corynebacterium jeikeium  - multi-drug resistant clinical isolate       GP30     Listeria monocytogenes  - antibiotic-susceptible clinical isolate                    
Gram negative strains in Tables 3 and 4 were as follow: (The lab ID is the strain catalogue number of the strains of the Quotient Bioresearch (Cambridgeshire, UK) collection)
 
         [0000]    
       
         
               
               
             
           
               
                   
               
               
                 Strains ID 
                 Gram negative strain information 
               
               
                   
               
             
             
               
                 GN01 
                   Escherichia coli  ATCC 25922 - antibiotic-susceptible type strain 
               
               
                 GN02 
                   Escherichia coli  ATCC 35218 - β-lactamase positive type strain 
               
               
                 GN03 
                   Escherichia coli  - multi-drug resistant clinical isolate 
               
               
                 GN41 
                   Escherichia coli  - ESBL - TEM 
               
               
                 GN42 
                   Escherichia coli  - ESBL - CTXM 
               
               
                 GN43 
                   Escherichia coli  - ESBL - SHV 
               
               
                 GN04 
                   Klebsiella aerogenes  NCTC 11228 - antibiotic-susceptible type strain 
               
               
                 GN05 
                   Klebsiella aerogenes  - multi-drug resistant clinical isolate 
               
               
                 GN44 
                   Klebsiella pneumoniae  - ESBL - TEM + SHV 
               
               
                 GN45 
                   Klebsiella pneumoniae  - ESBL - CTXM 
               
               
                 GN46 
                   Klebsiella pneumoniae  - ESBL - SHV 
               
               
                 GN48 
                   Klebsiella pneumoniae  NCTC 13443 - NDM-1 metallo-β-lactamase 
               
               
                 GN06 
                   Enterobacter  sp - antibiotic-susceptible clinical isolate 
               
               
                 GN07 
                   Enterobacter  sp - multi-drug resistant clinical isolate 
               
               
                 GN08 
                   Serratia marcescens  - antibiotic-susceptible clinical isolate 
               
               
                 GN09 
                   Serratia marcescens  - multi-drug resistant clinical isolate 
               
               
                 GN10 
                   Pseudomonas aeruginosa  ATCC 27853 - antibiotic-susceptible type strain 
               
               
                 GN11 
                   Pseudomonas aeruginosa  - multi-drug resistant clinical isolate 
               
               
                 GN40 
                   Pseudomonas aeruginosa  - Liverpool genotype LES 431 
               
               
                 GN63 
                   Pseudomonas aeruginosa  - levofloxacin-resistant clinical isolate 
               
               
                 GN64 
                   Pseudomonas aeruginosa  - levofloxacin-resistant clinical isolate 
               
               
                 GN65 
                   Pseudomonas aeruginosa  - levofloxacin-resistant clinical isolate 
               
               
                 GN66 
                   Pseudomonas aeruginosa  - levofloxacin-resistant clinical isolate 
               
               
                 GN67 
                   Pseudomonas aeruginosa  - levofloxacin-resistant clinical isolate 
               
               
                 GN68 
                   Pseudomonas aeruginosa  - levofloxacin-resistant clinical isolate 
               
               
                 GN69 
                   Pseudomonas aeruginosa  - levofloxacin-resistant clinical isolate 
               
               
                 GN70 
                   Pseudomonas aeruginosa  - levofloxacin-resistant clinical isolate 
               
               
                 GN71 
                   Pseudomonas aeruginosa  - levofloxacin-resistant clinical isolate 
               
               
                 GN12 
                   Stenotrophomonas maltophilia  - antibiotic-susceptible clinical isolate 
               
               
                 GN13 
                   Stenotrophomonas maltophila  - antibiotic-resistant clinical isolate 
               
               
                 GN14 
                   Burkholderia cepacia  - antibiotic-susceptible clinical isolate 
               
               
                 GN59 
                   Burkholderia cepacia  - antibiotic-susceptible clinical isolate 
               
               
                 GN60 
                   Burkholderia cepacia  - antibiotic-susceptible clinical isolate 
               
               
                 GN61 
                   Burkholderia cepacia  - antibiotic-susceptible clinical isolate 
               
               
                 GN62 
                   Burkholderia cepacia  - antibiotic-susceptible clinical isolate 
               
               
                 GN15 
                   Proteus mirabilis  - antibiotic-susceptible clinical isolate 
               
               
                 GN16 
                   Proteus mirabilis  - multi-drug resistant clinical isolate 
               
               
                 GN19 
                   Shigella  sp - antibiotic-susceptible clinical isolate 
               
               
                 GN20 
                   Shigella  sp - multi-drug resistant clinical isolate 
               
               
                 GN34 
                   Morganella morganii  - antibiotic-susceptible clinical isolate 
               
               
                 GN22 
                   Morganella morganii  - multi-drug resistant clinical isolate 
               
               
                 GN23 
                   Providencia stuartii  - antibiotic-susceptible clinical isolate 
               
               
                 GN24 
                   Providencia stuartii  - multi-drug resistant clinical isolate 
               
               
                 GN25 
                   Neisseria meningitidis  - antibiotic-susceptible clinical isolate susceptible 
               
               
                 GN35 
                   Haemophilus influenzae  - β-lactamase negative clinical isolate 
               
               
                 GN36 
                   Haemophilus influenzae  - β-lactamase positive clinical isolate 
               
               
                 GN37 
                   Haemophilus influenzae  β-lactamase negative ampicillin-resistant clinical 
               
               
                   
                 isolate 
               
               
                 GN29 
                   Moraxella catarrhalis  β-lactamase positive clinical isolate 
               
               
                 GN30 
                   Moraxella catarrhalis  β-lactamase positive clinical isolate 
               
               
                 GN31 
                   Acinetobacter baumannii  - antibiotic-susceptible clinical isolate 
               
               
                 GN32 
                   Acinetobacter baumannii  - multi-drug resistant clinical isolate 
               
               
                 GN49 
                   Acinetobacter baumannii  - levofloxacin-resistant clinical isolate 
               
               
                 GN50 
                   Acinetobacter baumannii  - levofloxacin-resistant clinical isolate 
               
               
                 GN51 
                   Acinetobacter baumannii  - levofloxacin-resistant clinical isolate 
               
               
                 GN52 
                   Acinetobacter baumannii  - levofloxacin-resistant clinical isolate 
               
               
                 GN53 
                   Acinetobacter baumannii  - levofloxacin-resistant clinical isolate 
               
               
                 GN54 
                   Acinetobacter baumannii  - levofloxacin-resistant clinical isolate 
               
               
                 GN55 
                   Acinetobacter baumannii  - levofloxacin-resistant clinical isolate 
               
               
                 GN56 
                   Acinetobacter baumannii  - levofloxacin-resistant clinical isolate 
               
               
                 GN57 
                   Acinetobacter baumannii  - levofloxacin-resistant clinical isolate 
               
               
                 GN58 
                   Acinetobacter baumannii  - levofloxacin-resistant clinical isolate 
               
               
                 GN38 
                   Citrobacter freundii  - antibiotic-susceptible clinical isolate 
               
               
                 GN39 
                   Citrobacter freundii  - resistant clinical isolate 
               
               
                   
               
             
          
         
       
     
       Biological Example 3 
       [0539]    A select number of examples were tested against a collection of bacterial pathogens resistant against quinolones antibiotics. MICs were determined as described in the latest CLSI guidelines—Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard—Eighth Edition. In brief, a standardized bacterial inoculum containing 5×10 5  cfu/mL of each strain was exposed to series of 2-fold dilutions of each test compound in 100 μL of Mueller-Hinton Broth (MHB) in 96-well plates. After incubation at 37° C. for 16-20 hours in a humidified incubator, plates were scored visually to determine the lowest test concentration that inhibited visible growth, which corresponds to the Minimum Inhibitory Concentration or MIC. Results are shown for representative bacteria in Table 5. The potassium salts of Table 5 were prepared synthetically as described in General Procedure D (supra). 
         [0000]    
       
         
               
               
             
               
               
               
               
               
               
             
               
               
             
               
               
               
               
               
               
             
               
               
             
               
               
               
               
               
               
             
               
               
             
               
               
               
               
               
               
             
           
               
                   
                 TABLE 5 
               
               
                   
                   
               
             
             
               
                   
                 MICs (μg/mL) 
               
               
                   
                 Quotient Bioresearch Strains Catalogue Number 
               
             
          
           
               
                   
                 GP5 
                 GP33 
                 GP82 
                 GP14 
                 GP17 
               
             
          
           
               
                   
                 Strains Description 
               
             
          
           
               
                   
                   
                 EMRSA16 
                 
                   Staphylococcus aureus 
                 
                   
                   
               
               
                   
                   
                 
                   Staphylococcus 
                 
                 levofloxacin-resistant 
                 
                   Enterococcus faecalis 
                 
                 
                   Enterococcus faecium 
                 
               
               
                   
                 
                   Staphylococcus aureus 
                 
                 
                   aureus 
                 
                 clinical isolate, 
                 vancomycin-resistant 
                 vancomycin-resistant 
               
               
                   
                 multi-drug-resistant 
                 (MRSA) - 
                 amino acid changes 
                 (VanB) 
                 (VanA) 
               
               
                   
                 clinical isolate 
                 SSCmec type 2 
                 GrlA, GrlB &amp; GyrA 
                 clinical isolate 
                 clinical isolate 
               
               
                   
               
               
                 Example 2 K 
                 0.06 
                 0.12 
                 0.06 
                 0.5 
                 2 
               
               
                 salt 
               
               
                 Example 21 
                 0.25 
                 0.25 
                 0.12 
                 1 
                 4 
               
               
                 K salt 
               
               
                 Example 23 
                 0.03 
                 0.03 
                 ≦0.015 
                 0.25 
                 0.5 
               
               
                 K salt 
               
               
                 Example 28 
                 0.06 
                 0.06 
                 0.03 
                 0.25 
                 1 
               
               
                 K salt 
               
               
                 Example 46 
                 0.06 
                 0.06 
                 0.03 
                 0.5 
                 1 
               
               
                 K salt 
               
               
                 Levofloxacin 
                 ≧16 
                 ≧16 
                 8 
                 ≧16 
                 ≧16 
               
               
                   
               
             
          
           
               
                   
                 MICs (μg/mL) 
               
               
                   
                 Quotient Bioresearch Strains Catalogue Number 
               
             
          
           
               
                   
                 GP24 
                 GN03 
                 GN64 
                 GN24 
                 GN54 
               
             
          
           
               
                   
                 Strains Description 
               
             
          
           
               
                   
                 
                   Streptococcus 
                 
                   
                 
                   Pseudomonas 
                 
                   
                 
                   Acinetobacter 
                 
               
               
                   
                 
                   pneumoniae 
                 
                 
                   Escherichia coli 
                 
                 
                   aeruginosa 
                 
                 
                   Providencia stuartii 
                 
                 
                   baumannii 
                 
               
               
                   
                 multi-drug resistant 
                 multi-drug resistant 
                 levofloxacin-resistant 
                 multi-drug resistant 
                 levofloxacin-resistant 
               
               
                   
                 clinical isolate 
                 clinical isolate 
                 clinical isolate 
                 clinical isolate 
                 clinical isolate 
               
               
                   
               
               
                 Example 2 K 
                 0.12 
                 16 
                 2 
                 1 
                 2 
               
               
                 salt 
               
               
                 Example 21 
                 0.12 
                 16 
                 4 
                 2 
                 4 
               
               
                 K salt 
               
               
                 Example 23 
                 0.03 
                 4 
                 2 
                 1 
                 1 
               
               
                 K salt 
               
               
                 Example 28 
                 0.06 
                 16 
                 4 
                 1 
                 2 
               
               
                 K salt 
               
               
                 Example 46 
                 0.12 
                 8 
                 4 
                 2 
                 2 
               
               
                 K salt 
               
               
                 Levofloxacin 
                 2 
                 ≧16 
                 ≧16 
                 ≧16 
                 ≧16 
               
               
                   
               
             
          
         
       
     
       Biological Example 4 
       [0540]    A number of examples were tested against a panel of class A and B select biothreat agents as defined by the CDC (Centers for Disease Control and Prevention). MICs were determined as described in the latest CLSI guidelines—Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard—Eighth Edition. In brief, a standardized bacterial inoculum containing 5×10 5  cfu/mL of each strain was exposed to series of 2-fold dilutions of each test compound in 100 μL of Mueller-Hinton Broth (MHB) in 96-well plates. After incubation at 37° C. for the indicated time in a humidified incubator, plates were scored visually to determine the lowest test concentration that inhibited visible growth, which corresponds to the Minimum Inhibitory Concentration or MIC. Experiments were performed under Biosafety Level 3 containment. Results are shown for representative bacteria in Table 6. (* F. tularensis  and  B. abortus  were incubated for 48±2 hours; all other strains were incubated for 24±2 hours.) The potassium salts of Table 6 were prepared synthetically as described in General Procedure D (supra). 
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                 TABLE 6 
               
             
             
               
                   
                   
               
               
                   
                 MIC (μg/mL) 
               
             
          
           
               
                   
                   
                   
                   
                 
                   Burkholderia 
                 
                   
                   
               
               
                   
                 
                   Bacillus anthracis 
                 
                 * Brucella abortus   
                 
                   Burkholderia mallei 
                 
                   pseudomallei  ATCC 
                 * Francisella tularensis   
                 
                   Yersinia pestis 
                 
               
               
                 Compounds 
                 Ames strain 
                 ATCC 23448 
                 ATCC 23344 
                 23343 
                 Schu S4 
                 CO92 
               
               
                   
               
             
          
           
               
                 Example 1 
                 0.004 
                 0.031 
                 0.25-0.5 
                 0.5 
                 0.016 
                 0.031 
               
               
                 K salt 
               
               
                 Example 2 
                 0.004 
                 0.016-0.031 
                 0.063 
                 0.063 
                 0.016 
                 0.031 
               
               
                 K salt 
               
               
                 Example 3 
                 0.008 
                 0.125 
                 0.5-1  
                 0.25 
                 0.031 
                 0.031-0.063 
               
               
                 K salt 
               
               
                 Example 8 
                 0.008 
                 0.063 
                 0.25 
                 0.125 
                 0.031 
                 0.031 
               
               
                 K salt 
               
               
                 Example 9 
                 0.008 
                 0.063 
                 0.125-0.25 
                 0.25 
                 0.016 
                 0.031 
               
               
                 K salt 
               
               
                 Example 16 
                 0.016 
                 0.063 
                 0.125 
                 0.125 
                 0.016-0.031 
                 0.031 
               
               
                 K salt 
               
               
                 Example 20 
                 0.031 
                 0.063 
                 0.125 
                 0.25 
                 0.008-0.016 
                 0.063 
               
               
                 K salt 
               
               
                 Example 21 
                 0.016 
                 0.063 
                 0.125-0.25 
                 0.25-0.5  
                 0.031 
                 0.031 
               
               
                 K salt 
               
               
                 Example 23 
                 0.004 
                 0.016 
                 0.063 
                 0.063 
                 0.016 
                 0.016-0.031 
               
               
                 K salt 
               
               
                 Example 28 
                 0.004 
                 00.031-0.063 
                 0.125-0.25 
                 0.125 
                 0.008 
                 0.016-0.031 
               
               
                 K salt 
               
               
                 Example 31 
                 0.016-0.031 
                 0.25 
                 0.5-1  
                 1 
                 0.125-0.5  
                 0.25 
               
               
                 K salt 
               
               
                 Example 42 
                 0.25 
                 40575 
                 2 
                 4 
                 0.25-0.5  
                 0.5-1   
               
               
                 Example 45 
                 0.016 
                 0.031 
                  0.063-0.125 
                 0.063-0.125 
                 0.008-0.016 
                 0.031 
               
               
                 K salt 
               
               
                 Example 46 
                 0.004 
                 0.031 
                 0.063 
                 0.063 
                 0.016 
                 0.008-0.016 
               
               
                 K salt 
               
               
                 Example 48 
                 0.008 
                 0.031 
                 0.125 
                 0.125 
                 0.016 
                 0.031 
               
               
                 K salt 
               
               
                 Ciprofloxacin 
                 0.063 
                 1 
                 4 
                 4 
                 0.063 
                 0.25 
               
               
                   
               
             
          
         
       
     
       Biological Example 5 
       [0541]    Inhibition of topoisomerases activity was carried out in vitro. A select number of examples were tested against bacterial gyrase and topoisomerase IV as well as human topoisomerases I and II. Protocols TG1003, TG1007, TG1015 and TG1001 from Topogen Inc., Port Orange, USA were used respectively. Results are shown for representative compounds in Table 7. The potassium salts of Table 7 were prepared synthetically as described in General Procedure D (supra). 
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                 TABLE 7 
               
             
             
               
                   
                   
               
               
                   
                 IC 50  (μM) 
               
             
          
           
               
                   
                 Gyrase 
                 Topo IV 
                 hTopo II 
                 hTopo I 
               
               
                 Compounds 
                 Assay 
                 Assay 
                 Assay 
                 Assay 
               
               
                   
               
             
          
           
               
                 Example 2 K salt 
                 ≦1.42 
                 4.43 
                   
                   
               
               
                 Example 21 K salt 
                 ≦1.49 
                 ≦2.33 
               
               
                 Example 23 K salt 
                 ≦1.39 
                 4.34 
                 &gt;35 
                 &gt;140 
               
               
                 Example 28 K salt 
                 0.68 
                 ≦8.45 
                 68 
                 135 
               
               
                 Ciprofloxacin 
                 ≦0.75 
                 ≦4.71 
                 &gt;150 
                 &gt;150 
               
               
                   
               
             
          
         
       
     
       Biological Example 6 
       [0542]    Metabolic stability of a select number of examples was tested in liver microsomes+/−addition of S9 fraction as described by Kuhnz, W. and Gieschen, H. (1998),  Drug Metab. Dispos.,  1120-1127. Test concentration was 1 μM and HPLC/MS-MS was used for detection. Results are shown for representative compounds in Table 8. The potassium salts of Table 8 were prepared synthetically as described in General Procedure D (supra). 
         [0000]    
       
         
               
               
             
               
               
               
             
               
               
               
               
               
             
               
               
               
               
               
             
           
               
                   
                 TABLE 8 
               
             
             
               
                   
                   
               
               
                   
                 Mean Parent Remaining (%) 
               
             
          
           
               
                   
                 Liver microsomes 
                 Liver microsomes + S9 
               
             
          
           
               
                 Compounds 
                 human 
                 mouse 
                 human 
                 mouse 
               
               
                   
               
             
          
           
               
                 Example 2 K salt 
                 90 
                 53 
                 95 
                 58 
               
               
                 Example 21 K salt 
                 85 
                 87 
                 93 
                 97 
               
               
                 Example 23 K salt 
                 67 
                 2 
                 80 
                 2 
               
               
                 Example 28 K salt 
                 97 
                 30 
                 93 
                 48 
               
               
                 Example 46 K salt 
                 86 
                 81 
                 97 
                 92 
               
               
                   
               
             
          
         
       
     
       Biological Example 7 
       [0543]    Groups of 21 mice were treated with select examples at 10 mg/kg. Mice were treated either intravenously or orally (by gavage). At predetermined time points (0.25, 0.5, 1, 2, 4, 8 and 24 hours), 3 mice were sacrificed and blood samples drawn by cardiac puncture. Plasma was obtained by centrifugation and stored at −80° C. Plasma samples were analyzed by LC-MS for remaining amounts of compounds. Results are shown for representative compounds in Table 9. The potassium salts of Table 9 were prepared synthetically as described in General Procedure D (supra). 
         [0000]    
       
         
               
               
               
               
             
               
               
               
               
               
               
               
               
             
               
               
               
               
               
               
               
               
             
           
               
                   
                 TABLE 9 
               
             
             
               
                   
                   
               
               
                   
                 p.o. 
                 i.v. 
                   
               
             
          
           
               
                   
                   
                 AUC 0-inf   
                 Elimination 
                   
                 AUC 0-inf   
                 Elimination 
                   
               
               
                   
                 C max   
                 (μg- 
                 Half life 
                 C max   
                 (μg- 
                 Half life 
               
               
                 Cmpd. 
                 (μg/mL) 
                 hr/mL) 
                 (hrs) 
                 (μg/mL) 
                 hr/mL) 
                 (hrs) 
                 % F 
               
               
                   
               
             
          
           
               
                 Ex. 2 
                 0.394 
                 0.642 
                 1.513 
                 2.104 
                 1.344 
                 1.477 
                 47.77 
               
               
                 K salt 
               
               
                 Ex. 21 
                 0.242 
                 0.471 
                 2.106 
                 0.467 
                 N.A. 
                 1.315 
                 N.A. 
               
               
                 K salt 
               
               
                 Ex. 23 
                 0.866 
                 1.75 
                 0.988 
                 3.432 
                 2.038 
                 1.162 
                 85.87 
               
               
                 K salt 
               
               
                 Ex. 28 
                 0.227 
                 0.71 
                 3.332 
                 2.854 
                 1.652 
                 1.073 
                 42.98 
               
               
                 K salt 
               
               
                 Ex. 46 
                 0.156 
                 0.389 
                 4.156 
                 1.055 
                 0.474 
                 1.07 
                 82.07 
               
               
                 K salt 
               
               
                   
               
             
          
         
       
     
       Biological Example 8 
       [0544]    For in vivo efficacy a mouse thigh model was used. Bacterial strains were injected into both lateral thigh muscles of mice immunosuppressed with cyclophosphamide. The first dose of compound examples was given orally one hour after infection followed by 2 more doses after 8 and 16 hours. Animals were sacrificed 24 hours after infection, the thigh muscles were surgically removed and homogenized, homogenates spread on agar plates in appropriate dilutions and incubated at 37° C. for 24 to 48 hours before counting the number of colony forming units (CFU). Results are shown for representative compounds in Table 10. The potassium salts of Table 10 were prepared synthetically as described in General Procedure D (supra). 
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                 TABLE 10 
               
             
             
               
                   
                   
               
               
                   
                 Log reduction (LgR) from vehicle control (CFU/g) 
               
               
                   
                 Examples 
               
             
          
           
               
                   
                 Example 
                 Example 
                 Example 
                   
                   
               
               
                   
                 21 K salt 
                 23 K salt 
                 46 K salt 
                 vancomycin 
                 ciprofloxacin 
               
               
                   
                   
               
             
          
           
               
                 Dosing 
                 30 mg/kg 
                 30 mg/kg 
                 30 mg/kg 
                 25 mg/kg 
                  20 mg/kg 
               
               
                   
                 TDS p.o. 
                 TDS p.o. 
                 TDS p.o. 
                 i.v. once 
                 i.v. TDS 
               
               
                 MRSA 
                 4.93 
                 4.66 
                 3.76 
                 2.71 
                 2.36 
               
               
                 ATCC 
               
               
                 43300 
               
               
                 Dosing 
                 30 mg/kg 
                 30 mg/kg 
                 30 mg/kg 
                 N.A. 
                 1.5 mg/kg 
               
               
                   
                 TDS p.o. 
                 TDS p.o. 
                 TDS p.o. 
                   
                 i.v. BD  
               
               
                 
                   E. coli 
                 
                 3.13 
                 2.82 
                 0.37 
                 N.A. 
                 3.18 
               
               
                 ATCC 
               
               
                 25922 
               
               
                   
               
             
          
         
       
     
       Biological Example 9 
       [0545]    A number of compounds were evaluated for thermodynamic solubility according to the shake flask technique at 200 μM. The solutions were incubated at room temperature for 24 hours before quantification by HPLC detection. Aqueous solubility was evaluated in simulated gastric fluid (SGF), simulated intestinal fluid (SIF) and phosphate buffer saline (PBS) pH 7.4. Aqueous solubility is expressed in Table 11 as mean solubility in μM. 
         [0000]    
       
         
               
               
             
               
               
               
               
             
               
               
               
               
             
           
               
                   
                 TABLE 11 
               
             
             
               
                   
                   
               
               
                   
                 Aqueous Solubility (Mean in μM) 
               
             
          
           
               
                   
                 Simulated Gastric 
                 Simulated Intestinal 
                 PBS 
               
               
                 Compounds 
                 Fluid 
                 Fluid 
                 pH 7.4 
               
               
                   
               
             
          
           
               
                 Example 2 K salt 
                 21 
                 171 
                 28 
               
               
                 Example 21 K salt 
                 200 
                 200 
                 200 
               
               
                 Example 23 K salt 
                 8 
                 105 
                 37 
               
               
                 Example 28 K salt 
                 12 
                 153 
                 6 
               
               
                 Example 46 K salt 
                 7 
                 153 
                 44