# Patent

## Title
Anti-mycobacterial drugs against tuberculosis

## Abstract

The present invention relates to the field of anti-mycobacterial therapeutics, in particular the treatment of tuberculosis, especially including pulmonary multidrug-resistant tuberculosis (MDR-TB), with applications in extensively drug-resistant tuberculosis (XDR-TB) and extremely drug-resistant tuberculosis (XXDR-TB), preferably in combination therapy.

## Background
RELATED APPLICATIONS AND GRANT SUPPORT
This application is a United States national phase application claiming the benefit of priority from international application no. PCT/US2013/030687, of identical title, filed on Mar. 13, 2013 which claims the benefit of priority from provisional application Ser. No. 61/618,707, filed Mar. 31, 2012, of identical title, the entire contents of each of said applications being incorporated by reference in its entirety herein.


The present invention was supported in the early phases of discovery through support from the National Institutes of Health under grant R01 AI 43181. Consequently, the government has certain rights in the invention.


FIELD OF THE INVENTION
The present invention relates to the field of anti-mycobacterial therapeutics, in particular the treatment of pulmonary multidrug-resistant tuberculosis (MDR-TB), with applications in extensively drug-resistant tuberculosis (XDR-TB) and extremely drug-resistant tuberculosis (XXDR-TB), preferably in combination therapy.
BACKGROUND AND DISCUSSION OF THE INVENTION
Mycobacterium tuberculosis (TB) is a contagious, largely pulmonary, disease that is spread through the air. Only a small number of TB bacilli are needed to cause an infection. Almost a third of the world's population is currently infected with TB. Of the people who are infected with TB but who are not infected with HIV, some 5-10% become sick or are infectious at some period during their lifetime (WHO Fact Sheet, November, 2010, WHO report 2011: Global Tuberculosis Control). People with HIV are much more likely to develop TB. An estimated 1.7 million people died from TB in 2009. Also, multidrug-resistant M. tuberculosis, MDR-TB, is spreading [Orenstein, et al., Lancet Infect. Dis. 9, 153-161 (2009); Russell, et al., Science 328, 852-856 (2010); Dye, et al., Science 328, 856-861; (2010)]. Further complicating the TB picture worldwide is the emergence of extensively drug-resistant tuberculosis, XDR-TB and extremely drug-resistant tuberculosis, XXDR-TB (WHO: Drug Resistant TB, 2012).
However, there have been relatively few new agents discovered in the last 40 years to treat TB [Aristoff, et al., Tuberculosis 90, 94-118 (2010), Koul., et al., Nature 469, 483-490 (2100)]. Among the most used TB drugs are rifampin and its analogs, isoniazid, pyrazinamide, ethambutol and fluoroquinolone. The drug pipeline today is relatively thin with only 10 new or repurposed drugs in clinical trials [Zumla, et al., Nat. Rev. Drug Discov. 11, 171-172 (2012); New TB Drugs Website, 2011, online; Sundaramurthi, et al., Tuberculosis 92, 133-138 (2012); Luetkemeyer, et al., Am. J. Respir. Crit. Care Med. 184, 1107-1113 (2011); Lienhardt, et al., Curr. Opin. Pulm. Med. 16, 186-193 (2010); Ma, et al., Lancet, 375, 2100-2109 (2010)]. One of those drugs [bedaquiline, also referred to as R207910, TMC207, Andries, et al., Science 307, 223-227 (2005), Koul, et al., CA2529265A1; Porstmann, F. R., et al., WO2006125769A1; Brickner, S. J., et al., WO2010026526A1; Devito, et al., WO2011139832A2] was approved by the FDA in December 2012 as part of a combination treatment regimen for MDR-TB (NDA 204-384). Examples of other drugs in the clinical phase of development include: gatifloxacin [Ma, et al., Lancet 375, 2100-2109 (2010), He, et al., CN102198138A, Patel, et al., WO2011101710A1, Ismail, et al., WO2012057599A1]; moxifloxacin [Ji, et al., Antimicrob. Agents Chemother. 42, 2066-2069 (1998), Miyazaki, et al., Antimicrob. Agents Chemother. 43, 85-89 (1999), Alvirez-Freites, et al., Antimicrob. Agents Chemother. 46, 1022-1025 (2002), Bosche, et al., WO2000027398A1; McCarthy, et al., WO2003099229A2; Zeldis, et al., WO2010093588A1]; sudoterb [Ginsberg, Drugs 70, 2201-2214 (2010), Arora, et al., WO2004026828A1, Arora, et al., WO2006109323A1]; PNU100480 [Williams, et al., Antimicrob. Agents Chemother. 53, 1314-1319 (2009), Barbachyn, et al., WO9507271A1, Watts, et al., WO2002002121A2; Brickner, et al., WO2010026526A1, Wallis, WO2010122456A1]; AZD5847 [Williams, et al., Antimicrob. Agents Chemother. 53, 1314-1319 (2009), Kim, et al., WO2012144790A1]; SQ109 [Protopopova, et al., J. Antimicrob. Chemother. 56, 968-974 (2005), Sutcliffe, WO2007133803A2, Meng, Q., et al., CN101468958A]; OPC67683 [Singh, et al., Science 322, 1392-1395 (2008), Singh, et al., WO2007133803A2]; PA824 [Singh, et al., Science 322, 1392-1395 (2008), Sutcliffe, WO2007133803A2, Papadopoulou, et al., US20080076797A1, Singh, et al., WO2008005651A2, Devito, et al., WO2011139832A2].
MDR-TB is resistant to isoniazid and rifampin, the two drugs that are used commonly for drug-susceptible TB and with treatment-adherent TB patients. MDR-TB that has also developed resistance to one of the injectable second line TB drugs (kanamycin, capreomycin or amikacin) and also to a fluoroquinolone drug is classed as XDR-TB. XDR-TB can be treated with other second-line TB drugs, but the treatment is more difficult, more expensive and there may be more side effects. XXDR-TB is resistant to both first line and second line TB drugs and is extremely difficult to treat. In general, treatment for all drug-resistant TB can be complicated, lengthy and may be problematic, in part because of issues of toxicity.
Our research work on retroviral integrase inhibitors has led to the discovery of highly active compounds against a diverse set of primary HIV-1 isolates [Nair, et al., US 2012 0282218 A1, Nair, et al., PCT International Patent Application No. WO 2011/071849 A2, Nair, et al., ASM ICAAC Conference H2-801 (2011)]. In investigating the molecular modeling details of the mechanism of action of our active integrase inhibitors, it was apparent that these inhibitors had one common feature, i.e., they were all interacting with the DDE catalytic triad and also with two divalent magnesium ions in the catalytic core domain of HIV integrase. The DDE motif is essential for integrase catalysis [Nair, et al., Rev. Med. Virol. 17, 277-295 (2007), Nair, et al., J. Med. Chem. 49, 445-447 (2006), Frankel, et al., Annu. Rev. Biochem. 67, 1-25 (1998)]. However, our best integrase inhibitors of this class, while exhibiting potent anti-HIV activity [Nair, et al., US 2012 0282218 A1, Nair, et al., PCT International Patent Application No. WO 2011/071849 A2, Nair, et al., ASM ICAAC Conference H2-801 (2011], did not show as compelling a level of anti-MDR TB activity as the novel compounds of the current invention.
The catalytic core domain of DNA-dependent RNA polymerase (RNAP) of bacteria is conserved among cellular organisms [Archambault, et al., Microbiol. Mol. Biol Rev. 57, 703-724 (1993)]. Examination of the crystal structure [Zhang, et al., Cell 98, 811-824 (1999)] of the RNAP of Thermus acquaticus (a model for TB RNAP), with bound rifampin, a first-line drug for TB, shows that rifampin binds to the β-site on the RNAP and inhibits RNA synthesis by blocking the path of the elongating RNA, which is believed to be its mechanism of action [Campbell, et al., Cell 104, 901-912 (2001)]. However, there are other sites existing on TB RNAP that could be targeted by inhibitors to interfere with this RNAP's functional mechanism. For example, there is a pocket on the TB RNAP catalytic core domain that contains a structural region that bears some resemblance to the catalytic triad area of the catalytic core domain of HIV-1 integrase [Frankel, et al., Annu. Rev. Biochem. 67, 1-25 (1998), Cox and Nair, Antimicrob. Agents Chemother. 17, 343-353 (2006)]. This is the β′-site of this RNAP, which is close to 18 Å away from the binding location of rifampin in the β-site. Computational chemical biology and molecular modeling experiments revealed that our novel anti-TB compounds described in this invention are capable of binding inside the catalytic channel of the RNAP β′-pocket, interacting with a Mg2+ ion and a number of other residues in the β′-pocket, as well as with a few residues that are in the structural region that forms the interface between β′- and β-pockets. Our compounds appear to bind to the TB RNAP holoenzyme either before or after binding of the promoter DNA, which produces obstruction of transcription, resulting in failure of RNAP catalysis to initiate transcription. It is relevant to state that our compounds are not alternate substrates or transition state mimics of the RNAP polymerization reaction.
The new class of compounds described in this invention are multifunctional and are designed with the following structural components: dibenzyl pyridinone scaffold, diketo-enolic functionality, and a piperazine carboxamide moiety that carries an aromatic or substituted aromatic group on the second piperazine nitrogen. The compounds have been designed as treatments for MDR-TB and have therapeutic applications in XDR-TB and XXDR-TB. An example is shown below (Figure 1). This compound is active against MDR-TB with a minimum inhibitory concentration (MIC, i.e., the lowest concentration to completely inhibit growth of MDR-TB) of <1 microgram/mL (Agar dilution susceptibility method). In addition, this compound exhibits significant in vitro anti-HIV activity in cell culture with EC90 (concentration for 90% inhibition of virus replication) in the nM range.




SUMMARY OF THE INVENTION
Multifunctional compounds that have a dibenzyl pyridinone scaffold, a diketo/enolic functionality, a piperazine carboxamide moiety, and a N-substituted aromatic or substituted aromatic group on the piperazine ring and methods for their preparation and use are disclosed. The compounds are represented by Formula I and include tautomers, geometric isomers, regioisomers and pharmaceutically acceptable salts thereof, wherein the pyridinone scaffold and R and X groups are as otherwise defined in the specification. These complex multifunctional compounds exhibit substantial activity as novel anti-TB agents. The compounds are useful in the prevention and/or reducing the likelihood, inhibition or treatment of infection by MDR-TB, with applications in XDR-TB and XXDR-TB, and in the treatment of drug-resistant TB where there is also co-infection with HIV, either as the compounds, or as pharmaceutically acceptable salts, with pharmaceutically acceptable carriers, used alone or in combination with other anti-TB agents, anti-AIDS compounds, other antivirals, anti-infectives, immunomodulators, antibiotics, vaccines, and other therapeutic agents, which can be used to create combination anti-TB cocktails. Methods of treating, preventing and/or reducing the likelihood of drug-resistant TB and methods of treating or preventing infection by drug-resistant TB are also described, the method comprising administering one or more compounds according to the present invention, optionally in combination with additional agents, including anti-HIV agents, in effective amounts to a patient or subject in need.
Compounds according to the present invention exhibit one or more of the following characteristics desired in anti-TB compounds: high efficacy against MDR-TB and other drug-resistant TB, low toxicity, favorable hydrophobicity, appropriate distribution of polar surface area, enhanced stability to metabolic degradation and a favorable drug-drug interaction profile. The present compounds represent a material advance in the treatment and/or prevention of MDR-TB or other drug-resistant TB and related secondary conditions and/or disease states or accompanying co-infections with HIV.
Pharmaceutical compositions which include one or more compounds according to the present invention in combination with a pharmaceutically acceptable carrier, additive or excipient, optionally in combination with at least one additional agent as otherwise described herein represent an additional aspect of the invention. A kit comprising a pharmaceutical composition according to the present invention and instructions on how to administer the composition to a patient in need represent a further aspect of the invention.


DETAILED DESCRIPTION OF THE INVENTION
The following terms are used throughout the specification to describe the present invention. Unless otherwise indicated, a term used to describe the present invention shall be given its ordinary meaning as understood by those skilled in the art.
The term “compound”, as used herein, unless otherwise indicated, refers to any specific chemical compound disclosed herein and includes tautomers and geometric isomers, as well as pharmaceutically acceptable salts thereof. Within its use in context, the term compound generally refers to a single chemically stable compound which can be administered to a patient or subject, but also may include other compounds such as tautomers and geometric isomers. The breadth of the term “compound” shall be construed within the context of the use of the term. It is noted that where a substituent should be present in context but is not specifically signified, it is understood that such substituent represents a hydrogen (H) atom.
The term “patient” or “subject” is used throughout the specification to describe an animal, generally a mammal and preferably a human, to whom treatment, including prophylactic treatment, with the compositions according to the present invention is provided. For treatment of those infections, conditions or disease states which are specific for a specific animal such as a human patient, the term patient refers to that specific animal.
The term “effective” is used herein, unless otherwise indicated, to describe an amount of a compound or composition or component which, in context, is used to produce or effect an intended result, whether that result relates to the treatment of a microbial, viral or other disease state, disorder or condition associated with TB or alternatively, is used to produce another compound, agent or composition. This term subsumes all other effective amount or effective concentration terms which are otherwise described in the present application.
The term “scaffold” is used to mean a dibenzyl pyridinone chemical structure. The dibenzyl group has R1, R2, R3 and R4 substituents which are as defined herein. The scaffold contains additional functionalities including a diketo-enol group and a substituted piperazine carboxamide moiety of which the X groups are as defined herein.
The term “minimum inhibitory concentration” is defined as the lowest concentration of an anti-mycobacterial compound that will inhibit completely the growth of the microorganism as visibly discerned after a delineated period.
The term “prevention” is used within context to mean “reducing the likelihood” of a condition or disease state from occurring as a consequence of administration or concurrent administration of one or more compounds or compositions according to the present invention, alone or in combination with another agent. Thus, the term prevention is used within the context of a qualitative measure and it is understood that the use of a compound according to the present invention to reduce the likelihood of an occurrence of a condition or disease state as otherwise described herein will not be absolute, but will reflect the ability of the compound to reduce the likelihood of the occurrence within a population of patients or subjects in need of such prevention.
The term “multi-drug resistant Mycobacterium tuberculosis,” which is referred to with the acronym, MDR-TB, describes tuberculosis that is resistant to isoniazid and rifampin, the two drugs that are used commonly for drug-susceptible TB and with treatment-adherent TB patients.
The term “extensively drug-resistant Mycobacterium tuberculosis,” which is referred to with the acronym, XDR-TB, describes MDR-TB that has also developed resistance to one or more of the injectable second line TB drugs (kanamycin, capreomycin or amikacin) and also to a fluoroquinolone drug. The term “extremely drug-resistant Mycobacterium tuberculosis,” referred to as XXDR-TB, is TB that is resistant to both first line and second line TB drugs.
The term “human immunodeficiency virus” or “HIV” shall be used to describe human immunodeficiency viruses 1 and 2 (HIV-1 and HIV-2). The terms “ARC” and “AIDS” refer to syndromes of the immune system caused by the human immunodeficiency virus, which are characterized by susceptibility to certain diseases and T cell counts which are depressed compared to normal counts. HIV progresses from Category 1 (Asymptomatic HIV Disease) to Category 2 (ARC), to Category 3 (AIDS), with the severity of the disease.
The term “coadministration” shall mean that at least two compounds or compositions are administered to the patient at the same time, such that effective amounts or concentrations of each of the two or more compounds may be found in the patient at a given point in time. Although compounds according to the present invention may be co-administered to a patient at the same time, the term embraces both administration of two or more agents at the same time or at different times, provided preferably that effective concentrations of coadministered compounds or compositions are found in the subject at a given time. The term coadministration also encompasses, in certain instances, the serial administration of agents which are administered serially in a patient to produce an intended effect, regardless of the time of administration and concentration of agent found in the subject.
The term “independently” is used herein to indicate that a variable, which is independently applied, varies independently from application to application.
The present invention is directed to compounds of the general molecular Formula below, including tautomer, geometric isomer and pharmaceutically acceptable salts thereof. The groups labeled as A and B represent unsubstituted and fluoro-substituted phenyl rings, with substitutions from mono- through to tetra-substituted, involving the ortho, meta and para positions (with reference to the methylene group to which the phenyl group is bound), and combinations thereof. The groups attached to the piperazine ring nitrogen and labeled as X are aromatic groups which term includes heteroaromatic groups. The groups R and X are as otherwise described in the specification.




Particular compounds of Formula I with respect to phenyl rings labeled A and B, which also carry the group X substitutions, include the following:

    
    
        R1=H, R2=H, R3=H, R4=H
        R1=H, R2=o-F, R3=o-F, R4=p-F
        R1=o-F, R2=o-F, R3=o-F, R4=m-F
        R1=o-F, R2=o-F, R3=o-F, R4=p-F
        R1=o-F, R2=o-F, R3=m-F, R4=m-F
        R1=o-F, R2=o-F, R3=m-F, R4=p-F
        R1=o-F, R2=m-F, R3=m-F, R4=p-F
        R1=H, R2=m-F, R3=m-F, R4=p-F
        R1=m-F, R2=o-F, R3=o-F, R4=m-F
        R1=m-F, R2=o-F, R3=o-F, R4=p-F
        R1=m-F, R2=o-F, R3=m-F, R4=m-F
        R1=m-F, R2=o-F, R3=m-F, R4=p-F
        R1=m-F, R2=m-F, R3=m-F, R4=p-F
        R1=H, R2=o-F, R3=o-F, R4=m-F
        R1=p-F, R2=o-F, R3=o-F, R4=m-F
        R1=p-F, R2=o-F, R3=o-F, R4=p-F
        R1=p-F, R2=o-F, R3=m-F, R4=m-F
        R1=p-F, R2=o-F, R3=m-F, R4=p-F
        R1=p-F, R2=m-F, R3=m-F, R4=p-F
        R1=o-F, R2=m-F, R3=m-F, R4=H
        R1=o-F, R2=p-F, R3=H, R4=H and
        R1=o-F, R2=o-F, R3=o-F, R4=H

By way of convention, o-F represents ortho substituted fluorine, m-F represents meta substituted fluorine and p-F represents para substituted fluorine.

    
    


Particular compounds of Formula I with respect to group X which are directed to optionally substituted aromatic groups, including heteroaryl groups, preferably include the following groups. These also carry the substitutions shown above in the rings A and B. These preferred X groups are as follows:




Also embraced by the present invention are pharmaceutical compositions useful for the treatment of MDR-TB, comprising an effective amount of at least one compound of this invention as described herein, and a pharmaceutically acceptable carrier, additive or excipient. Pharmaceutical compositions useful for treating infection by drug-resistant TB or for treating, in combination with other drugs, MDR-TB co-infections such as those with HIV, are included by the present invention. In addition, the present invention is directed to a pharmaceutical composition comprising, in effective combination, a therapeutically effective amount of at least one compound of the present invention and a suitable and effective combination with: (i) one or more other TB drugs, including drugs against resistant TB; (ii) a therapeutically effective amount of an agent(s) for the treatment of AIDS; (iii) an anti-infective agent, (iv) an immunomodulator, (v) other useful therapeutic agents, including antibiotics, vaccines and other antiviral agents.
Other applications are also part of this invention. For example, the compounds of this invention may also be useful for treatments of drug resistant forms of TB, including XDR-TB and XXDR-TB and in combination therapeutic treatment for these resistant TB infections as well as co-infections involving HIV and other viral infections.
The compounds of the present invention also embrace geometric isomers and these forms are also included in the present invention.
Tautomeric forms may also exist with compounds of the present invention. Thus, the terminology “and tautomers thereof” is used in describing tautomeric forms of compounds of Formula I such as Ia and Ib (shown below). By naming compounds as being represented by the general Formula I and tautomers thereof, it is understood that for the purposes of the present invention, that tautomers 1a and 1b are also included. Similarly, by referring to compound (1a), it is understood for the purposes of the present application that tautomers (1) and (1b) are also intended to be included. The same holds true for references to tautomer (1b).




When the variables involving R1, R2, R3, and R4 occur more than once in any Formula I, the definition on each occurrence is independent of its definition at every other occurrence. Combinations of pyridinones and R and X variables are permissible only if, in context, such combinations result in stable compounds.
For the X groups, the term “aromatic,” in context, refers to a substituted or unsubstituted aromatic group having a single ring (e.g., benzene) or multiple condensed rings (e.g., naphthyl, anthracenyl, phenanthryl).
Particular compounds of Formula I include:


    1. 4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
    2. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    3. 4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
    4. 4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-hydroxybut-3-ene-1,2-dione
    5. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    6. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    7. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    8. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    9. 4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
    10. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    11. 4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
    12. 1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    13. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    14. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    15. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    16. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    17. 4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
    18. 4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
    19. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    20. 4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-hydroxybut-3-ene-1,2-dione
    21. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    22. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    23. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    24. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    25. 4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
    26. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    27. 4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
    28. 4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-hydroxybut-3-ene-1,2-dione
    29. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    30. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    31. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    32. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    33. 4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
    34. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    35. 4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
    36. 4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-hydroxybut-3-ene-1,2-dione
    37. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    38. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    39. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-(4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    40. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    41. 4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
    42. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    43. 4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
    44. 1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    45. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    46. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    47. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    48. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    49. 4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
    50. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    51. 4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(15naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
    52. 1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    53. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    54. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    55. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    56. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    57. 4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
    58. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    59. 4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
    60. 1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    61. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    62. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    63. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    64. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    65. 4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
    66. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    67. 4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
    68. 1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    69. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    70. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    71. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    72. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    73. 4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
    74. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    75. 4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
    76. 1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    77. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    78. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    79. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    80. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    81. 4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
    82. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    83. 4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
    84. 1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    85. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    86. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    87. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    88. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    89. 4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
    90. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    91. 4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
    92. 4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-hydroxybut-3-ene-1,2-dione
    93. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    94. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    95. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    96. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    97. 4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
    98. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    99. 4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalene-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
    100. 1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    101. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    102. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    103. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    104. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    105. 4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
    106. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    107. 4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalene-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
    108. 1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    109. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    110. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    111. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    112. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    113. 4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
    114. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    115. 1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    116. 4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
    117. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    118. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    119. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    120. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    121. 4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione
    122. 1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    123. 4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione
    124. 1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    125. 1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    126. 1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    127. 1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione
    128. 1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione


Therapeutically effective amounts of the compounds of the present invention may be administered to patients orally, including buccally, parenterally, by inhalation spray, topically, or rectally, in dosage unit formulations containing pharmaceutically-acceptable carriers, adjuvants and vehicles including nanoparticle drug delivery approaches. The term “pharmaceutically acceptable” is meant to infer that the carrier, diluent, excipient or other additive is biologically compatible with the other ingredients of the formulation and not deleterious to the patient or recipient. Pharmaceutical compositions are in pharmaceutical dosage form and may be administered in the form of orally-administrable suspensions or tablets, nasal sprays and injectable preparations (injectable aqueous or oleagenous suspensions or suppositories). This method of treatment is part of the invention. The administration approaches used (e.g., orally as solution or suspension, immediate release tablets, nasal aerosol or inhalation, injectable solutions or suspensions or rectally administered in the form of suppositories) involve techniques that are well-known in the art of pharmaceutical formulation.
The compounds of this invention can be administered orally to humans in a preferred form (such as tablets) and in an effective amount within a preferred dosage range. The specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including compound activity, compound metabolism and duration of action, patient age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the condition of the patient undergoing therapy.
The present invention also includes therapeutically effective combinations of compounds of formula I with one or more other therapeutic agents such as other anti-TB drugs, AIDS antivirals, other antiviral agents, immunomodulators, anti-infectives, antibiotics, vaccines or other therapeutic agents. Some examples are given below.
Anti-TB Drugs, Antiviral Agents, Anti-Infectives, Immunomodulators, Opportunistic Infection Drugs, Other Relevant Drugs TB Treatments and TB Co-Infections












Drug Name
Manufacturer Examples
Therapeutic Use







Rifampin (Rifadin,
Sanofi Aventis LLC US
TB and TB-related


Rimactane)

mycobacterial infections


Rifapentine
Sanofi Aventis LLC US 
TB


Isoniazid (Nydrazid)
Bristol Myers Squibb
TB



Eli Lilly




Hoffmann La Roche Inc.




Novartis




Sandoz Inc.



Ethambutol
Barr laboratories Inc.
Adjunct, in the treatment



STI Pharma LLC
TB



West ward




pharmaceutical corp.



Ethionamide
Wyeth Inc.
TB


Para-aminosalicylic
Bristol Myers Squibb Co.
TB


acid (PAS)




Capreomycin
Akorn Inc.
Treatment of TB in




combination with other




drugs.


Amikacin
Abbott
Mycobacterium avium and M. tb.


Rifabutin (Mycobutin)
Pharmacia
Disseminated Mycobacterium




avium complex (MAC)




disease in patients with




advanced HIV infection.


Streptomycin
Eli Lilly, Pfizer
TB


Pyrazinamide
Dava Inc., Mikart Inc.
Initial treatment of active




TB in adults and children




when combined with other




TB agents


Cycloserine
Purdue GMP Center
Used in combination with



LLC, Chao Center
other drugs to treat



Industrial pharmacy
Mycobacterium avium




complex (MAC) and TB.


Ciprofloxacin
Bayer, Teva, Baxter,
TB and other infections



Ranbaxy, Sandoz Inc.
caused by susceptible




organisms.


Ofloxacin
Ortho McNeil, Sandoz
TB and accompanying



Inc., Ranbaxy, Teva
infections.


Levofloxacin
Ortho McNeil
TB and accompanying




infections.


Clofazimine
Novartis
TB


Bedaquiline
Johnson & Johnson
Multidrug-resistant TB




(MDR TB)


097
Hoechst/Bayer
HIV infection, AIDS,




ARC (NNRT inhibitor)


Amprenivir
Glaxo Wellcome
HIV infection, AIDS,


141W94, GWI41

ARC (protease inhibitor)


Abacavir (1592U89)
Glaxo Wellcome
HIV infection, AIDS,


GW 1592

ARC (RT inhibitor)


Acemannan
Carrington Labs (Irving,
ARC



TX)



Acyclovir
Burroughs Wellcome
HIV infection, AIDS,




ARC, in combination with




AZT


AD-439
Tanox Biosystems
HIV infection, AIDS,




ARC


AD-519
Tanox Biosystems
HIV infection, AIDS,




ARC


Adefovir dipivoxil AL-
Gilead Sciences
HIV infection


721
Ethigen (Los Angeles,
ARC, PGL HIV positive,



CA)
AIDS


Alpha Interferon
Glaxo Wellcome
Kaposi's sarcoma, HIV in




combination w/Retrovir


Ansamycin LM427
Adria Laboratories
ARC



(Dublin, OH)




Erbamont (Stamford, CT)



Antibody which
Advanced Biotherapy
AIDS, ARC


neutralizes pH labile 
Concepts (Rockville,



alpha aberrant
MD)



Interferon




AR 177
Aronex Pharm
HIV infection, AIDS,




ARC


Beta-fluoro-ddA
National Cancer Institute
AIDS-associated diseases


BMS-232623,
Bristol-Myers
HIV infection, AIDS,


(CGP-73547)
Squibb/Novartis
ARC (protease inhibitor)


BMS-234475
Bristol-Myers
HIV infection, AIDS,


(CGP-61755)
Squibb/Novartis
ARC (protease inhibitor)




HIV infection, AIDS,




ARC (protease inhibitor)


CI-1012
Warner-Lambert
HIV-1 infection


Cidofovir
Gilead Science
CMV retinitis, herpes,




Papillomavirus


Curdlan sulfate
AJI Phanna USA
HIV infection


Cytomegalovirus
MedImmune
CMV retinitis


Immune globin




Cytovene
Syntex
Sight threatening CMV


Ganciclovir

Peripheral CMV




Retinitis


ddI
Bristol-Myers Squibb
HIV infection, AIDS,


Dideoxyinosine

ARC; combination with




AZT/d4T


DMP-450
AVID (Camden, NJ)
HIV infection, AIDS,




ARC (protease inhibitor)


Efavirenz (DMP-266)
DuPont Merck
HIV infection, AIDS,




ARC (non-nucleoside RT




Inhibitor


EL10
Elan Corp, PLC
HIV infection



(Gainesville, GA)



Famciclovir
Smith Kline
Herpes zoster, herpes




simplex


FTC
Emory University
HIV infection, AIDS,




ARC (reverse transcriptase




inhibitor)


GS 840
Gilead
HIV infection, AIDS,




ARC (reverse transcriptase




inhibitor)


HBY097
Hoechst Marion Roussel
HIV infection, AIDS,




ARC (non-nucleoside




reverse transcriptase




inhibitor)


Hypericin
VIMRx Phann.
HIV infection, AIDS,




ARC


Recombinant Human
Triton Biosciences
AIDS, Kaposi's sarcoma,


Interferon Beta
(Almeda, CA)
ARC


Interferon alfa-n3
Interferon Sciences
ARC, AIDS


Indinavir
Merck
HIV infection, AIDS,




ARC, asymptomatic HIV




positive; combination with




AZT/ddI/ddC


Isentress (Raltegravir)
Merck
HIV infection, AIDS,




ARC (integrase inhibitor)


ISIS-2922
ISIS Pharmaceuticals
CMV retinitis


KNI-272
Natl. Cancer Institute
HIV-associated diseases


Lamivudine, 3TC
Glaxo Wellcome
HIV infection, AIDS,




ARC (reverse transcriptase




inhibitor); also with AZT


Lobucavir
Bristol-Myers Squibb
CMV infection


Nelfinavir
Agouron
HIV infection, AIDS,



Pharmaceuticals
ARC (protease inhibitor)


Nevirapine
Boeheringer Ingleheim
HIV infection, AIDS,




ARC (RT inhibitor)


Novapren
Novaferon Labs, Inc.
HIV inhibitor



(Akron, OR)



Peptide T
Peninsula Labs
AIDS


Octapeptide Sequence
(Belmont, CA)



Trisodium
Astra Pharm. Products
CVV retinitis, HIV


Phosphonoformate.
Inc,
infection, other CMV


PNU-140690
Pharmacia Upjohn
HIV infection, AIDS,




ARC (protease inhibitor)


Probucol
Vyrex
HIV infection, AIDS


RBC-CD4
Sheffield Med. Tech
HIV infection, AIDS,



(Houston, TX)
ARC


Ritonavir
Abbott
HIV infection, AIDS,




ARC (protease inhibitor)


Saquinavir
Roffmann-LaRoche
HIV infection, AIDS,




ARC (protease inhibitor)


Stavudine; d4T
Bristol-Myers Squibb
HIV infection, AIDS,


Didehydrodeoxythy-

ARC


midine




Valaciclovir
Glaxo Wellcome
Genital HSV & CMV




infections


Virazole Ribavirin
Viratek/ICN (Costa
Asymptomatic HIV



Mesa, CA)
positive, LAS, ARC


VX-478
Vertex
HIV infection, AIDS,




ARC


Zalcitabine
Hoffmann-LaRoche
HIV infection, AIDS,




ARCwithAZT


Zidovudine; AZT
Glaxo Wellcome
HIV infection, AIDS,




ARC, Kaposi's sarcoma, in




combination with




other therapies


Tenofovir diisoproxil 
Gilead
HIV infection, AIDS,


fumarate salt (Viread ®)

(RT inhibitor)


Combivir ®
GSK
HIV infection, AIDS,




(RT inhibitor)


Abacavir succinate (or
GSK
HIV infection, AIDS,


Ziagen ®)

(reverse transcriptase




inhibitor)


Fuzeon ® (or T-20)
Roche/Trimeris
HIV infection, AIDS,




viral Fusion inhibitor


AS-101
Wyeth-Ayerst
AIDS


Bropirimine
Pharmacia Upjohn
Advanced AIDS


Acemannan
Carrington Labs, Inc.
AIDS, ARC



(Irving, TX)



CL246,738
American Cyanamid
AIDS, Kaposi's sarcoma



Lederle Labs



EL10
Elan Corp, PLC
HIV infection



(Gainesville, GA)



FP-21399
Fuki Immuno PHARM
Blocks HIV fusion with




CD4 + cells


Gamma Interferon
Genentech
ARC, in combination




w/TNF


Granulocyte
Genetics Institute
AIDS


Macrophage Colony
Sandoz



Stimulating Factor




Granulocyte
Hoeschst-Roussel
AIDS


Macrophage Colony
Immunex



Stimulating Factor




Granulocyte
Schering-Plough
AIDS, combination


Macrophage Colony

w/AZT


Stimulating Factor




HIV Core Particle
Rorer
Seropositive HIV


Immunostimulant




IL-2
Cetus
AIDS, in combination


Interleukin-2

w/AZT


IL-2
Hoffman-LaRoche
AIDS, ARC, HIV, in




Interleukin-2 1mmunex




combination w/AZT


IL-2 lnterleukin-2
Chiron
AIDS, increase in CD4


(aldeslukin)

cell counts


Immune Globulin
Cutter Biological
Pediatric AIDS, in


(human)
Intravenous
combination w/AZT



(Berkeley, CA)



IMREG-1
Imreg (New Orleans,
AIDS, Kaposi's sarcoma,



LA)
ARC, PGL


IMREG-2
Imreg (New Orleans,
AIDS, Kaposi's sarcoma,



LA)
ARC, PGL


Imuthiol Diethyl
Merieux Institute
AIDS, ARC


Dithio Carbamate




Alpha-2 Interferon
Schering Plough
Kaposi's sarcoma w/AZT,




AIDS


Methionine-Enkephalin
TNI Pharmaceutical
AIDS, ARC



(Chicago, IL)



MTP-PE
Ciba-Geigy Corp.
Kaposi's sarcoma


Muramyl-Tripeptide




Granulocyte
Amgen
AIDS, in combination


Colony Stimulating

w/AZT


Factor




Remune
Immune Response Corp.
Immunotherapeutic


rCD4
Genentech
AIDS, ARC


Recombinant Soluble




Human CD4-IgG




rCD4-IgG Hybrids

AIDS, ARC


Recombinant Soluble
Biogen
AIDS, ARC


HumanCD4




Interferon Alfa 2a
Hoffman-LaRoche
Kaposi's sarcoma, AIDS,




AR, combination w/AZT


SK&F1-6528
Smith Kline
HIV infection


Soluble T4




Thymopentin
Immunobiology
HIV infection



Research Institute




(Annandale, NJ)



Tumor Necrosis Factor
Genentech
ARC, in combination


(TNF)

w/gamma Interferon


AK602
Kumamoto University
HIV infection (entry and



Japan
fusion inhibitor)


Alovudine
Medivir, UK Ltd.
HIV infection (nucleoside




RT inhibitor)


Amdoxovir
RFS Pharma, LLC
Treatment of HIV and




HBV infections




(nucleoside RT Inhibitor)


AMD070
AnorMED, Inc.
HIV infection (entry and




fusion inhibitor)


Atazanavir (Reyataz) 
Bristol-Myers Squibb
HIV infection (protease




inhibitor)


AVX754 (apricitabine)
Avexa Ltd.
HIV infection (nucleoside




RT inhibitor)


Bevirimat
Panacos Pharmaceuticals
HIV infection (maturation




inhibitor)


BI-201
Biolnvent
HIV infection (gene




therapy, blocks HIV tat




gene).


BMS-378806
Bristol-Myers Squibb
HIV infection (entry




inhibitor)


BMS-488043
Bristol-Myers Squibb 
HIV infection (entry and




fusion inhibitor)


BMS-707035
Bristol-Myers Squibb 
HIV infection (integase




inhibitor)


C31G
Cellegy Inc.
Pharmaceuticals, HIV




infection and other




sexually transmitted




diseases (STDs)


Carbopol 974P
ReProtect, LLC
Sexual transmission of




HIV


Calanolide A
Sarawak MediChem
HIV infection (non-



Pharmaceuticals, Inc.
nucleoside RT inhibitor)


Carrageenan
FMC Biopolymer
HIV microbicide


Cellulose sulfate
Polydex
Prevention of HIV



Pharmaceuticals, Ltd.
infection and other




sexually transmitted




diseases


Cyanovirin-N
Cellegy Pharmaceuticals, 
Prevention of sexual



Inc.
transmission of HIV




infection


Darunavir
Tibotec
HIV infection




(coadministered with




ritonavir)


Delavirdine
Pfizer
HIV infection




(nonnucleoside




RT inhibitor)


Dextran sulfate
Ueno Fine Chemicals
Prevention of transmission



Industry, Ltd.
of HIV


Didanosine (Videx,
Bristol-Myers Squibb
HIV infection (nucleoside


Videx EC)

RT inhibitor)


Efavirenz
Bristol-Myers Squibb
HIV infection




(nonnucleoside RT




inhibitor)


Elvucitabine
Achillion
HIV infection




Pharmaceuticals




(nucleoside RT inhibitor)


Emtricitabine
Gilead Sciences
HIV infection (nucleoside




RT inhibitor)


Fosamprenavir
GlaxoSmithKline
HIV infection (protease


(Lexiva)

inhibitor)


Fozivudine tidoxil
Heidelberg Pharma
HIV infection (entry and




fusion inhibitor)


Elvitegravir
Gilead Sciences
HIV infection (integase




inhibitor)


GSK-873, 140
GlaxoSmithKline
HIV infection (entry and


(aplaviroc)

fusion inhibitor)


GSK-364735
Glaxo SmithKline
HIV infection (integase




inhibitor)


GW640385
GlaxoSmithKline
HIV infection (protease


(brecanavir)

inhibitor)


HG0004
Human Genome
HIV infection (entry and



Sciences
fusion inhibitor)


HGTV43
Enzo Therapeutics
HIV infection (antisense




drug)


Hydroxyethyl cellulose
Union Carbide
Prevent sexual




transmission of HIV


INCB9471
Incyte Corporation
HIV infection (entry and




fusion inhibitor)


KP-1461
Koronis Pharmaceuticals 
HIV infection (nucleoside




RT inhibitor)


Lopinavir
Abbott Laboratories
HIV infection (protease




inhibitor)


Mifepristone
Viral Genomix
HIV infection (gene


(VGX410, RU486)

therapy,interferes with




vpr)


MK-0518
Merck
HIV infection (integase




inhibitor)


PA-457 (bevirimat)
Panacos
Treatment of HIV



Pharmaceuticals, Inc.
(maturation inhibitor)


Poly(I)-Poly(C12U)
Hemispherx Biopharma,
Biological response


(Ampligen)
Inc.
modifier


PPL-100
Merck
HIV infection (protease




inhibitor)


PRO 140
Progenics
HIV infection (entry and



Pharmaceuticals, Inc.
fusion inhibitor)


PRO 542
Progenics
HIV infection (entry and



Pharmaceuticals, Inc.
fusion inhibitor)


PRO 2000
Indevus Pharmaceuticals, 
Microbicide



Inc.



Racivir
Pharmasset, Inc.
HIV infection (nucleoside




RT inhibitor)


SCH-D (vicriviroc)
Schering-Plough Corp
HIV infection (entry and




fusion inhibitor)


SP01A
Samaritan
HIV infection (entry and



Pharmaceuticals
fusion inhibitor)


SPL7013
Starpharma
Microbicide


TAK-652
Takeda
HIV infection (entry and




fusion inhibitor)


Tipranavir (Aptivus)
Boehringer Ingelheim
HIV infection (protease



Pharmaceuticals
inhibitor)


TNX-355
Tanox, Inc.
HIV infection (entry and




fusion inhibitor)


TMC125 (etravirine)
Tibotec
HIV infection (non-




nucleoside RT inhibitor)


UC-781
Cellegy Pharmaceuticals,
Microbicide



Inc



UK-427,857
Pfizer
HIV infection (entry and


(Maraviroc)

fusion inhibitor)


Valproic acid
Abbott
Treating seizures in HIV




infection


VRX496
VIRxSYS
Gene therapy


Zalcitabine (Hivid)
Roche
HIV infection (nucleoside




T inhibitor)


Valganciclovir
Roche
Antiviral (CMV retinitis in


(Valcyte)

AIDS)


Clindamycin with
Pharmacia Upjohn
PCP


Primaquine




Fluconazole
Pfizer
Cryptococcal meningitis,




candidiasis


Pastille
Squibb Corp.
prevention of oral


Nystatin Pastille

candidiasis


Ornidyl
Merrell Dow
PCP


Eflornithine




Pentamidine
LyphoMed (Rosemont,
PCP treatment


Isethionate (IM & IV)
IL)



Trimethoprim

Antibacterial


Trimethoprim/sulfa

Antibacterial


Piritrexim
Burroughs Wellcome
PCP treatment


Pentamidine isethionate
Fisons Corporation
PCP prophylaxis


Spiramycin
Rhone-Poulenc
Cryptosporidial diarrhea


Intraconazole-R51211
Janssen Pharm
Histoplasmosis;




cryptococcal meningitis


Trimetrexate
Warner-Lambert
PCP


Daunorubicin
NeXstar, Sequus
Karposi's sarcoma


Recombinant Human
Ortho Pharm. Corp.
Severe anemia assocated


Erythropoietin

w/AZT therapy


Recombinant Human
Serono
AIDS-related wasting,


Growth Hormone

cachexia


Megestrol Acetate
Bristol-Myers Squibb
Treatment of anorexia




associated w/AIDS


Testosterone
Alza, Smith Kline
AIDS-related wasting


Total Enteral Nutrition
Norwich Eaton
Diarrhea and



Pharmaceuticals
malabsorption in AIDS


Aldesleukin
Chiron Corp
Biological response


(Proleukin)

modifier


Amphotericin B
Pfizer, Bristol-Myers
Antifungal


(Abelecet,
Squibb



AmBisome, Amphocin,




Amphotec, Fungizone)




Azithromycin
Pfizer
Antibacterial antibiotic


(Zithromax)




Calcium
Bioform Medical, Inc.
Dermal filler


hydroxyapatite




(Radiesse




Doxorubicin
Ortho Biotech, Alza
Antineoplastic


(liposomal) (Doxil)
Corporation



Dronabinol (Marinol)
Unimed Pharmaceuticals,
Antiemetics



Inc.



Entecavir (Baraclude)
Bristol-Myers Squibb
Antiviral


Epoetin alfa (Epogen,
Ortho Biotech
Anemia


Procrit)




Etoposide (Etopophos
Pfizer, Bristol-Myers
Antineoplastic


(phosphate salt),
Squibb



Toposar, VePesid)




Fluconazole (Diflucan)
Pfizer
Antifungal


Interferon alfa-2
Roche, Schering-Plough
Biological response


(Intron A (2b),

modifiers


Roferon-A (2a)




Itraconazole
Ortho Biotech, Janssen
Antifungal


(Sporanox)
Pharmaceutica



Megestrol (Megace,
Bristol-Myers Squibb
Anticachectic


Megace ES)




Paclitaxel (Onxol,
Bristol-Myers Squibb,
Antineoplastic


Taxol)
IVAX Pharmaceuticals



Peginterferon alfa-2
Roche, Schering-Plough
Antiviral


(PEG-Intron (2b),




Pegasys (2a))




Pentamidine
American
Antiprotozoal


(Nebupent)
Pharmaceutical Partners, 




Fujisawa Health Care,




Inc.



Poly-L-lactic acid
Dermik Laboratories
Dermal Filler


(Sculptra)




Somatropin
Pharmacia Corporation,
Synthetic human growth



Serono Inc
hormone


Sulfamethoxazole/
Alpha care Inc, Women
Antibacterial


Trimethoprim
First Health Care, King



(Bactrim, Septra)
Pharmaceuticals



(Serostim)




Testosterone
Pfizer Inc, Unimed
Androgens


(Androderm, Androgel,
Pharmaceuticals, Inc.,



Depo-Testosterone)
Alza Corporation,




Watson Laboratories



Trimetrexate
United States Bioscience
Antiprotozoal


(Neutrexin)
Inc, Medimmune, Inc.









The combinations of the anti-TB compounds of this invention with AIDS antivirals (including anti-HIV integrase-based antivirals), other antivirals, another TB drug and/or a TB drug that is active against drug-resistant TB; immunomodulators, anti-infectives, antibiotics, vaccines, other therapeutic agents are not limited to the list in the above Table, but includes, in principle, any combination with any pharmaceutical composition useful for the treatment against infection by HIV or for treating AIDS or ARC. Preferred combinations are simultaneous or alternating treatments of a compound of the present invention and a protease inhibitor (e.g., indinavir, nelfinavir, ritonavir, saquinavir and others), a reverse transcriptase (RT) inhibitor (e.g., AZT, 3TC, ddC, ddI, d4T, abacavir and others), an integrase inhibitor (e.g., raltegravir, evitegravir) and/or non-nucleoside RT inhibitors (e.g., efavirenz, nevirapine, and others), or some combination of two or more of these inhibitors (see Table above). A few representative examples of relevant patents citing combinations are: EPO 0,484,071, U.S. Pat. No. 5,413,999, WO 9962513.
In such combinations, the compound of the present invention and other active agents may be separately administered or concurrently administered (coadministered). In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of other agent(s).

    Rifampin (Rifadin, Rimactane)
    Rifapentine
    Isoniazid (Nydrazid)
    Ethambutol
    Ethionamide
    Para-aminosalicylic acid (PAS)
    Capreomycin
    Amikacin
    Rifabutin (Mycobutin)
    Streptomycin
    Pyrazinamide
    Cycloserine
    Ciprofloxacin
    Ofloxacin
    Levofloxacin
    Clofazimine
    Bedaquiline
    (−)βDioxolane-G; DXG;
    (−)β-Arctigenin; Arctigenin;
    (−)-Carbovir; (−)-C-D4G; (−)-Carbovir;
    (+13-D-2,6-Diaminopurine dioxolane; Amdoxovir; DAPD; APD
    (+)-2′-Deoxy-3′-oxa-4′-thiocytidine; dOTC (+)
    (+)-2′-Deoxy-3′-oxa-4′-thio-5-fluorocytidine; dOTFC (+)
    (+/−)-Cyclobut-G; A-69992; (+/−)-Lobucavir; C-Oxt-G; Cyclobut-G; C-Oxetanocin-G
    (R)-2QuinCOAsnPhe[CHOHCH2]PipCONHtBu
    (R)-3,6-Diamino-N-(aminomethyl)hexanamide; Bellenamine
    (R)-PMPA; (R)-9-(2-Phosphonylmethoxypropyl)adenine; PMPA-(R); Tenofovir
    (R)-PMPDAP; PMPDAP-(R)
    (S)-PMPA; (S)-9-(2-Phosphonylmethoxypropyl)adenine; PMPA(S)
    (S)-9-(2-Phosphonylmethoxypropyl)adenine; (S)-PMPA
    α-APA; R89439; Loviride
    α-APA deriv.; R87232
    α-APA deriv.; R88703
    α-APA enantiomer; R90385
    α-L-AZT; AZT-α-L
    α-L-DXC; α-L-Dioxalane-C; DXC-α-L-
    α-L-FTC; FTC-α-L-
    α-Monofluoromethyldehydroornithine methyl ester; MFMOME
    1,1′-Azobisformamide; ADA; Azodicarbonamide
    1-(11-Octylamino-10-hydroxyundecyl)-3,7-dimethylxanthine; CT-2576
    1-(2′,3′-Dideoxy-2′-fluoro-β-D-threo-pentofuranosyl)cytosine; Ro 31-6840
    1-(2′-Fluoro-2′,3′-dideoxy-B-D-erythro-pentofuranosyl)thymine; 2′FddT
    1-(2OHPr)-4-Substit-piperazine, thienyl carbamate deriv.
    1-(2OHPr)-4-Substit-piperazine, thienyl carbamate deriv.
    1-(2OHPr)-4-Substit-piperazine, thienyl carbamate deriv.
    1-(2OHPr)-4-Substit-piperazine, thienyl carbamate deriv.
    1-[(2-Hydroxyethoxy)methyl]-6-(3-methylphenyl)thio)thymine; HEPT-M
    1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)-2-thiothymine; HEPT-S
    1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio)thymine; HEPT
    1-Deoxynojirimycin; Deoxynojirimycin
    141 W94; VX-478; Amprenavir; Agenerase®; Approved
    1592U89 Succinate; Abacavir Succinate; Ziagen® Approved
    1-Aminooxyethylamine; AEA
    1-Methoxyoxalyl-3,5-dicaffeoylquinic acid; 1-MO-3,5-DCQA; Dicaffeoylquinic acid deriv.
    1OH-2(Cbz-Tle)3PhPr[14]paracyclophane deriv.
    1OH-2(Cbz-ValNH)3PhPr[13]metacyclophane deriv.
    1OH-2(Cbz-ValNH)3PhPr[13]paracyclophane deriv.
    1OH-2(Cbz-ValNH)3PhPr[14]paracyclophane deriv.
    1OH-2(Cbz-ValNH)3PhPr[17]paracyclophane deriv.
    12-Deoxyphorbol-13-(3E,5E-decadienoate); Phorbol deriv.
    16.alpha.-Bromoepiandrosterone; Epi-Br; Inactivin; HE 2000; HE2000; PPB2; DHEA deriv.
    1-β-D-arabinofuranosyl-5-(2-bromovinyl)uracil; BV-ara-U; BVaraU; BV ara-U; Sorivudine; SQ-32756; Bravavir; Brovavir; Usevir; YN-72; Bromovinyl araU; BVAU
    2′,3′-Didehydro-3′-deoxycytidine; D4C
    2′,3′-Dideoxydidehydroguanosine; D4G
    2′,3′-Didehydro-3′-deoxythymidine; D4T; Stavudine; Zerit® Approved
    2′,3′-Dideoxy-3′-fluoro-4-thiothymidine; 3′-F-4-Thio-ddT
    2′,3′-Dideoxy-3′-fluoro-5-bromouridine; FddBrU
    2′,3′-Dideoxy-3′-fluoro-5-chlorocytidine; 3′-F-5-Cl-ddC
    2′,3′-Dideoxy-3′-fluoro-5-chlorouridine; 935U83; 5-Chloro-2′,3′-dideoxy-3′-fluorouridine; FddClU; Raluridine
    2′,3′-Dideoxy-5-ethylcytidine; 5-Et-ddC
    2′,3′-Dideoxyadenosine; D2A; ddAdo; ddA
    2′,3′-Dideoxydidehydroadenosine; d4A
    2′,3′-Dideoxyguanosine; D2G; ddG
    2′,3′-Dideoxy-3′-hydroxymethyl cytidine; 3′-Hydroxymethyl-ddC; BEA-005
    2,5′-Anhydro-3′-azido-2′,3′-dideoxyuridine; AZU-2,5′-anhydro
    2,5′-Anhydro-3′-azido-3′-deoxythymidine; AZT-2,5′-anhydro
    2′,5′diSilySpiroT; TSAO-T
    2′,5′diSilySpiroT; TSAO-me^3T
    2,6-Diamino-2′,3′-dideoxypurine-9-ribofuranoside; ddDAPR; DAPDDR; 2,6-Diamino-ddP
    2,6-Diaminopurine-2′,3′-dideoxydidehydroriboside; ddeDAPR
    2,6-Diaminopurine-3′-fluoro-2′,3′-dideoxyribo side; 3′-F-ddDAPR
    2-Aminobenzylstatine Valyl Cbz deriv.; Statine deriv.
    2-Glycine amide-5-chlorophenyl 2-pyrryl ketone; GCPK
    [2-PyridCH2NCH3CO-Val-NHCH(Bz)]CHOHCHOH; A-77003
    2′-Azido-2′,3′-dideoxyadenosine; 9-(2′-Azido-2′,3′-dideoxy-β-D-erythropentofuranosyl)adenine; 2′-N3ddA
    2′-FddA(B-D-threo); F-ddA; 2′-F-dd-ara-A; 9-(2′-Fluoro-2′,3′-dideoxy-B-D-threopentafuranosyl)adenine; Lodensine
    2′-N3ddA (B-D-threo); 9-(2′-Azido-2′,3′-dideoxy-β-threopentafuranosyl)adenine
    2-NaphCOAsnPhe[CHOHCH2]Pro-OtBu
    2-Nitrophenylphenylsulfone; NPPS
    3-(3-Oxo-1-propenyl)-3′-azido-3′-deoxythymidine; 3-(3-Oxo-1-propenyl)AZT
    3-(Phenylsulfonyl)-indole deriv.; L-737,126
    3,5-DCQA; 3,5-Dicaffeoylquinic acid; Dicaffeoylquinic acid
    3′-Azido-2′,3′-dideoxy-5-[(cyanomethyl)oxy]uridine; 3′-N3-5-Cyanomethyloxy-ddU
    3′-Azido-2′,3′-dideoxy-5-aminouridine; 3′-N3-5-NH2-ddU
    3′-Azido-2′,3′-dideoxy-5-aza-6-deazauridine; C-analog of 3′-N3-ddU
    3′-Azido-2′,3′-dideoxy-5-bromouridine; 3′-N3-5-Br-ddU; AZddBrU
    3′-Azido-2′,3′-dideoxy-5-chlorocytidine; 3′-Az-5-Cl-ddC
    3′-Azido-2′,3′-dideoxy-5-dimethylaminouridine; 3′-N3-5-NMe2-ddU
    3′-Azido-2′,3′-dideoxy-5-ethyluridine; 3′-N3-5-EtddU; CS-85; AZddEtU
    3′-Azido-2′,3′-dideoxy-5-fluorocytidine; 3′-N3-5-F-ddC
    3′-Azido-2′,3′-dideoxy-5-fluorouridine; AZddFU
    3′-Azido-2′,3′-dideoxy-5-hydroxyuridine; 3′-N3-5-OH-ddU
    3′-Azido-2′,3′-dideoxy-5-iodouridine; 3′-N3-5-I-ddU; AZddIU
    3′-Azido-2′,3′-dideoxy-5-methyaminouridine; 3′-N3-5-NHMe-ddU
    3′-Azido-2′,3′-dideoxy-5-methylcytidine; CS-92; 3′-N3-5-Me-ddC
    3′-Azido-2′,3′-dideoxy-5-thiocyanatouridine; 3′-N3-5-SCN-ddU
    3′-Azido-2′,3′-dideoxy-5-trifluoromethyluridine; 3′-N3-5-CF3-ddU
    3′-Azido-2′,3′-dideoxycytidine; CS-91; 3′-N3-ddC
    3′-Azido-2′,3′-dideoxyguanosine; AZG; 3′-N3ddG
    3′-Azido-2′,3′-dideoxy-N4-5-dimethylcytidine; 3′-N3-N4-5-diMe-ddC
    3′-Azido-2′,3′-dideoxy-N4-OH-5-methylcytidine; 3′-N3-N4-OH-5-Me-ddC
    3′-Azido-2′,3′-dideoxyuridine; CS-87; 3′-N3ddU; AZdU; Uravidine
    3′-Azido-3′-deoxy-6-azathymidine; 3′AZ-6AzaT
    3-Azido-3′-deoxythymidilyl-(5′,5′)-2′,3′-dideoxy-5′-adenylic acid; AZT-P-ddA
    3′-Azido-3′-deoxythymidilyl-(5′,5′)-2′,3′-dideoxy-5′-adenylic acid, 2-cyanoethyl ester; AZT-P(CyE)-ddA
    3′-Azido-3′-deoxythymidilyl-(5′,5′)-2′,3′-dideoxy-5′-inosinic acid; AZT-P-ddI
    3′-Azido-3′-deoxythymidine-5′-(butylmethoxyvalinyl)phosphate; 5′MeOValPO3(Bu)AZT
    3′-Azido-5-chloro-2′,3′-dideoxyuridine; AzddClUrd; AzddClU
    3′-Deoxythymidine; ddT
    3′-FddA (B-D-Erythro); 9-(3′-Fluoro-2′,3′-dideoxy-B-D-erythropentafuranosyl)adenine
    3′-FddC; 3′-Fluoro-2′,3′-dideoxycytidine
    3′-FddG; 3′-Fluoro-2′,3′-dideoxyguanosine
    3′-FddT; Alovudine; FddT; FddThD; 3′-FLT; FLT
    3′-FddU; 3′-Fluoro-2′,3′-dideoxyuridine
    3′-Fluoro-2′,3′-dideoxy-5-iodouridine; FddIU
    3′-N3-ddA; 9-(3′-Azido-2′,3′-dideoxy-B-D-erythropentafuranosyl)adenine
    3TC; Lamivudine; Epivir® Approved;
    Lamivudine & Zidovudine; Combivir® 3TC & AZT; Approved
    4′-Acetoamidophenyl4-guadinobenzoate; AGB
    4′-Az-3′-dT; 4′-Azido-3′-deoxythymidine
    4′-Az-5CldU; 4′-Azido-5-chloro-2′-deoxyuridine
    4′-AzdA; 4′-Azido-2′-deoxyadenosine
    4′-AzdC; 4′-Azido-2′-deoxycytidine
    4′-AzdG; 4′-Azido-2′-deoxyguanosine
    4′-AzdI; 4′-Azido-2′-deoxyinosine
    4′-AzdU; 4′-Azido-2′-deoxyuridine
    4′-Azido-2′-deoxy-β-D-erythro-pentofuranosyl-5-methyl-2,4-dioxopyrimidine; 4′-Azidothymidine
    4′-Cyanothymidine; 4′-CN-T
    4-Methyl-5-(pyrazinyl)-3H-1,2-dithiole-3-thione; Oltipraz
    5′-[(1,4-Dihydro-1-methyl-3-pyridinylcarbonyl)oxy]-3′-azido-2′,3′-deoxythymidine; DP-AZT; HP-AZT; AZT Prodrug; AZT-DHP
    5′-[[(Z)-4-amino-2-butenyl]methylamino]-5′-deoxyadenosine; MDL 73811
    5′-Alkylglycosidecarbonate of 3′-azido-3′-deoxythymidine; AcNHGlc-hexyl-CO3 AZT
    5Cl3PhS-2IndolCONH2
    5-Fluoro-2′,3′-dideoxycytidine; 5-F-ddC
    5-Methyl-3′-azido-2′,3′-dideoxyisocytidine; MeAZddIsoC
    6-O-Butanoylcastanospermine; BuCast; MDL 28,574; Celgosivir
    6-Chloro-9-(2,3-dideoxy-b-D-glyceropentofuranosyl)-9H-purine; D2ClP; 6-Chloro-ddP; CPDDR; 6Cl-ddP
    6-Dimethylaminopurine-2′,3′-dideoxyriboside; N-6-dimethylddA; DMAPDDR
    7-Chloro-N-methyl-5-(1H-pyrrol-2-yl)-3H-1,4-benzodiazepin-2-amine; Ro 24-7429
    7-Chloro-5-(2-pyrryl)-3H-1,4-benzodiazepin-2(H)-one; Ro 5-3335
    8-Chloro-TIBO; Tivirapine; R86183
    9-(2,3-Dideoxy-β-D-ribofuranosyl)-6-(methylthio)purine; D2SMeP
    9-[Bis(OHMe)cBu]A; A-69463; Cyclobutyl-A; Cyclobut-A; C-oxetanocin A
    A-76890
    A-77212
    A-80987; Ritonavir deriv., A-81525; Ritonavir deriv., A-83962; Ritonavir deriv.
    A-98881; Azacyclic urea deriv.
    AA; L-ascorbic acid; Calcium Ascorbate
    AAP-BHAP; U-104489; PNU-104489
    Abacavir & Lamivudine & Zidovudine; Trizivir® ABC & (−)-3TC & AZT
    ABT-378; Lopinavir; Component of Kaletra; Aluviran®
    ABT-378 & ABT-538; Kaletra®; Lopinavir & Ritonavir; Aluviran® & Norvir®
    ABT-538; Norvir®; Ritonavir; Component of Kaletra; Approved
    Acemannan
    Adefovir; PMEA; GS-0393
    Adefovir dipivoxil; BisPom PMEA; GS-840; Preveon®
    AG-1343; Viracept®; Nelfinavir; Approved
    AG1350; LY316957; Nelfinavir-octahydro-thienopyridine analog
    AHPBA analog; R-87366
    Alpha-lipoic acid; α-Lipoic acid; Thioctic acid
    ALX40-4C
    AMD3100; JM3100
    Amprenavir phosphate; VX-175; GW433908; GW433908A (*Sodium Salt*); GW433908G (*Calcium Salt*); Fosamprenavir
    Ancer 20; Z-100
    Anti-sense 25-mer phosphorothioate; GEM91
    Atazanavir; CGP-73547; BMS-232632; BMS 232632; Zrivada; Latazanavir; Reyataz®
    Atevirdine; U-87201E; BHAP deriv.
    Aurintricarboxylic acid; Dupont ATA; Dupont DA639; SD-095345; ATA
    AY 9944; trans-1,4-Bis(2-dichlorobenzylaminoethyl)cyclohexane dichlorhydrate
    AZT; Zidovudine; Azidothymidine; Retrovir®
    AZT-PO3(CH3)-AZT; O,O′-Bis(3′-azido-3′-deoxythymidin-5′-yl)methylphosphonate
    Baicalin; TJN-151
    Betulinic acid; Mairin
    Betulinic acid, 3-O-(3′,3′-dimethylsuccinate)
    BHAP deriv.
    BHAP deriv.; Rescriptor®; Delavirdine; U-90152
    BHAP deriv.; U-88204E
    BI-RG-587; Nevirapine; Viramune® Approved
    BILA 1906 BS, BILA 2011 BS; Palinavir, BILA 2185 BS
    Bis(2-nitrophenyl)sulfone; Bis(2NO2Ph)SO2; NSC633001
    bis-ValHOEt-N2aza-peptide isostere; CGP 53820
    bis-ValHOEt-N2aza-peptide isostere; CGP 53820 analog
    BMS-186318
    BocPhe[CHOH(CH2)3CH═CHPhCO]IleAMBI; L-687,908
    BzOCValPhe[diCHOH(RR)]PheValBzOC
    BzOCValPhe[diCHOH(SS)]PheValBzOC
    C2-Sym Phosphinic amide deriv. (HOECHST AG)
    Calanolide A; NSC675451, Calanolide B
    Capravirine; S-1153
    Castanospermine
    CbzAF(CHOHCH2)AVVOMe
    Cbz-Asn-Apns-Pro-NH-tBu; KNI-102
    CGP 61755; Lasinavir, CGP 64222
    CNI-H0294
    Coactinon; I-EBU; HEPT deriv.; MKC-442; Emivirine
    Conocurvone; NSC650891
    Coviracil; (−)FTC; (−)-2′,3′-Dideoxy-5-fluoro-3′-thiacytidine; Emtricitabine; Emtriva
    C-Oxetanocin-G; A-69992; (+−)Lobucavir; C-Oxt-G; Cyclobut-G; (+−)Cyclobut-G
    Crixivan®; Indinavir; MK639; L-735,524; Approved
    Curdlan Sulfate
    CV-N; Cyanovirin-N
    Cyclic Urea Amide; SD 146
    Cyclosporin A; Sandimmune®
    [Me-Ile-4]Cyclosporin A; SDZ NIM 811
    D4A (L); L-2′,3′-Didehydro-2′,3′-dideoxyadenosine
    D4FC; D-D4FC; 2′,3′-Didehydro-2′,3′-dideoxy-5-fluorocytidine; DPC 817
    D4FC (L); L-2′,3′-Didehydro-2′,3′-dideoxy-5-fluorocytidine
    D4G (L); L-2′,3′-Didehydro-2′,3′-dideoxyguanosine
    D4I (L); L-2′,3′-Didehydro-2′,3′-dideoxyinosine
    DABO
    ddC; Dideoxycytidine; Zalcitabine; Hivid®
    ddI; Dideoxyinosine; Didanosine; Videx®
    Dehydroepiandrosterone; DHEA; Prasterone; Dehydroisoandrosterone; EL-10
    Dextran Sulfate
    Dicaffeic acid ester; L-Chicoric acid
    DMP-266; Sustiva®; Efavirenz; Approved
    DMP-323; XM-323
    DMP-450
    Docosanol; n-Docosanol
    dOTC (−); (−)-2′-Deoxy-3′-oxa-4′-thiocytidine
    dOTFC (−); (−)-2′-Deoxy-3′-oxa-4′-thio-5-fluorocytidine
    DP-178; Pentafuside; T-20; GP41 127-162 AA; Enfuvirtide; Fuzeon®
    E-BPTU; HEPT deriv.; NSC 648400
    E-EBU; HEPT deriv.; MKC-442 deriv.
    E-EBU-dM; HEPT deriv.; MKC-442 deriv.
    E-EPSeU; HEPT deriv.; MKC-442 deriv.
    E-EPU; HEPT deriv.; MKC-442 deriv.
    Ebselen
    Etoposide
    Epoxy steriod deriv.; (4α,5α,17β)-17-Hydroxy-3-oxo-4,5-epoxyandrostane-2-carboxamide
    Eulicin
    Fenalamide A1; Phenalamide A1; Stipiamide
    Fleephilone
    Fluoroquinolone deriv.; K-12
    Fortovase®; Invirase®; Saquinavir; Ro31-8959; Approved
    Foscarnet; Phosphonoformic acid; Foscavir;
    FPMDAP, FPMPA, FPMPG
    GPGRAF Octomer; SPC3
    Hammerhead anti-gag RNA Ribozyme B
    Harziphilone
    HBY 097; Quinoxaline deriv.
    HEPT deriv.; MKC-442 deriv.
    HOCH2CH2 isostere; ThienopyridCON thienyl urethane deriv.
    HOCH2CH2 isostere; ThienopyridCONthienyl urethane deriv.; LY326188
    HPMPA
    HPMPDAP
    HU; Hydroxyurea; Hydrea
    Hydroxocobalamin
    Hypericin
    Ingenol 3,5,20-triacetate; ITA; RD3-2118
    Ingenol deriv.; RD4-2138
    Inophyllum B, Inophyllum P
    iQoa-Mta-Apns-Thz-NH-tBu; KNI-272
    Isentress (Raltegravir)
    IsoquinCON furanyl urethane analog
    IsoquinCON thienyl urethane analog
    KNI-154; Noa-Asn-Apns-Thz-NH-tBu, KNI-174; Noa-Asn-Apns-Dmt-NH-tBu
    KNI-227; Qoa-Mta-Apns-Thz-NH-tBu
    L-685,434, L-685,434-6-Hydroxy derivative, L-685,434-OEtMorphderivative; L-689,502
    L-685,434-OEtNMe2, L-685,434-OPrMorph derivative, L-697,593; 2-Pyridinone deriv.
    L-697,639; 2-Pyridinone deriv., L-697,661; 2-Pyridinone deriv.
    L-FddC; β-L-5F-ddC
    Lamivudine & Zidovudine; Combivir® 3TC & AZT; Approved
    LY289612, LY289612 analog, LY289612 analog
    LY-300046-HCl; PETT deriv.; Trovirdine
    LY314163; Saquinavir/Nelfinavir deriv.
    LY-73497; N-(2-Phenethyl)-N′-(2-thiazolyl)thiourea; PETT
    MAP; Methyl acetylenic putrescine
    Michellamine A; NSC650898, Michellamine B; NSC649324, Michellamine F
    N-6-Et-ddA; N-Ethyl-2′,3′-dideoxyadenosine
    N-6-methyl ddA; N6-Methyl-2′,3′-dideoxyadenosine
    Naphthalene 2-sulphonate polymer; PRO 2000
    Nelfinavir-octahydro-thienopyridine analog
    Nonoxynol 9
    NSC625487; Thiazolobenzimidazole; TBZ
    Oxathiin deriv.; UC-38, Oxathiin deriv.; UC-84
    P9941
    Penicillin Et(NH)2 Sym dimer, Penicillin G, ET(NH)2 deriv.
    Penicillin, 2Isoquin-OHPrNH2 analog
    Pentosan Sulfate; Elmiron; SP54; Xylan Sulfate;
    PETT Cl, F deriv., PETT deriv.
    Phenoxan
    Phorbol deriv.; Prostratin
    Platanic acid
    PMEDAP, PMEG, PMEHx; PMEI, PMEMAP, PMET
    PNU-140690; U-140690; Tipranavir
    Pyridinone deriv.
    Quinoxalin2thione deriv; S-2720
    R14458; TIBO deriv.
    R82150; TIBO deriv.
    R82913; TIBO deriv.
    Resobene
    Ribavirin; Virazole
    Ro 31-8959-bis-thf deriv.
    Saquinavir/Nelfinavir deriv.
    SB-205569; Val-Phe-Phe-HOCH2CH2 isostere analog
    SC-52151; Telinavir
    SDZ PRI 053
    Suramin Sodium
    T22
    Thalidomide
    Thiangazole; (−)-Thiangazole, Thiazoloisoindol-5-one, Thiazoloisoindol-5-one, deriv.
    Tle-Val-Sta, 5PhBuCOOH deriv.; Statine deriv.
    UC-781
    Val-Val-Sta, 5PhBuCOOH deriv.; Statine deriv.
    VB-11,328
    Viread®; Tenofovir Disoproxil


An alternative list of drugs and/or bioactive agents useful in the treatment of TB infections, or conditions or disease states which are secondary to TB infections is set forth herein below. One or more of these agents may be used in combination (coadministered) with at least one anti-MDR TB agent as otherwise disclosed herein to treat MDR-TB or other drug-resistant TB and co-infections with other conditions or disease states, including AIDS/ARC, Kaposi's sarcoma, hepatitis B and C virus infections, and other microbial infections. When used, these compounds are also included in effective amounts.
These list of drugs and/or bioactive agents include those at the following website: aidsinfo.nih.gov/DrugsNew/DrugDetailNT.aspx?MenuItem=Drugs&Search=On&int_id=257 FDA Approved: Tuberculosis Rifampin (Rifadin, Rimactane); Rifapentine; Isoniazid (Nydrazid); Ethambutol; Ethambutol Hydrochloride; Ethionamide; Para-aminosalicylic acid (PAS); Capreomycin; Amikacin; Rifabutin (Mycobutin); Streptomycin; Pyrazinamide; Cycloserine; Ciprofloxacin; Ofloxacin; Levofloxacin; Clofazimine; Bedaquiline; Moxifloxacin Hydrochloride; HIV Combination Drugs Atripla; Combivir; Complera; Epzicom; Kaletra; Stribild; Trizivir; Truvada; Entry and Fusion Inhibitors Enfuvirtide; Maraviroc; Integrase Inhibitors Raltegravir; Non-nucleoside Reverse Transcriptase Inhibitors Delavirdine; Efavirenz; Etravirine; Nevirapine; Rilpivirine Nucleoside Reverse Transcriptase Inhibitors Abacavir; Abacavir/Lamivudine; Abacavir/Lamivudine/Zidovudine; Didanosine; Emtricitabine; Emtricitabine/Tenofovir Disoproxil Fumarate; Lamivudine; Lamivudine/Zidovudine; Stavudine; Tenofovir Disoproxil Fumarate; Zidovudine Protease Inhibitors Atazanavir; Darunavir; Fosamprenavir; Indinavir; Lopinavir/Ritonavir; Nelfinavir; Ritonavir; Saquinavir; Tipranavir. Opportunistic Infections Aspergillosis; Amphotericin B; Voriconazole; Coccidioidomycosis; Amphotericin B; Fluconazole; Itraconazole; Cryptococcosis; Amphotericin B; Fluconazole; Flucytosine; Itraconazole; Cryptosporidiosis/Microsporidiosis Albendazole; Itraconazole; Cytomegalovirus Disease Foscarnet Sodium; GanciClovir; Valganciclovir Hydrochloride; Disseminated Mycobacterium avium Complex Disease Azithromycin; Ciprofloxacin; Clarithromycin; Ethambutol Hydrochloride; Levofloxacin; Moxifloxacin Hydrochloride; Rifabutin; Hepatitis B Virus Infection Hepatitis B Vaccine; Peginterferon Alfa-2a; Hepatitis C Virus Infection Peginterferon Alfa-2a; Peginterferon Alfa-2b; Ribavirin; Herpes Simplex Virus Disease Acyclovir; Famciclovir; Foscarnet Sodium; Imiquimod; Valacyclovir Hydrochloride; Histoplasmosis Amphotericin B; Itraconazole; Human Herpesvirus-8 Diseases Ganciclovir; Valganciclovir Hydrochloride; Isosporiasis Ciprofloxacin; Pyrimethamine; Sulfamethoxazole/Trimethoprim; Leishmaniasis Amphotericin B; Mucocutaneous Candidiasis Amphotericin B; Butoconazole Nitrate; Clotrimazole; Fluconazole; Itraconazole; Miconazole; Terconazole; Voriconazole; Penicilliosis marneffei Amphotericin B; Itraconazole; Pneumocystis; Pneumonia Clindamycin; Primaquine Phosphate; PyrimethamineiSulfamethoxazole/Trimethoprim; Toxoplasma gondii Encephalitis Azithromycin; Clindamycin; Pyrimethamine; Sulfadiazine; Sulfamethoxazole/Trimethoprim; Varicella-Zoster Virus Diseases Acyclovir; Famciclovir; Foscarnet Sodium; Ganciclovir; Valacyclovir Hydrochloride; Varicella Virus Vaccine Live
Investigational: HIV Entry and Fusion Inhibitors AMD-070; BMS-663068; Cenicriviroc; INCB-9471; Ibalizumab; PRO-140: Integrase Inhibitors Dolutegravir; S/GSK1265744; Non-nucleoside Reverse Transcriptase Inhibitors Lersivirine; Nucleoside Reverse Transcriptase Inhibitors BMS-986001; Elvucitabine; GS-7340; Racivir.

Chemical Synthesis: General Synthetic Scheme

A general scheme for the synthesis is shown below in Scheme 1. The precursors to the target molecules are indicated. These precursors were synthesized by modifications of methodologies developed in the Nair laboratory [J. Org. Chem. 72, 8577-8579 (2007); ACS Med. Chem. Lett. 2, 877-881 (2011); J. Med. Chem. 49, 445447 (2006); J. Am. Chem. Soc. 109, 7223-7224 (1987); J. Org. Chem. 53, 30513057 (1988)]. The key and most important step in the synthesis is the conversion of these precursors to the target molecules and the methodologies for these conversions are indicated.







CHEMICAL SYNTHESIS: REPRESENTATIVE EXAMPLES
The following representative examples are provided to illustrate details for the preparation of the compounds of the present invention. The examples are not intended to be limitations on the scope of the present invention and they should not be so construed. Furthermore, the compounds described in the following examples are not to be viewed as forming the only set of compounds that is considered as the invention, and any combination of components of the compounds or their moieties may itself form a set. This has been addressed previously in this patent document. Those skilled in the art will readily comprehend that known variations of reaction conditions and synthetic conversions described in the following preparative procedures can be used to readily prepare these other compounds routinely.
Representative Example 1
4-(1-(2-Fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione (2)




To a chilled solution of 4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-2-oxobut-3-enoic acid 1, prepared using modifications of methodologies previously described by us, J. Org. Chem. 72, 8577-8579 (2007); ACS Med. Chem. Lett. 2, 877-881 (2011), (103 mg, 0.224 mmol) in dimethylformamide (DMF) (1.3 mL) was added hydroxybenzotriazole (HOBT) (33 mg, 0.246 mmol), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI-HCl) (47 mg, 0.246 mmol). The mixture was stirred at 0° C. for 20 minutes and then 4-(naphthalen-1-yl)piperazin-1-ium chloride 3, (61 mg, 0.2463 mmol) and NaHCO3 (21 mg, 0.246 mmol) were added. Stirring was continued for 2.5 h at 0° C. Water was then added to precipitate the product, which was filtered and washed with additional water. This solid was dissolved in ethyl acetate (50 mL) and the solution washed with water (4×50 mL) The ethyl acetate extract was concentrated in vacuo and the resulting oily product was dried in vacuo to give the crude product, which was passed through a short silica gel column with chloroform as the eluting solvent. The eluent was removed and the residue was triturated with pentane to give a yellow amorphous powder (44.1 mg, 30%). UV (methanol): λ 387 nm (ε 16,349); 305 nm (ε 10,899). 1H-NMR (DMSO-d6, 500 MHz), δ 15.00 (bs, 1H), 8.21-8.12 (m, 3H), 7.95-7.91 (m, 1H), 7.68-7.00 (m, 12H), 5.25 (bs, 214), 3.88-3.74 (m, 6H), 3.74-2.82 (m, 4H). HRMS: calculated mass 656.2172 for C37H30F4N3O4[M+H]+; found 656.2170.
Representative Example 2
4-(1,5-Dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione (4)




The title compound 4 was synthesized using the procedure described above for compound 2 using 4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-2-oxobut-3-enoic acid as the precursor. The product was isolated as a yellow solid. UV (methanol): λ 390 nm (ε 15,333), 302 nm (ε 10,810). 1H-NMR (DMSO-d6, 500 MHz), δ 15.04 (bs, 1H), 8.34 (bs, 8.19 (m, 114), 7.91 (m, 1H), 7.65 (m, 1H), 7.55-7.16 (m, 16H), 5.23 (s, 2H), 3.86-3.73 (m, 6H), 3.04 (m, 4H).
HRMS: calculated mass 584.2549 for C37H34N3O4 [M+H]+; found 584.2543.
Representative Example 3
1-(4-([1,1′-Biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione (5)




To a chilled solution of 4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-2-oxobut-3-enoic acid 1, (100 mg, 0.217 mmol) in DMF (1.3 mL) was added hydroxybenzotriazole (HOBT) (32 mg, 0.238 mmol), followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI-HCl) (46 mg, 0.238 mmol). The mixture was stirred for 30 minutes, treated with 1-([1,1′-biphenyl]-4-yl)piperazine 6, (57 mg, 0.238 mmol) and the resulting reaction mixture was stirred for 2.5 h at 0° C. Water was then added to precipitate the product, which was filtered and washed with additional water. This solid was dissolved in ethyl acetate (50 mL) and the solution washed with water (4×50 mL) and finally with brine (100 mL). The ethyl acetate extract was concentrated in vacuo and the resulting oily product was dried in vacuo to give the crude product, which was passed through a short silica gel column with chloroform as the eluting solvent. The eluent was removed and the residue was triturated with pentane to give a yellow amorphous powder (83 mg, 56%). UV (methanol): λ 389 nm (ε 16,746), λ 284 nm (ε 27,712). 1H-NMR (CDCl3, 500 MHz), δ 15.15 (bs, 1H), 8.24 (m, 1H), 7.60-7.03 (m, 19H), 6.74 (t, 2H), 5.20 (bs, 2H), 3.88-3.86 (m, 2H), 3.80 (s, 2H), 3.78-3.75 (m, 2H), 3.34-3.21 (m, 4H). HRMS: calculated mass 682.2329 for C39H32F4N3O4 [M+H]+; found 682.2326.
Representative Example 4
1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-2-ene-1,4-dione (7)




The title compound 7 was synthesized by the procedure described above for compound 5 using appropriate precursors. The product was a yellow solid. UV (methanol): λ 389 nm (ε 15,521), 266 nm (ε 23,131). 1H-NMR (CDCl3, 500 MHz): δ 8.19-8.20 (m, 1H), 7.79 (s, 1H), 7.50-7.57 (m, 2H), 7.42-7.45 (m, 1H), 7.28-7.33 (m, 3H), 7.19-7.23 (m, 2H), 7.06-7.14 (m, 2H), 6.94-6.99 (m, 2H), 6.69 (t, 2H, J=8.0 Hz), 5.16 (s, 2H), 3.71-3.83 (m, 6H), 3.16-3.28 (m, 4H), 1.25 (s, 1H). HRMS: calculated for C36H30F4N5O4 [M+H]+672.2234, found 672.2241.
Representative Example 5
1-(4-([1,1′-Biphenyl]-3-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl) 1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione (8)




The title compound was synthesized by the procedure described above for compound 5 using appropriate precursors. The product was a yellow powder. UV (methanol): λ 388 nm (ε 13,958), 307 nm (ε 5,696), 241 nm (ε 35,609). 1H-NMR (CDCl3, 500 MHz), δ 8.14 (bs, 1H), 7.51-7.19 (m, 10H), 7.08-7.00 (m, 4H), 6.86 (d, 1H), 6.65-6.61 (m, 2H), 5.08 (bs, 21-1), 3.77-3.67 (m, 6H), 3.23-3.12 (m, 411). HRMS: calculated mass 682.2329 for C39H32F4N3O4 [M+H]+; found 682.2326.
Representative Example 6
1-(4-(4-(Dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione (9)




The title compound 9 was synthesized by the procedure described above for compound 5 using appropriate precursors. The product was a dark yellow solid. UV (methanol): λ 387 nm (ε 12,272), 315 nm (ε 5,766), 261 nm (ε 17,968). 1H-NMR (DMSO, 500 MHz): δ 8.20 (s, 1H), 8.14-8.05 (m, 1H), 7.38-7.18 (m, 7H), 6.88-6.69 (m, 4H), 5.25 (s, 2H), 3.88 (s, 2H), 3.67-3.47 (m, 4H), 3.35 (bs, 2H), 3.01-2.95 (m, 3H), 2.82-2.78 (m, 6H). HRMS: calculated mass 649.2438 for C35H33F4N4O4 [M+H]+; found 649.2414.
Representative Example 7
1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione (10)




The title compound 10 was synthesized by the procedure described above for compound 5 using appropriate precursors. The product was a yellow solid. UV (methanol): λ 390 nm (ε 18,858), 266 nm (ε 29,129). 1H-NMR (CDCl3, 500 MHz): δ 8.11, 8.13 (dd, 1H, J=2.5 Hz), 7.70 (s, 1H), 7.48 (s, 1H), 7.04-7.29 (m, 14H), 6.91 (d, 2H, J=8.5 Hz), 6.82 (d, 11-1, J=8.5 Hz), 5.07 (s, 2H), 3.59-3.76 (m, 6H), 2.95-3.20 (m, 4H). HRMS: Calculated for C36H34N5O4 [M+H]+ 600.2611, found 600.2612.
Representative Example 8
1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione (11)




The title compound 11 was synthesized by the procedure described above for compound 5 using appropriate precursors. The product was a yellow solid. UV (methanol): λ 373 nm (ε 12,483), 269 nm (ε 28,993). 1H-NMR (CDCl3, 500 MHz): δ 8.18, 8.20 (dd, 1H, J=3.0, 2.5 Hz), 7.50-7.55 (m, 2H), 7.44 (t, 1H, J=7.75 Hz), 7.29-7.33 (m, 4H), 6.92-7.14 (m, 6H), 6.66-6.71 (m, 2H), 6.31 (s, 2H), 5.16 (s, 2H), 3.70-3.83 (m, 6H), 3.12-3.24 (m, 4H). HRMS: calculated mass for C37H31F4N4O4 [M+H]+ 671.2281; found 671.2259.
Representative Example 9
1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione (12)




The title compound 12 was synthesized by the procedure described above for compound 5 using appropriate precursors. The product was a yellow solid. UV (methanol): λ 368 nm (ε 13,413), 271 nm (ε 29,880). 1H-NMR (CDCl3, 500 MHz): δ 8.18, 8.21 (dd, 1H, J=3.0 Hz), 7.55 (s, 1H), 7.24-7.36 (m, 13H), 7.11-7.14 (m, 2H), 6.96-7.01 (m, 2H), 6.88 (d, 1H, J=8.0 Hz), 6.31 (t, 2H, J=2.0 Hz), 5.14 (s, 2H), 3.68-3.83 (m, 6H), 3.19-3.24 (m, 4H). HRMS: calculated mass 599.2658 for C37H35N4O4 [M+H]+; found 599.2640.
Representative Example 10
1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione(13)




The title compound 13 was synthesized by the procedure described above for compound 5 using appropriate precursors. The product was a yellow solid. UV (methanol): 376 nm (ε 15,065), 269 nm (ε 31,601). 1H-NMR (CDCl3, 500 MHz): δ 8.15 (d, 1H, J=2.5 Hz), 7.58 (s, 1H), 7.50-7.55 (m, 2H), 7.32-7.36 (m, 3H), 7.10-7.20 (m, 2H), 7.00-7.05 (m, 4H), 6.68-6.78 (m, 3H), 6.36 (t, 2H, J=1.75 Hz), 5.22 (s, 2H), 3.88 (bs, 2H), 3.80 (s, 2H), 3.77 (bs, 2H), 3.25-3.29 (m, 4H). HRMS: calculated mass 653.2376 for C37H32F3N4O4 [M+H]+; found 653.2357.
Representative Example 11
1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione (14)




The title compound 14 was synthesized by the procedure described above for compound 5 using appropriate precursors. The product was a yellow solid. UV (methanol): λ 388 nm (ε 15,140), 269 nm (ε 25,878). 1H-NMR (CDCl3, 500 MHz) δ 8.24 (s, 111), 7.52-7.15 (m, 7H), 7.13-6.89 (m, 8H), 6.32 (s, 2H), 5.16-5.15 (m, 2H), 4.44 (s, 0.3H), 3.81-3.72 (m, 6H), 3.23-3.20 (m, 4H). HRMS: calculated mass 653.2376 for C37H32F3N4O4 [M+H]+; found 653.2360.
Representative Example 12
1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione (15)




The title compound 15 was synthesized by the procedure described above for compound 5 using appropriate precursors. The product was a yellow solid. UV (methanol): λ 390 nm (ε 14,942), 269 nm (ε 25,779). 1H-NMR (CDCl3, 500 MHz): δ 3.12-3.25 (m, 4H), 3.71-3.91 (m, 711), 4.47 (s, 0.3H), 5.14-5.16 (m, 2H), 6.32-6.33 (m, 2H), 6.93-7.15 (m, 1011), 7.15-7.52 (m, 7H), 8.13-8.14 (m, 1H). HRMS: calculated mass 635.2470 for C37H33F2N4O4 [M+H]+; found 653.2451.
Representative Example 13
4-(1-(2-Fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione (16)




The title compound 16 was synthesized by the procedure described above for compound 2 using appropriate precursors. The product was a yellow solid. UV (methanol): λ 385 nm (ε 12,721), 247 nm (ε 11,768). 1H-NMR (CDCl3, 500 MHz): δ=15.10-15.12 (m, 0.5H), 8.18-8.20 (m, 1H), 7.44-7.57 (m, 2H), 7.24-7.33 (m, 4H), 7.06-7.14 (m, 2H), 6.90-6.94 (m, 3H), 6.66-6.71 (m, 2H), 5.14-5.15 (m, 2H), 3.69-3.82 (m, 6H), 3.12-3.24 (m, 4H). HRMS: calculated mass 606.2016 for C33H28F4N3O4 [M+H]+; found 606.2012.
Biology
Method for Agar Dilution Drug Susceptibility Assays Against Multidrug-Resistant Mycobacterium Tuberculosis (MDR-TB)
The following assays were conducted against MDR-TB following the screening guidelines of the Clinical and Laboratory Standards Institute (CLSI).
Materials.
The compounds were stable at room temperature and were stored at room temperature until the day of the drug susceptibility assay. Prior to screening, the compounds were solubilized in a minimum amount of DMSO. The screening was done with an isolate of MDR-TB that was resistant to both isoniazid (INH) and rifampin (R). This isolate used for the screening assays was an aliquot from a working stock culture collection that had been stored frozen at −80° C. The aliquot was allowed to thaw at room temperature and subsequently diluted in test media. The screening assays used the following positive and negative controls: (a) organism only (negative control); (b) streptomycin (anti-MDR-TB drug, positive control).
Methods.
The agar dilution susceptibility assay method and format were utilized for susceptibility testing. The agar medium, Middlebrook 7H10 (BD BioSciences; Sparks, Md.), was prepared according to the manufacturer's guidelines and the test compounds were serially diluted two-fold to achieve a testing concentration range from 25 micrograms/mL to 0.012 micrograms/mL (total of 12 concentrations). Each concentration of compound was mixed with Middlebrook 7H10 agar, poured into sterile petri dishes (plates) and allowed to solidify. The plates were subsequently inoculated with approximately 2.0×103 CFU M. tuberculosis and incubated for 21 days at 37° C. Testing was conducted in triplicate and the MICs (minimum inhibitory concentrations) were reported as the lowest concentration (micrograms/mL) of drug that completely inhibited growth of the organism as visibly determined.
Activity.
Anti-MDR TB activities were observed for a significant number of compounds of this invention. The X substitutions were aromatic groups and also those in which the X aromatic group was additionally substituted with heterocyclic rings. The more active compounds had MICs against MDR-TB that were either less than one microgram/mL or significantly less than one microgram/mL.

## Claims

1. A compound according to Formula I, including tautomers, geometric isomers and pharmaceutically acceptable salts thereof



wherein R1, R2, R3 and R4 are each independently H or F; and
X is a phenyl group which is optionally substituted with dimethylamine or a nitrogen containing heterocyclic group selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl and triazolyl, or X is a biphenyl, naphthyl, anthracenyl or phenanthryl group.

2. A compound according to claim 1 wherein
R1=H, R2=H, R3=H, R4=H;
R1=H, R2=o-F, R3=o-F, R4=p-F;
R1=o-F, R2=o-F, R3=o-F, R4=m-F;
R1=o-F, R2=o-F, R3=o-F, R4=p-F
R1=o-F, R2=o-F, R3=m-F, R4=m-F;
R1=o-F, R2=o-F, R3=m-F, R4=p-F
R1=o-F, R2=m-F, R3=m-F, R4=p-F;
R1=H, R2=m-F, R3=m-F, R4=p-F;
R1=m-F, R2=o-F, R3=o-F, R4=m-F;
R1=m-F, R2=o-F, R3=o-F, R4=p-F;
R1=m-F, R2=o-F, R3=m-F, R4=m-F;
R1=m-F, R2=o-F, R3=m-F, R4=p-F;
R1=m-F, R2=o-F, R3=m-F, R4=p-F
R1=H, R2=o-F, R3=o-F, R4=m-F;
R1=p-F, R2=o-F, R3=o-F, R4=m-F;
R1=p-F, R2=o-F, R3=o-F, R4=p-F;
R1=p-F, R2=o-F, R3=m-F, R4=m-F;
R1=p-F, R2=o-F, R3=m-F, R4=p-F;
R1=p-F, R2=m-F, R3=m-F, R4=p-F;
R1=o-F, R2=m-F, R3=m-F, R4=H;
R1=o-F, R2=p-F, R3=H, R4=H or
R1=o-F, R2=o-F, R3=o-F, R4=H.

3. A compound according to claim 1 wherein X is

4. A compound according to claim 1 wherein X is a phenyl group or a naphthyl, anthracenyl or phenanthryl group.

5. The compound according to claim 1 wherein X is a phenyl group which is substituted with a dimethylamine or a nitrogen-containing heterocyclic group selected from the group consisting of pyrrolyl, imidazolyl, pyrazolyl and triazolyl and wherein said pyrrolyl group is a 1H-pyrrol-1-yl group, said imidazolyl group is a 1H-imidazol-1-yl group, said pyrazolyl group is a 1H-pyrazol-1-yl group and said triazolyl group is a 1H-1,2,4-triazolyl group.

6. The compound according to claim 5 wherein said nitrogen-containing heterocyclic group is selected from the group consisting of 1H-pyrrol-1-yl group, a 1H-imidazol-1-yl group and a 1H-pyrazol-1-yl group.

7. The compound according to claim 5 wherein said nitrogen-containing group is a 1H-1,2,4-triazolyl group.

8. The compound according to claim 1 which is:
4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;
1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;
4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1,5-dibenzyl-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;
1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;
1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-5-(4-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;
4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;
1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(5-(2,6-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;
1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;
1-(4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(5-(3,5-difluorobenzyl)-1-(2-fluorobenzyl)-2-oxo-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;
1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;
4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;
1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;
1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;
1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;
1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione; or
1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(4-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione.

9. The compound according to claim 1 which is:
4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;
1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;
1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;
1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;
1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;
1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;
1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione; or
1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione.

10. The compound according to claim 1 which is:
4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;
1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(2-fluorobenzyl)-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;
1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;
4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-benzyl-2-oxo-5-(3,4,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;
1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalene-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;
1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione, or
1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione.

11. The compound according to claim 1 which is:
1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;
1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalene-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;
1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,4,6-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;
1-(4-([1,1′-biphenyl]-4-yl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;
1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,5-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-phenylpiperazin-1-yl)but-3-ene-1,2-dione;
1-(4-([1,1′-biphenyl]-4-yl)piperazin-l-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxy-1-(4-(naphthalen-1-yl)piperazin-1-yl)but-3-ene-1,2-dione;
1-(4-(4-(dimethylamino)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrrol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-imidazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione;
1-(4-(4-(1H-pyrazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione; or
1-(4-(4-(1H-1,2,4-triazol-1-yl)phenyl)piperazin-1-yl)-4-(1-(3-fluorobenzyl)-2-oxo-5-(2,3,4-trifluorobenzyl)-1,2-dihydropyridin-3-yl)-4-hydroxybut-3-ene-1,2-dione.

12. A pharmaceutical composition for treating TB, MDR-TB or XDR-TB, comprising a therapeutic amount of a compound according to claim 1 in combination with a pharmaceutically acceptable carrier, additive or excipient.

13. The pharmaceutical composition of claim 12 wherein said composition treats said TB infection by inhibiting TB DNA-dependent RNA polymerase, both wild type and mutants, in the human host.

14. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1, a pharmaceutically acceptable carrier, additive or excipient in combination with a therapeutically effective amount of at least one compound selected from the group consisting of: (i) another TB drug and/or a TB drug that is active against drug-resistant TB; (ii) a therapeutically effective amount of an agent for the treatment of AIDS; (iii) an anti-infective agent, (iv) an immunomodulator, (v) another bioactive agent selected from the group consisting of antibiotics, vaccines and an additional antiviral agent, and mixtures thereof.

15. The composition according to claim 12 in oral or parenteral dosage form.

16. The composition according to claim 12 formulated for administration as an inhalation spray or a rectal suppository.

17. A method of treating a TB infection in a patient, said method comprising administering to said patient an effective amount of a composition according to claim 12.

18. A method of treating a patient with TB comprising administering to said patient a therapeutically effective amount of a compound according to claim 1.

19. A method of inhibiting TB DNA-dependent RNA polymerase in a subject, said method comprising administering to said subject a therapeutically effective amount of a compound according to claim 1.

20. The method according to claim 17 wherein said subject is a human.

21. The method according to claim 17 wherein said TB infection is caused by TB which is drug-resistant.

22. The method according to claim 21 wherein said drug-resistant TB is extensively drug-resistant TB (XDR-TB).

23. The method according to claim 21 wherein said drug-resistant TB is extremely drug-resistant TB (XXDR-TB).

24. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 in combination with an effective amount of at least one additional anti-TB agent and optionally at least one anti-HIV compound, in combination with a pharmaceutically acceptable carrier, additive or excipient.

25. The composition according to claim 24 wherein said anti-HIV compound is combined with an anti-infective agent.

26. The composition according to claim 24 wherein said anti-HIV compound treats said TB infection by inhibiting at least TB DNA-dependent RNA polymerase, both wild type and mutants, in the human host.

27. The composition according to claim 24 in oral or parenteral dosage form.

28. The composition according to claim 24 formulated for administration as an inhalation spray or a rectal suppository.

29. A method of treating a TB infection in a human host comprising administering to said host in combination, an effective amount of at least one compound according to claim 1 in combination with at least one anti-HIV agent and at least one other anti-TB compound in combination with a pharmaceutically acceptable carrier, additive or excipient.

30. A method of treating a TB infection in a patient, said method comprising administering to said patient an effective amount of a composition according to claim 24.

31. A method of inhibiting TB DNA-dependent RNA polymerase in a subject, said method comprising administering to said subject a therapeutically effective amount of a composition according to claim 24.

32. The method according to claim 30 wherein said patient is a human.

33. A kit comprising a pharmaceutical composition according to claim 12 and instructions for a medical professional and/or a patient on how to administer said composition.