Nitro-containing compounds that kill mycobacteria

Abstract

Compounds, and pharmaceutically acceptable salts thereof, useful as inhibitors of mycobacterial growth are provided. Also provided are pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts and methods of using the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions in the treatment of various disorders, including Mycobacterium tuberculosis and Mycobacterium abscessus infection.

Description

Attorney Docket No.98211-410936 (TEC2023-0076) NITRO-CONTAINING COMPOUNDS THAT KILL MYCOBACTERIA CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Application No.63 / 525,775, filed July 20, 2023, which is incorporated by reference herein in its entirety. GOVERNMENT SUPPORT

[0002] This invention was made with government support under AI153454 awarded by the U.S. National Institutes of Health. The government has certain rights in the invention. BACKGROUND

[0003] The high prevalence of tuberculosis (TB), coupled with growing antibiotic resistance, highlights the need to develop new TB drugs (1). With the recent approval of pretomanid and delamanid for TB treatment (2, 3), nitro-containing compounds have emerged as important agents to control TB. Pretomanid and delamanid are classified as nitroimidazoles. Other antitubercular nitro-containing chemical scaffolds include benzothiazinones, dinitrobenzamides, nitrobenzamides, and nitrofurans, among others (2, 4, 5). Some compounds from these series such as PBTZ-169 and BTZ-043 have been shown to be efficacious in clinical trials for TB treatment (3).

[0004] Pretomanid and delamanid kill Mycobacterium tuberculosis (Mtb) by targeting essential cellular processes such as respiration or cell wall biogenesis and are effective against non-replicating Mtb (6-11). They are prodrugs and require reductive activation by the mycobacterial-specific deazaflavin- dependent nitroreductase (Ddn) (7, 12, 13). Their prodrug status enables them to specifically inhibit the growth of the infecting Mtb while limiting dysbiotic effect on the host microbiome. Despite their promising use for TB treatment, pretomanid and delamanid have some limitations. There are reports of Mtb isolates that are naturally resistant to either drug due to genetic polymorphism in Ddn or other genes in the F420biosynthesis pathway, and the F420-dependent glucose-6-phosphate dehydrogenase-1 (fdg1) (14, 15). Fdg1 mediates one of the earliest steps in the pentose phosphate pathway of mycobacteria. It uses F420, instead of the canonical NAD(P), in catalyzing its reaction. In this process, F420is reduced and can be used by Ddn in the activation of pretomanid or delamanid (7, 10, 12, 13, 16, 17). Clinical strains that have developed resistance to either pretomanid or delamanid have been isolated in different parts of the world (9, 14). The pharmacokinetic profile and side effects of the compounds can make them less ideal for certain patients. Delamanid has a relatively poor oral bioavailability and can have a modest effect on QT prolongation (2, 9, 18). Due to these challenges, there are ongoing efforts to develop new antitubercular nitro-containing compounds with improved properties.

[0005] The inventors previously conducted a whole cell high-throughput screen of the ~340,000 compound Molecular Libraries Small Molecular Repository (MLSMR) for inhibitors of the DosRST two- component regulatory system (19). From this primary HTS, the inventors identified compounds that inhibited Mtb growth independent of the targeted pathway. Many of these growth-inhibiting compounds contained a nitro group as a presumptive pharmacophore.

[0006] The rising incidence of drug-resistant Mycobacterium tuberculosis and the paucity of drugs in the TB drug development pipeline highlight the need to further understand the physiology of the pathogen and discover new drugs and targets. SUMMARY

[0007] This disclosure provides mechanistic insight into 10 antitubercular compounds, some of which need the F420activation machinery for their activity, and novel analogs thereof. Unexpectedly, the F420-dependent compounds are also active against M. abscessus, a related pathogen that is challenging to treat with antibiotics. One of the compounds, HC2210, was found to be orally bioavailable and efficacious to treat Mtb-infected mice, highlighting its potential development as a new TB drug.

[0008] Accordingly, in one aspect, the disclosure relates to a compound described herein, or a pharmaceutically acceptable salt thereof.

[0009] In another aspect, the disclosure relates to a pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

[0010] In still another aspect, the disclosure relates to a method of inhibiting the growth of a Mycobacterium by contacting the mycobacterium with a compound, pharmaceutically acceptable salt, or pharmaceutical composition of the disclosure.

[0011] In yet another aspect, the disclosure relates to a method of treating a Mycobacterium infection in a subject by administering a compound, pharmaceutically acceptable salt, or pharmaceutical composition of the disclosure to the subject.

[0012] In another aspect, the disclosure relates to a method of treating Mycobacterium tuberculosis infection in a subject by administering a compound, pharmaceutically acceptable salt, or pharmaceutical composition of the disclosure to the subject.

[0013] In still another aspect, the disclosure relates to a method of treating Mycobacterium abscessus infection in a subject by administering a compound, pharmaceutically acceptable salt, or pharmaceutical composition of the disclosure to the subject.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 shows nitro-containing compounds that inhibit Mtb growth. Panel A shows Fdg1- dependent nitrofurans. Panel B shows Fdg1-independent nitrofurans. Panetl C shows dinitrobenzamides that are putative DrpE inhibitors. Panel D shows pretomanid, a nitro-containing FDA approved TB drug.

[0015] Figure 2 generally shows dose-dependent growth inhibition of Mtb by nitro-containing compounds. Panel A shows dose response curves for HC2210 inhibition of Mtb growth relative to pretomanid and isoniazid. Panel B shows dose response curves for other nitrofurans. Panel C shows dose Response curves for the dinitrobenzamides. In all panels, the dotted line represents the growth inhibition of the negative control (DMSO). The error bars represent the standard deviations of two to three biological replicates. All experiments were independently conducted at least twice with similar results.

[0016] Figure 3 generally shows in vitro time and concentration dependent killing of Mtb. Panel A shows a comparison of the bactericidal activity of HC2210 with those of pretomanid and isoniazid, demonstrating that it is weakly bactericidal. Panel B shows the other tested nitrofurans that killed Mtb in a dose- and time-dependent manner. For both time points, HC2233 completely sterilized the culture at 50 µM. Hence, the line is not shown in the graph. After 10 days of treatment, 50 µM of HC2234 completely sterilized the culture below the limit of detection. Hence, the graph line ended at 4 days. Panel C shows the time- and dose-dependent killing of Mtb by the tested dinitrobenzamides. Panel D shows the bactericidal activity of the compounds against non-replicating Mtb in a hypoxic shift-down assay. The upper black dotted lines in panels A, B, and C represent the starting cell concentration of 1.7 x 108CFU / ml. The limit of detection in this assay is ~20 CFU. The error bars represent the standard deviations of two technical replicates for A-C or two biological replicates for D. Asterisks denote statistically significant differences between the compared groups in an unpaired Student's t-test (**p value ≤ 0.01). ns = statistically nonsignificant with p value > 0.05.

[0017] Figure 4 generally shows resistance of the ddn and fdg1 spontaneous mutants against the tested nitrofurans and pretomanid. fdg mutants provide full resistance and ddn mutants provide partial resistance against HC2210. Pretomanid entirely loses its activity in the tested fdg and ddn mutants. fdg and ddn mutants did not provide resistance to HC2234 or HC2250. The dotted lines represent the growth inhibition of the negative control (DMSO). The error bars represent the standard deviations of three biological replicates. All experiments were independently repeated three times with similar results.

[0018] Figure 5 generally shows resistance to dinitrobenzamides and HC2250 in dprE1 mutants. HC2238 and HC2226 lose activity against the spontaneous dprE1 mutants, while partial resistance is observed towards HC2250. HC2234 is active against the tested dprE mutant. The dotted lines represent the growth inhibition of the negative control (DMSO). The LJfdg mutant is included as a control showing the compounds are independent of the F420-dependent activation. The error bars represent the standarddeviations of three biological replicates. All experiments were independently conducted two times with similar results.

[0019] Figure 6 generally shows that HC2210 delivered orally reduces Mtb survival in a chronic model of Mtb infection. Mycobacterial burden is reduced in the lung and spleen of infected C57BI / 6 mice following four weeks of treatment with HC2210. HC2210 treatment was performed by oral gavage once daily, 5 days a week at 75 mg / kg. Rifampin treatment was twice daily, 5 days a week at 10 mg / kg. “p.i” is an acronym denoting “post-infection”. “1d p.i” refers to the mycobacterial burden of the mice a day after infection. “39d p.i” refers the mycobacterial burden of the untreated mice 39 days post-infection, prior to treatment. The vehicle control is 95% corn oil / 5% DMSO. Asterisks denote statistically significant differences between the compared groups in an unpaired Student's t-test (**p value ≤ 0.01; ***p value ≤ 0.001). ns = statistically nonsignificant with p value > 0.05.

[0020] Figure 7 shows confirmation of spontaneous resistant mutants that were generated from plates containing either A.100 nM or B.300 nM of HC2210. The dotted lines represent the growth inhibition of the negative control (DMSO). All experiments were repeated twice with similar results.

[0021] Figure 8 shows the activity of the nitrofurans against ddn and fdg1 spontaneous mutants. fdg1 mutants lead to full resistance to HC2209 and HC2211 and only a slight impact on susceptibility to HC2233. ddn mutants are partially resistant to HC2209 and HC2211, and fully susceptible to HC2233. The dotted lines represent the growth inhibition of the negative control (DMSO). The error bars represent the standard deviations of three biological replicates. All experiments were independently confirmed at least twice will similar results.

[0022] Figure 9 shows that dinitrobenzamides do not depend on Ddn or Fdg1 for its activity. The dotted lines represent the growth inhibition of the negative control (DMSO). The error bars represent the standard deviations of three biological replicates. All experiments were repeated at least twice with similar results.

[0023] Figure 10 shows the generation of dprE1 resistant mutants and testing for the activity of other compounds against the mutants. Panel A shows resistance screening of spontaneous mutants that were generated from 7H9 / OADC plates containing HC2238 as a selection agent. Panel B shows that DprE1 mutations confer resistance to HC2217, but not HC2233 or ethambutol. The dotted lines represent the growth inhibition of the negative control (DMSO). Dose responses in Panel B were repeated twice with similar results and the error bars represent the standard deviations of three biological replicates.

[0024] Figure 11 shows the activity of the nitrofurans against Mycobacterium abscessus. The dose responses were repeated twice with similar results.

[0025] Figure 12 shows resistance screening of Mycobacterium smegmatis mutants against different dinitrobenzamides. Panel A shows confirmation of mutants that were generated in selection platescontaining HC2217. Panel B shows confirmation of mutants that were generated in selection plates containing HC2238.

[0026] Figure 13 shows cross-resistance screening of Mycobacterium smegmatis MSMEG_6503 and dprE1 spontaneous mutants against HC2217, HC2238, HC2239. All three compounds have decreased potency against the spontaneous mutants. DETAILED DESCRIPTION

[0027] This disclosure explores the mechanisms of action of 10 nitro-containing compounds that inhibit mycobacterial growth and describes novel analogs thereof. In particular, the inventors have identified a genetic basis for the antimycobacterial activities of the compounds disclosed herein. The inventors show that, like pretomanid and delamanid, several of the nitrofurans described herein depend on cofactor F420-dependent enzymes for activation. Unlike the nitroimidazoles that depend only on Ddn, these nitrofurans partially depend on Ddn and possibly a second, unknown F420-dependent enzyme for activation. Additionally, the inventors show that the nitrofurans are active against Mycobacterium abscessus (Mab), whereas pretomanid had limited inhibition of Mab growth. Other nitro-containing compounds, including dinitrobenzamides and a nitrofuran, are proposed to target decaprenyl-phosphoryl- ribose 2'-epimerase 1 (DprE1), an essential protein involved in cell wall biogenesis. These putative DprE1 inhibitors were active against both Mtb and Mycobacterium smegmatis (Msm). The inventors additionally demonstrate that a novel nitrofuran-piperazine-nitrophenol compound, HC2210, is effective, when delivered orally, in a chronic murine Mtb infection model. Finally, the inventors have identified a series of HC2210 analogs that demonstrate the ability to inhibit the growth of Mycobacterium tuberculosis and Mycobacterium abscessus.

[0028] In one aspect, the disclosure relates to a compound of formula (I): or a pharmaceuticallyX is N or CH; Y is N or CH;L1is selected from bond, –O–, –NR’–, C1-C3alkylene, –C(O)–, –C(O)NR’–, –NR’C(O)–, –C(O)O–, –OC(O)–, and –S(O)2–; A is selected from H, –NR’R’’, C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, –(C1-C3alkylene)-(C3-C10cycloalkyl), –(C1-C3alkylene)-(C6-C10aryl), –(C1-C3alkylene)-(5- to 10-membered heterocyclyl), and –(C1-C3alkylene)-(5- to 10-membered heteroaryl), wherein said C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, –(C1-C3alkylene)-(C3-C10cycloalkyl), –(C1-C3alkylene)-(C6-C10aryl), –(C1-C3alkylene)-(5- to 10-membered heterocyclyl), or –(C1-C3alkylene)-(5- to 10-membered heteroaryl) is optionally substituted with 1-3 Ra; each Rais independently selected from halo, –CN, –NO2, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, –C(O)R’’’, –C(O)NR’R’’, –C(O)OR’, –S(O)2(C1-C3alkyl), –Si(C1-C3alkyl)3, C6-C10aryl, and 3- to 10-membered heterocyclyl, wherein said aryl or heterocyclyl is optionally substituted with 1-4 substituents independently selected from halo, C1-C3alkyl, and C1-C6haloalkyl; L2is selected from bond, –O–, –NR’–, C1-C3alkylene, –C(O)–, –C(O)NR’–, –NR’C(O)–, –C(O)O–, –OC(O)–, and –S(O)2–; Ring B is C6-C10aryl or 5- to 10-membered heteroaryl, wherein said aryl or heteroaryl is optionally substituted with 1-3 Rb; each Rbis independently selected from halo, –CN, C1-C3alkyl, C1-C6haloalkyl, and C1-C6alkoxy; L3is bond or C6-C10arylene; R2aand R2bare independently selected from H, C1-C6alkyl, C1-C6haloalkyl, and C1-C6alkoxy, or R2aand R2btogether form oxo; each R3aand R3bare independently selected from H, C1-C6alkyl, C1-C6haloalkyl, and C1-C6alkoxy, or R3aand R3btogether form oxo; R5aand R5bare independently selected from H, C1-C6alkyl, C1-C6haloalkyl, and C1-C6alkoxy, or R4aand R4btogether form oxo; R6aand R6bare independently selected from H, C1-C6alkyl, C1-C6haloalkyl, and C1-C6alkoxy, or R2aand R2btogether form oxo; or R3aand R6ajoin to form a bicyclic heterocyclyl; each R’ and R’’ is independently selected from H and C1-C6alkyl; each R’’’ is independently selected from H, C1-C6alkyl, C6-C10aryl, and 5- to 10-membered heteroaryl, wherein said aryl or heteroaryl is optionally substituted with 1-4 substituents independently selected from halo, C1-C3alkyl, C1-C6haloalkyl, and C1-C6alkoxy; and n is 0, 1, or 2,provided that at least one of X and Y is N.

[0029] For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, general principles of organic chemistry are described in “Organic Chemistry,” Thomas Sorrell, University Science Books, Sausalito: 1999, and “March’s Advanced Organic Chemistry,” 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0030] As used herein, the term “compounds of the disclosure” refers to the compounds of formula (I) and all of the embodiments thereof (e.g., formulas (I-A), (I-B), and (I-C), etc.), as described herein, and to the compounds identified in Table A and Table B.

[0031] As described herein, the compounds of the disclosure comprise multiple variable groups (e.g., X, Y, A, B, L1, L2, L3, Ra, Rb, R2a, R2b, R3a, R3b, R5a, R5b, etc.). As one of ordinary skill in the art will recognize, combinations of groups envisioned by this disclosure are those combinations that result in the formation of stable or chemically feasible compounds. The term “stable,” in this context, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and preferably their recovery, purification, and use for one or more of the purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is one that is not substantially altered when kept at a temperature of 40 ^C or less, in the absence of moisture or other chemically reactive conditions, for at least a week.

[0032] As used herein, the term “halo” means F, Cl, Br or I.

[0033] As used herein, the term “alkyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having the specified number of carbon atoms, which is attached to the rest of the molecule by a single bond. For example, a “C1-C6alkyl” group is an alkyl group having between one and six carbon atoms.

[0034] As used herein, the term “alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing one or more carbon-carbon double bonds, and having the specified number of carbon atoms, which is attached to the rest of the molecule by a single bond. For example, a “C2-C6alkenyl” group is an alkenyl group having between two and six carbon atoms.

[0035] As used herein, the term “cycloalkyl” refers to a stable, non-aromatic, mono- or bicyclic (fused, bridged, or spiro) saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, having the specified number of carbon ring atoms, and which is attached to the rest of the molecule by a single bond. For example, a “C3-C8cycloalkyl” group is a cycloalkyl group having between three and eight carbon atoms.

[0036] The term “aryl” refers to monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring carbon atoms, wherein at least one ring in the system is aromatic and wherein each ring in the system contains 3 to 7 ring carbon atoms. The term “aryl” may be used interchangeably with the term “aryl ring.”

[0037] As used herein, the term “alkoxy” refers to a radical of the formula -OR where R is an alkyl group having the specified number of carbon atoms. For example, a “C1-C6alkoxy” group is a radical of the formula -OR where R is an alkyl group having the between one and six carbon atoms.

[0038] As used herein, the term “haloalkyl” refers to an alkyl group having the specified number of carbon atoms, wherein one or more of the hydrogen atoms of the alkyl group are replaced by halo groups. For example, a “C1-C6haloalkyl” group is an alkyl group having between one and six carbon atoms, wherein one or more of the hydrogen atoms of the alkyl group are replaced by halo groups.

[0039] As used herein, the term “haloalkenyl” refers to an alkenyl group having the specified number of carbon atoms, wherein one or more of the hydrogen atoms of the alkenyl group are replaced by halo groups. For example, a “C1-C6haloalkenyl” group is an alkenyl group having between one and six carbon atoms, wherein one or more of the hydrogen atoms of the alkenyl group are replaced by halo groups.

[0040] As used herein, the term “haloalkoxy” refers to an alkoxy group having the specified number of carbon atoms, wherein one or more of the hydrogen atoms of the of the alkyl group are replaced by halo groups.

[0041] As used herein, the term “alkylene” refers to a divalent, straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having the specified number of carbon atoms, which is attached to the rest of the molecule by two single bonds. For example, a “C1-C6alkylene” group is an alkylene group having between one and six carbon atoms.

[0042] As used herein, the term “alkenylene” refers to a divalent, straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing one or more carbon- carbon double bonds, and having the specified number of carbon atoms, which is attached to the rest of the molecule by two single bonds. For example, a “C2-C6alkenylene” is an alkenylene group having between one and six carbon atoms.

[0043] As used herein, the term “haloalkylene” refers to an alkylene group having the specified number of carbon atoms, wherein one or more of the hydrogen atoms of the alkylene group are replaced by halo groups. For example, a “C1-C6haloalkylene” group is an alkylene group having between one and six carbon atoms, wherein one or more of the hydrogen atoms of the alkylene group are replaced by halo groups.

[0044] As used herein, the term “arylene” refers to an aryl group having the specified number of carbon atoms, which is attached to the rest of the molecules by two single bonds. For example, a “C6-C10arylene” group is an arylene having between six and ten carbon atoms.

[0045] As used herein, the term “heterocyclyl” refers to a stable, non-aromatic, mono-, bi-, or tricyclic (fused, bridged, or spiro) radical in which one or more ring atoms is a heteroatom (e.g., a heteroatom independently selected from N, O, P, S, and B), which has the specified number of ring atoms, and which is attached to the rest of the molecule by a single bond. Heterocyclic rings can be saturated, or can contain one or more double or triple bonds. In some embodiments, the “heterocyclyl” group has the indicated number of ring members, in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, phosphorus, and boron and each ring in the ring system contains 3 to 7 ring members. For example, a 6-membered heterocyclyl includes a total of 6 ring members, at least one of which is a heteroatom (e.g., a heteroatom independently selected from N, O, P, S, and B).

[0046] As used herein, the term “heteroaryl” refers to a stable mono-, bi-, or tricyclic ring radical having the specified number of ring atoms, wherein at least one ring in the system is aromatic, at least one aromatic ring in the system contains one or more heteroatoms (e.g., one or more heteroatoms independently selected from N, O, P, and S). In some embodiments, each ring in the system contains 3 to 7 ring members. For example, a 6-membered heteroaryl includes a total of 6 ring members, at least one of which is a heteroatom selected from N, S, O, and P. The term “heteroaryl” may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”.

[0047] Unless otherwise specified, the compounds of the disclosure, whether identified by chemical name or chemical structure, include all stereoisomers (e.g., enantiomers and diastereomers), double bond isomers (e.g., (Z) and (E)), conformational isomers, and tautomers of the compounds identified by the chemical names and chemical structures provided herein. In addition, single stereoisomers, double bond isomers, conformational isomers, and tautomers as well as mixtures of stereoisomers, double bond isomers, conformational isomers, and tautomers are within the scope of the disclosure.

[0048] As used herein, in any chemical structure or formula, a non-bold, straight bond attached to a stereocenter of a compound, such as in , denotes that the configurationmay have any configuration, or a mixture of configurations, at the stereocenter.

[0049] As used herein, the term “compound,” when referring to the compounds of the disclosure, refers to a collection of molecules having identical chemical structures, except that there may be isotopic variation among the constituent atoms of the molecules. The term “compound” includes such a collection of molecules without regard to the purity of a given sample containing the collection of molecules. Thus, the term “compound” includes such a collection of molecules in pure form, in a mixture (e.g., solution, suspension, colloid, or pharmaceutical composition, or dosage form) with one or more other substances, or in the form of a hydrate, solvate, or co-crystal.

[0050] In the specification and claims, unless otherwise specified, any atom not specifically designated as a particular isotope in any compound of the disclosure is meant to represent any stable isotope of the specified element. In the Examples, where an atom is not specifically designated as a particular isotope in any compound of the disclosure, no effort was made to enrich that atom in a particular isotope, and therefore a person of ordinary skill in the art would understand that such atom likely was present at approximately the natural abundance isotopic composition of the specified element.

[0051] As used herein, the term “stable,” when referring to an isotope, means that the isotope is not known to undergo spontaneous radioactive decay. Stable isotopes include, but are not limited to, the isotopes for which no decay mode is identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0052] As used herein in the specification and claims, “H” refers to hydrogen and includes any stable isotope of hydrogen, namely1H and D. In the Examples, where an atom is designated as “H,” no effort was made to enrich that atom in a particular isotope of hydrogen, and therefore a person of ordinary skill in the art would understand that such hydrogen atom likely was present at approximately the natural abundance isotopic composition of hydrogen.

[0053] As used herein, “1H” refers to protium. Where an atom in a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is designated as protium, protium is present at the specified position with at least the natural abundance concentration of protium.

[0054] As used herein, “D,” “d,” and “2H” refer to deuterium.

[0055] In some embodiments, the compounds of the disclosure and pharmaceutically acceptable salts thereof, include each constituent atom at approximately the natural abundance isotopic composition of the specified element.

[0056] In some embodiments, the compounds of the disclosure and pharmaceutically acceptable salts thereof, include one or more atoms having an atomic mass or mass number which differs from the atomic mass or mass number of the most abundant isotope of the specified element (“isotope-labeled” compounds and salts). Examples of stable isotopes which are commercially available and suitable for thedisclosure include without limitation isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, for example2H,13C,15N,18O,17O, and31P, respectively.

[0057] The isotope-labeled compounds and salts can be used in a number of beneficial ways, including as medicaments. In some embodiments, the isotope-labeled compounds and salts are deuterium (2H)-labeled. Deuterium (2H)-labeled compounds and salts are therapeutically useful with potential therapeutic advantages over the non-2H-labeled compounds. In general, deuterium (2H)-labeled compounds and salts can have higher metabolic stability as compared to those that are not isotope-labeled owing to the kinetic isotope effect described below. Higher metabolic stability translates directly into an increased in vivo half-life or lower dosages, which under most circumstances would represent a preferred embodiment of the present disclosure. The isotope-labeled compounds and salts can usually be prepared by carrying out the procedures disclosed in the synthesis schemes, the Examples and the related description, replacing a non-isotope-labeled reactant by a readily available isotope-labeled reactant.

[0058] The deuterium (2H)-labeled compounds and salts can manipulate the rate of oxidative metabolism of the compound by way of the primary kinetic isotope effect. The primary kinetic isotope effect is a change of the rate for a chemical reaction that results from exchange of isotopic nuclei, which in turn is caused by the change in ground state energies of the covalent bonds involved in the reaction. Exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond and thus causes a reduction in the rate-limiting bond breakage. If the bond breakage occurs in or in the vicinity of a saddle-point region along the coordinate of a multi-product reaction, the product distribution ratios can be altered substantially. For example, if deuterium is bonded to a carbon atom at a non- exchangeable position, rate differences of kH / kD= 2-7 are typical. For a further discussion, see S. L. Harbeson and R. D. Tung, Deuterium In Drug Discovery and Development, Ann. Rep. Med. Chem.2011, 46, 403-417, incorporated in its entirety herein by reference.

[0059] The concentration of an isotope (e.g., deuterium) incorporated at a given position of an isotope-labeled compound of the disclosure, or a pharmaceutically acceptable salt thereof, may be defined by the isotopic enrichment factor. The term “isotopic enrichment factor,” as used herein, means the ratio between the abundance of an isotope at a given position in an isotope-labeled compound (or salt) and the natural abundance of the isotope.

[0060] Where an atom in a compound of the disclosure, or a pharmaceutically acceptable salt thereof, is designated as deuterium, such compound (or salt) has an isotopic enrichment factor for such atom of at least 3000 (~45% deuterium incorporation). In some embodiments, the isotopic enrichment factor is at least 3500 (~52.5% deuterium incorporation), at least 4000 (~60% deuterium incorporation), at least 4500 (~67.5% deuterium incorporation), at least 5000 (~75% deuterium incorporation), at least 5500 (~82.5% deuterium incorporation), at least 6000 (~90% deuterium incorporation), at least 6333.3 (~95%deuterium incorporation), at least 6466.7 (~97% deuterium incorporation), at least 6600 (~99% deuterium incorporation), or at least 6633.3 (~99.5% deuterium incorporation).

[0061] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is N. In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein X is CH.

[0062] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is N. In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Y is CH.

[0063] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 0. In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 1. In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein n is 2.

[0064] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L1is bond, –O–, C1-C3alkylene, –C(O)–, –C(O)NR’–, –C(O)O–, or –S(O)2–. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L1is bond. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L1is –O–. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L1is C1-C3alkylene. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L1is –C(O)–. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L1is –C(O)NR’–. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L1is –C(O)O–. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L1is –S(O)2–. In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L1is bond, –O–, –CH2–, –C(O)–, –C(O)NH–, –C(O)O–, or –S(O)2–. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L1is –CH2–. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L1is –C(O)NH–.

[0065] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is H, –NR’R’’, C1-C6alkyl, C6-C10aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or –(C1-C3alkylene)-(C6-C10aryl), whereinsaid C6-C10aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or –(C1-C3alkylene)- (C6-C10aryl) is optionally substituted with 1-3 Ra. In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is H, –NR’R’’, C1-C6alkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or –(C1-C3alkylene)-(C6-C10aryl), wherein said C6-C10aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or –(C1-C3alkylene)-(C6-C10aryl) is optionally substituted with 1-3 Ra. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is H. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is –NR’R’’. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is C1-C6alkyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is C6-C10aryl optionally substituted with 1-3 Ra. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is 5- to 10-membered heterocyclyl optionally substituted with 1-3 Ra. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is 5- to 10-membered heteroaryl optionally substituted with 1-3 Ra. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is –(C1-C3alkylene)-(C6-C10aryl) optionally substituted with 1-3 Ra.

[0066] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each Rais independently selected from halo, –CN, –NO2, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, –C(O)R’’’, –C(O)NR’R’’, –C(O)OR’, –S(O)2(C1-C3alkyl), –Si(C1-C3alkyl)3, C6-C10aryl, and 3- to 10-membered heterocyclyl, wherein said aryl or heterocyclyl is optionally substituted with 1-4 substituents independently selected from halo, C1-C3alkyl, and C1-C6haloalkyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais halo. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –CN. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –NO2. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais C1-C6alkyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais C1-C6haloalkyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais C1-C6alkoxy. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais–C(O)R’’’. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)NR’R’’. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)NH2. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)NH(C1-C6alkyl). In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)N(C1-C6alkyl)2. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)OR’. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –S(O)2(C1-C3alkyl). In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –Si(C1-C3alkyl)3. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais C6-C10aryl optionally substituted with 1-4 substituents independently selected from halo, C1-C3alkyl, and C1-C6haloalkyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais 3- to 10-membered heterocyclyl optionally substituted with 1-4 substituents independently selected from halo, C1-C3alkyl, and C1-C6haloalkyl.

[0067] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each Rais independently selected from F, Cl, Br, I, –CN, –NO2, –C(CH3)3, –CF3, –OCH3, –C(O)H, –C(O)CH3, –C(O)-(phenyl), –C(O)N(CH3)2, –C(O)OCH2CH3, –S(O)2CH3, –Si(CH3)3, . In other embodiments, the disclosure relates to a compound of formula (I),salt thereof, wherein at least one Rais F. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais Cl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais Br. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais I. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(CH3)3. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –CF3. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein atleast one Rais –OCH3. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)H. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)CH3. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)-(phenyl). In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)NH2. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)N(CH3)2. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)NHCH3. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein aat least one R is –C(O)OCH2CH3. In other embodiments, the disclosure to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –S(O)2CH3. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –Si(CH3)3. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rais phenyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Ra. In other embodiments, the disclosure relates to a compoundof formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Ra.

[0068] In some embodiments, the disclosure relates to a compound of formulapharmaceutically acceptable salt thereof, wherein A is selected from: H, –N(CH3)2, –CH3, –CH(CH3)2, Br ,O , ,thereof, wherein A is H. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is –N(CH3)2. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is –CH3. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is –CH(CH3)2. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is –C(CH3)3. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formulaBr (I), or a pharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I), or asalt thereof, wherein A is . In other embodiments, the disclosure relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I), or a acceptable salt thereof, wherein Ais . In other embodiments, the disclosure relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I), or a salt thereof, wherein A is. In other embodiments, the disclosure relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I), or aacceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I), or aacceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I), or aacceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein A . In other embodiments, thedisclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, In other embodiments, the disclosure relates to a compound of formula (I), salt thereof, wherein Aother embodiments, the disclosure relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, In other embodiments, the disclosure relates to a compound of formula (I), salt thereof, wherein Ais . In other embodiments, the disclosure relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, . In other embodiments, the disclosure relates to a compound of formula (I),salt thereof, wherein A other embodiments, the disclosure relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, In other embodiments, the disclosure relates to a compound of formula (I),salt thereof, wherein A. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, In other embodiments, the disclosure relates to a compound of formula (I), salt thereof, wherein Aother embodiments, the disclosure relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I), or a acceptable salt thereof, wherein A. In other embodiments, the disclosure relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I), or aacceptable salt thereof, wherein A other embodiments, the disclosure relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I), or aacceptable salt thereof, wherein A is . In other embodiments, the disclosure relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherei In other embodiments, the disclosure relates to a compound of formula (I), cceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I), or a salt thereof, wherein Ais . In other embodiments, the disclosure relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I), or asalt thereof, wherein A is . In other embodiments, the disclosure relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I), or asalt thereof, wherein A is . In other embodiments, the disclosure relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein A is . In other embodiments, the disclosure relates to a compound of formula (I), or aacceptable salt thereof, wherein A is . In other embodiments, the disclosure relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein A . In other embodiments, thedisclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is . In other embodiments, the disclosure relates to a compound of formula (I), or athe A. In other embodiments, the disclosure relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, wherein A .

[0069] In some embodiments, the disclosure of formula (I), or apharmaceutically acceptable salt thereof, wherein L2is bond, –NR’–, C1-C3alkylene, –C(O)–, –NR’C(O)–, or –S(O)2–. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L2is bond. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L2is –NR’–. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L2is C1-C3alkylene. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L2is –C(O)–. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L2is –NR’C(O)–. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L2is –S(O)2–. In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L2is bond, –NH–, –CH2, –C(O)–, –NHC(O)–, or –S(O)2–. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L2is bond. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L2is –NH–. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L2is –CH2–. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L2is –NHC(O)–.

[0070] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from phenyl, furanyl, imidazolyl, pyrazolyl, pyrrolyl, thiophenyl, and pyrazolo[1,5-a]pyrimidinyl. In some embodiments, the disclosurerelates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from phenyl, furanyl, pyrazolyl, pyrrolyl, thiophenyl, and pyrazolo[1,5-a]pyrimidinyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring B is furanyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring B is imidazolyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring B is pyrazolyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring B is pyrrolyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring B is thiophenyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring B is pyrazolo[1,5-a]pyrimidinyl.

[0071] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each Rbis independently selected from halo, –CN, C1-C3alkyl, C1-C6haloalkyl, and C1-C6alkoxy. In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each Rbis independently selected from C1-C3alkyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rbis halo. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rbis –CN. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rbis C1-C3alkyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rbis C1-C6haloalkyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rbis C1-C6alkoxy. In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one Rbis –CH3.

[0072] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L3is bond or C6-C10arylene. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L3is bond. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L3is C6-C10arylene. In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L3is bond or phenylene.In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L3is phenylene.

[0073] In some embodiments, the disclosure relates to a compound of formula (I), or a ,O , or apharmaceutically acceptable salt thereof, embodiments, the disclosure relates to asalt thereof,In other embodiments, the disclosure relates to acompound of formula (I), or a pharmaceutically acceptable salt thereof, is. In other embodiments, the disclosure relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, . In other embodiments, the disclosure relates to a acceptable saltthereof, . In other embodiments, the disclosure relates toa compound of formula (I), or a pharmaceutically acceptable salt thereof, is. In other embodiments, the disclosure relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, . In other embodiments, the disclosure relates to aacceptable salt . In other embodiments, the disclosure relates toa compound of formula (I), or a pharmaceutically acceptable salt thereof, is. In other embodiments, the disclosure relates to a compound of formula (I), or apharmaceutically acceptable salt thereof, . In other embodiments, the disclosure relates to aacceptable salt thereof, wherein .

[0074] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R2aand R2bare independently selected from H, C1-C6alkyl, C1-C6haloalkyl, and C1-C6alkoxy, or R2aand R2btogether form oxo. In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R2aand R2bare independently selected from H and C1-C6alkyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of R2aand R2bis H. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of R2aand R2bis C1-C6alkyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of R2aand R2bis C1-C6haloalkyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of R2aand R2bis C1-C6alkoxy. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R2aand R2btogether form oxo.

[0075] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R2ais H or C1-C6alkyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R2ais H. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R2ais C1-C6alkyl. In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R2ais H or –CH3. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R2ais –CH3.

[0076] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R2bis H.

[0077] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R3aand R3bare each H.

[0078] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R6aand R6bare each H.

[0079] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R3aand R6ajoin to form a bicyclic heterocyclyl.

[0080] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5aand R5bare independently selected from H and C1-C6alkyl. In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of R5aor R5bis H. In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, whereinat least one of R5aor R5bis C1-C6alkyl. In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5aand R5bare independently selected from H and –CH3. In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of R5aor R5bis –CH3.

[0081] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5ais H or –CH3. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5ais H. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5ais –CH3.

[0082] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R5bis H.

[0083] In some embodiments, the disclosure relates to a compound of formula (I-A):or a pharmaceutically acceptable salt thereof, wherein: L1is selected from bond, –O–, –NR’–, C1-C3alkylene, –C(O)–, –C(O)NR’–, –NR’C(O)–, –C(O)O–, –OC(O)–, and –S(O)2–; A is selected from H, –NR’R’’, C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, –(C1-C3alkylene)-(C3-C10cycloalkyl), –(C1-C3alkylene)-(C6-C10aryl), –(C1-C3alkylene)-(5- to 10-membered heterocyclyl), and –(C1-C3alkylene)-(5- to 10-membered heteroaryl), wherein said C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, –(C1-C3alkylene)-(C3-C10cycloalkyl), –(C1-C3alkylene)-(C6-C10aryl), –(C1-C3alkylene)-(5- to 10-membered heterocyclyl), or –(C1-C3alkylene)-(5- to 10-membered heteroaryl) is optionally substituted with 1-3 Ra; each Rais independently selected from halo, –CN, –NO2, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, –C(O)R’’’, –C(O)NR’R’’, –C(O)OR’, –S(O)2(C1-C3alkyl), –Si(C1-C3alkyl)3, C6-C10aryl,and 3- to 10-membered heterocyclyl, wherein said aryl or heterocyclyl is optionally substituted with 1-4 substituents independently selected from halo, C1-C3alkyl, and C1-C6haloalkyl; L2is selected from bond, –O–, –NR’–, C1-C3alkylene, –C(O)–, –C(O)NR’–, –NR’C(O)–, –C(O)O–, –OC(O)–, and –S(O)2–; Ring B is C6-C10aryl or 5- to 10-membered heteroaryl, wherein said aryl or heteroaryl is optionally substituted with 1-3 Rb; each Rbis independently selected from halo, –CN, C1-C3alkyl, C1-C6haloalkyl, and C1-C6alkoxy; R2aand R2bare independently selected from H, C1-C6alkyl, C1-C6haloalkyl, and C1-C6alkoxy, or R2aand R2btogether form oxo; R3ais independently selected from H, C1-C6alkyl, C1-C6haloalkyl, and C1-C6alkoxy; R5ais independently selected from H, C1-C6alkyl, C1-C6haloalkyl, and C1-C6alkoxy; R6ais independently selected from H, C1-C6alkyl, C1-C6haloalkyl, and C1-C6alkoxy; or R3aand R6ajoin to form a bicyclic heterocyclyl; each R’ and R’’ is independently selected from H and C1-C6alkyl; and each R’’’ is independently selected from H, C1-C6alkyl, and C6-C10aryl.

[0084] In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L1is bond, C1-C3alkylene, –C(O)–, –C(O)NR’–, –C(O)O–, or –S(O)2–. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L1is bond. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L1is C1-C3alkylene. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L1is –C(O)–. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L1is –C(O)NR’–. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L1is –C(O)O–. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L1is –S(O)2–. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L1is bond, –CH2–, –C(O)–, –C(O)NH–, –C(O)O–, or –S(O)2–. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L1is –CH2–. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L1is –C(O)NH–.

[0085] In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A is H, –NR’R’’, C1-C6alkyl, C6-C10aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or –(C1-C3alkylene)-(C6-C10aryl), wherein said C6-C10aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or –(C1-C3alkylene)-(C6-C10aryl) is optionally substituted with 1-3 Ra. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A is H, –NR’R’’, C1-C6alkyl, C6-C10aryl, 5- to 10-membered heteroaryl, or –(C1-C3alkylene)-(C6-C10aryl), wherein said C6-C10aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or –(C1-C3alkylene)-(C6-C10aryl) is optionally substituted with 1-3 Ra. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A is H. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A is –NR’R’’. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A is C1-C6alkyl. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A is C6-C10aryl optionally substituted with 1-3 Ra. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A is 5- to 10-membered heterocyclyl optionally substituted with 1-3 Ra. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A is 5- to 10-membered heteroaryl optionally substituted with 1-3 Ra. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A is –(C1-C3alkylene)-(C6-C10aryl) optionally substituted with 1-3 Ra.

[0086] In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein each Rais independently selected from halo, –CN, –NO2, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, –C(O)R’’’, –C(O)NR’R’’, –C(O)OR’, –S(O)2(C1-C3alkyl), –Si(C1-C3alkyl)3, C6-C10aryl, and 3- to 10-membered heterocyclyl, wherein said aryl or heterocyclyl is optionally substituted with 1-4 substituents independently selected from C1-C3alkyl and C1-C6haloalkyl. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais halo. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –CN. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –NO2. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais C1-C6alkyl. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one RaisC1-C6haloalkyl. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais C1-C6alkoxy. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)R’’’. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)NR’R’’. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)OR’. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –S(O)2(C1-C3alkyl). In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –Si(C1-C3alkyl)3. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais C6-C10aryl optionally substituted with 1-4 substituents independently selected from C1-C3alkyl and C1-C6haloalkyl. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais and 3- to 10-membered heterocyclyl optionally substituted with 1-4 substituents independently selected from C1-C3alkyl and C1-C6haloalkyl. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein each Rais independently selected from F, Cl, Br, I, –CN, –NO2, –C(CH3)3, –CF3, –OCH3, –C(O)H, –C(O)CH3, –C(O)-(phenyl), –C(O)N(CH3)2, –C(O)OCH2CH3, –S(O)2CH3, –Si(CH3)3, . In some embodiments, the disclosure relates to a compound of formula (I- salt thereof, whereinat least one Rais F. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais Cl. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais Br. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais I. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(CH3)3. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –CF3. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –OCH3. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)H. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof,wherein at least one Rais –C(O)CH3. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)-(phenyl). In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)N(CH3)2. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)OCH2CH3. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –S(O)2CH3. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –Si(CH3)3. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais phenyl. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rais . In some embodiments, the disclosure relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Ra.

[0087] In some embodiments, the disclosure relates to a compound of, or a pharmaceutically acceptable salt thereof, wherein A is selected from: H, –N(CH3)2, –CH3, –CH(CH3)2, Br, , , . In other embodiments, the disclosure salt thereof, wherein A is H. Into a (I-A), or a pharmaceutically acceptable salt thereof, wherein A is –N(CH3)2. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A is –CH3. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A is –CH(CH3)2. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A is –C . In other embodiments, the disclosure relates to a compound of formula (I-A), or aacceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound offormula (I-A), or a pharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I-A), oracceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound offormula (I-A), or a pharmaceutically acceptable salt thereof, wherein A . In otherembodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound offormula (I-A), or a pharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I-A), or acceptable saltthereof, wherein A . In other embodiments, the disclosure relates to a compound offormula (I-A), or a pharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I-A), or acceptable saltthereof, wherein A . In other embodiments, the disclosure relates to a compound offormula (I-A), or a pharmaceutically acceptable salt thereof, embodiments, the disclosure relates to a compound of formula (I-salt thereof, wherein A . In other embodiments, the disclosure relates to a compound offormula (I-A), or a pharmaceutically acceptable salt thereof, wherein A embodiments, the disclosure relates to a compound of formula (I-A), orsalt thereof, wherein A . In other embodiments, the disclosure relates to a compound offormula (I-A), or a pharmaceutically acceptable salt thereof, In other embodiments, the disclosure relates to a compound of formula (I-acceptable saltthereof, wherein . In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, In other embodiments, the disclosure relates to a compound of formula (I- saltthereof, other embodiments, the disclosure relates to a compound of Oformula (I-A), or a pharmaceutically acceptable salt thereof, wherein A embodiments, the disclosure relates to a compound of formula (I-A), or saltthereof, . In other embodiments, the disclosure relates to a compoundof formula (I-A), or a pharmaceutically acceptable salt thereof, In other embodiments, the disclosure relates to a compound of formula (I-A),salt thereof, other embodiments, the disclosure relates to a compound offormula (I-A), or a pharmaceutically acceptable salt thereof, embodiments, the disclosure relates to a compound of formula (I-salt thereof, . In other embodiments, the disclosure relates to a compound offormula (I-A), or a pharmaceutically acceptable salt thereof, where In other embodiments, the disclosure relates to a compound of formula (I-A eptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound offormula (I-A), or a pharmaceutically acceptable salt thereof, wherein A is embodiments, the disclosure relates to a compound of formula (I-A), or a saltthereof, wherein A . In other embodiments, the disclosure relates to a compound offormula (I-A), or a pharmaceutically acceptable salt thereof, . In other embodiments, the disclosure relates to a compound of formula (I- acceptable salt. In other embodiments, the disclosure relates to a compound offormula (I-A), or a pharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I-A), oracceptable salt thereof, other embodiments, the disclosure relates to a compound offormula (I-A), or a pharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I-A), oracceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound offormula (I-A), or a pharmaceutically acceptable salt thereof, wherein A is . In other embodiments, the disclosure relates to a compound of formula (I-A), or acceptable saltthereof, wherein A . In other embodiments, the disclosure relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I-A), or a acceptable salt thereof, whereinA . In other embodiments, the disclosure relates to a compound of formula (I-A), or apharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I-A), acceptable salt thereof, whereinA . In other embodiments, the disclosure relates to a compound of formula (I-A), or apharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I-A),acceptable salt thereof, wherein A is . In other embodiments, the disclosure relates to a compound of formula (I-A), or apharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I-A), oracceptable salt thereof, wherein A is . In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A . In other embodiments, thedisclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A . embodiments, the disclosure relates to a compound of formula (I-A), or aacceptable salt thereof, wherein L2is bond, –NR’–, C1-C3alkylene, –C(O)–, or –S(O)2–. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L2is bond. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L2is –NR’–. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L2is C1-C3alkylene. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L2is –C(O)–. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L2is –S(O)2–. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L2is bond, –NH–, –CH2–, –C(O)–, or –S(O)2–. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L2is –NH–. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L2is –CH2–.

[0089] In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from phenyl, furanyl, imidazolyl, pyrazolyl, pyrrolyl, thiophenyl, and pyrazolo[1,5-a]pyrimidinyl. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from phenyl, furanyl, pyrazolyl, pyrrolyl, thiophenyl, and pyrazolo[1,5-a]pyrimidinyl. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring B is furanyl. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring B is imidazolyl. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring B is pyrazolyl. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring B is pyrrolyl. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring B is thiophenyl. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring B is pyrazolo[1,5-a]pyrimidinyl.

[0090] In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein each Rbis independently selected from C1-C3alkyl. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one Rbis –CH3.

[0091] In some embodiments, the disclosure relates to a compound of formula (I-A), or asome embodiments, the disclosure relates to a compound ofother embodiments, the disclosure relates to a compound offormula (I-A), or a pharmaceutically acceptable salt thereof, . In other embodiments, the disclosure relates to a compound ofacceptable salt thereof,In other embodiments, the disclosurerelates to a compound ofacceptable salt thereof, wherein . In other embodiments, the disclosure relates to a compound of formula(I-A), or a pharmaceutically acceptable salt thereof, . In other embodiments, the disclosure relates to a compound of acceptable saltthereof, . In other embodiments, the disclosure relates to acompound of formula (I-A), or a pharmaceutically acceptable salt thereof, isother embodiments, the disclosure relates to a compound of formula (I-A), or apharmaceutically acceptable salt thereof, embodiments, the disclosure relates to a acceptable saltthereof, . In other embodiments, the disclosure relates to acompound of formula (I-A), or a pharmaceutically acceptable salt thereof, is. In other embodiments, the disclosure relates to a compound of formula (I-A), or apharmaceutically acceptable salt thereof, .

[0092] In some embodiments, the(I-A), or a pharmaceutically acceptable salt thereof, wherein R2aand R2bare independently selected from H and C1-C6alkyl.

[0093] In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R2ais H or –CH3and R2bis H. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof,wherein R2ais H and R2bis H. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R2ais –CH3and R2bis H. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R2aand R2btogether form oxo.

[0094] In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R3aand R6aare each H. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R3aand R6ajoin to form a bicyclic heterocyclyl.

[0095] In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R5ais H or C1-C6alkyl. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R5ais H. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R5ais C1-C6alkyl. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R5ais –CH3

[0096] In some embodiments, the disclosure relates to a compound of formula (I-B): or aL1is bond, C1-C3alkylene, –C(O)–, –C(O)NR’–, or –S(O)2–; A is C6-C10aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or –(C1-C3alkylene)-(C6-C10aryl), wherein said C6-C10aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or –(C1-C3alkylene)-(C6-C10aryl) is optionally substituted with 1-2 Ra; each Rais independently selected from halo, –CN, –NO2, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, –C(O)R’’’, –C(O)NR’R’’, –C(O)OR’, –S(O)2(C1-C3alkyl), –Si(C1-C3alkyl)3, C6-C10aryl, and 3- to 10-membered heterocyclyl, wherein said aryl or heterocyclyl is optionally substituted with 1-4 substituents independently selected from C1-C3alkyl and C1-C6haloalkyl; L2is bond, C1-C3alkylene, –C(O)–, or –S(O)2–; R2aand R2bare independently selected from H and C1-C6alkyl, or R2aand R2btogether form oxo; R5ais H or C1-C6alkyl;each R’ and R’’ is independently selected from H and C1-C6alkyl; and each R’’’ is independently selected from H, C1-C6alkyl, and C6-C10aryl.

[0097] In some embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein A is C6-C10aryl, 5- to 10-membered heteroaryl, or –(C1-C3alkylene)-(C6-C10aryl), wherein said C6-C10aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or –(C1-C3alkylene)-(C6-C10aryl) is optionally substituted with 1-2 Ra.

[0098] In some embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein L1is bond, –CH2–, –C(O)–, –C(O)NH–, or –S(O)2–. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein L1is bond. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein L1is –CH2–. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein L1is –C(O)–. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein L1is –C(O)NH–. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein L1is –S(O)2–.

[0099] In some embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein each Rais independently selected from F, Cl, Br, I, –CN, –NO2, –C(CH3)3, –CF3, –OCH3, –C(O)H, –C(O)CH3, –C(O)-(phenyl), –C(O)N(CH3)2, –C(O)OCH2CH3, –S(O)2CH3, –Si(CH3)3, . In other embodiments, the disclosure relates to a compound of formula (I-salt thereof, wherein at least one Rais F. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one Rais Cl. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one Rais Br. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one Rais I. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –CN. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –NO2. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(CH3)3. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –CF3. In other embodiments, thedisclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –OCH3. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)H. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)CH3. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)-(phenyl). In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)N(CH3)2. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)OCH2CH3. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –S(O)2CH3. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –Si(CH3)3. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one Rais phenyl. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one Rais . In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one .

[0100] In some embodiments, the disclosure relates to a compound of formulaBr ,, , . Br , ,, rein A . In some embodiments, the disclosure relates to a compound of formula (I-B), or apharmaceutically acceptable salt thereof, wherein A . In some embodiments, the disclosure relates to a compound of formula (I-B), or acceptable salt thereof, whereinA . In some embodiments, the disclosure relates to a compound of formula (I-B), or apharmaceutically acceptable salt thereof, wherein A . In some embodiments, the disclosure relates to a compound of formula (I-B),acceptable salt thereof, wherein A . In some embodiments, the disclosure relates to a compound of formula (I-B), or apharmaceutically acceptable salt thereof, wherein A . In some embodiments, the disclosure relates to a compound of formula (I-B), or asalt thereof, wherein A is . In some embodiments, the disclosure relates to a compound of formula (I-B), or apharmaceutically acceptable salt thereof, wherein A . In some embodiments, the disclosure relates to a compound of formula (I-B),acceptable salt thereof, wherein A . In some embodiments, the disclosure relates to a compound of formula (I-B), or apharmaceutically acceptable salt thereof, wherein A i . In some embodiments, the disclosure relates to a compound of formula (I-B), or ically acceptable salt thereof, wherein some embodiments, the disclosure relates to a compound of formula (I-B), or apharmaceutically acceptable salt thereof, wherein A . In some embodiments, the disclosure relates to a compound of formula (I-B), acceptable salt thereof, whereinA is . In some embodiments, the disclosure relates to a compound of formula (I-B), or apharmaceutically acceptable salt thereof, wherein A . In some embodiments, the disclosure relates to a compound of formula (I-B),acceptable salt thereof, wherein some embodiments, the disclosure relates to a compound of formula (I-B), or apharmaceutically acceptable salt thereof, In some embodiments, the disclosure relates to a compound of formula (I-acceptable salt thereof, wherein . In some embodiments, the disclosure relates to a compound of formula (I-B),or a pharmaceutically acceptable salt thereof, In some embodiments, the disclosure relates to a compound of formula (I-B),salt thereof, whereinO O A . In some embodiments, the disclosure relates to a compound of formula (I-B),or a pharmaceutically acceptable salt thereof, In some embodiments, the disclosure relates to a compound of formula (I- salt thereof,some embodiments, the disclosure relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, . In some embodiments, the disclosure relates to a compound of formula (I-B), or a salt thereof,. In some embodiments, the disclosure relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, . In some embodiments, the disclosure relates to a compound of formula (I-B), or asalt thereof, . In some embodiments, the disclosure relates to a compound offormula (I-B), or a pharmaceutically acceptable salt thereof, wherein A embodiments, the disclosure relates to a compound of formula (I-B), orsalt thereof, wherein A . In some embodiments, the disclosure relates to a compound offormula (I-B), or a pharmaceutically acceptable salt thereof, wherein A embodiments, the disclosure relates to a compound of formula (I-B), or saltthereof, . In some embodiments, the disclosure relates to a compound offormula (I-B), or a pharmaceutically acceptable salt thereof, wherein A embodiments, the disclosure relates to a compound of formula (I-B), or saltthereof, wherein A . In some embodiments, the disclosure relates to a compound offormula (I-B), or a pharmaceutically acceptable salt thereof, In some embodiments, the disclosure relates to a compound of formula (I- acceptable saltthereof, wherein A . In some embodiments, the disclosure relates to a compound offormula (I-B), or a pharmaceutically acceptable salt thereof, wherein A . In some embodiments, the disclosure relates to a compound of formula (I-B), oracceptable salt thereof, wherein A . In some embodiments, the disclosure relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein A . In some embodiments, the disclosure relates to a compound of formula (I-B), or aacceptable salt thereof, wherein A is . In some embodiments, the disclosure relates to a compound of formula (I-B), or apharmaceutically acceptable salt thereof, wherein A . In some embodiments, the disclosurerelates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein A is . In some embodiments, the disclosure relates to a compound of formula (I-B), or apharmaceutically acceptable salt thereof, wherein A . In some embodiments, the disclosure relates to a compound of formula (I-B), acceptable salt thereof, whereinA is . In some embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein A . In some embodiments, the disclosure relates to a compound of formula (I-B), or acceptable salt thereof, whereinA is . In some embodiments, the disclosure relates to a compound of formula (I-B), or apharmaceutically acceptable salt thereof, wherein A is . In some embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein .embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein L2is bond, –CH2–, –C(O)–, or –S(O)2–. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein L2is bond. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein L2is –CH2–. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein L2is –C(O)–. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein L2is –S(O)2–.

[0102] In some embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R2ais H or –CH3, and R2bis H. In some embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R2ais H and R2bis H. In some embodiments, the disclosure relates to a compound of formula(I-B), or a pharmaceutically acceptable salt thereof, wherein R2ais –CH3and R2bis H. In some embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R2aand R2btogether form oxo.

[0103] In some embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R5ais H or –CH3. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R5ais H. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R5ais –CH3.

[0104] In some embodiments, the disclosure relates to a compound of formula (I-C): or a 1L is bond, C1-C3alkylene, –C(O)–, –C(O)NR’–, or –S(O)2–; each Rais independently selected from halo, –CN, –NO2, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, –C(O)R’’’, –C(O)NR’R’’, –C(O)OR’, –S(O)2(C1-C3alkyl), –Si(C1-C3alkyl)3, C6-C10aryl, and 3- to 10-membered heterocyclyl, wherein said aryl or heterocyclyl is optionally substituted with 1-4 substituents independently selected from C1-C3alkyl and C1-C6haloalkyl; L2is bond, C1-C3alkylene, –C(O)–, or –S(O)2–; R2aand R2bare independently selected from H and C1-C6alkyl, or R2aand R2btogether form oxo; R5ais H or C1-C6alkyl; each R’ and R’’ is independently selected from H and C1-C6alkyl; each R’’’ is independently selected from H, C1-C6alkyl, and C6-C10aryl; and p is 0, 1, or 2.

[0105] In some embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein L1is selected from bond, –CH2–, –C(O)–, –C(O)NH–, and –S(O)2–. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein L1is bond. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein L1is –CH2–. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein L1is –C(O)–. In other embodiments, the disclosurerelates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein L1is –C(O)NH–. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein L1is –S(O)2–.

[0106] In some embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein each Rais independently selected from F, Cl, Br, I, –CN, –NO2, –C(CH3)3, –CF3, –OCH3, –C(O)H, –C(O)CH3, –C(O)-(phenyl), –C(O)N(CH3)2, –C(O)OCH2CH3, –S(O)2CH3, –Si(CH3)3, . In other embodiments, the disclosure relates to a compound of formula (I- salt thereof, wherein aat least one R is F. In other embodiments, the of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one Rais Cl. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one Rais Br. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one Rais I. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –CN. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –NO2. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(CH3)3. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –CF3. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –OCH3. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)H. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)CH3. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)-(phenyl). In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)N(CH3)2. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –C(O)OCH2CH3. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –S(O)2CH3. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one Rais –Si(CH3)3. In other embodiments, the disclosure relates to a compound offormula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one Rais phenyl. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one Rais . In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one .

[0107] In some embodiments, the disclosure relates to a compound of formulapharmaceutically acceptable salt thereof, wherein p is 0. In some embodiments, the to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein p is 1. In some embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein p is 2.

[0108] In some embodiments, the disclosure relates to a compound of formula (I-C), or a ,. In other embodiments, the acceptable salt thereof, wherein . In other embodiments, the disclosure relates to a compound of formulasalt. In other embodiments, the disclosure relates to acompound of formula (I-C), or a pharmaceutically acceptable salt thereof, is. In other embodiments, the disclosure relates to a compound of formula (I-C), or apharmaceutically acceptable salt thereof, . In other embodiments, the disclosure relates to a compound of formulasalt thereof, . In other embodiments, the disclosure relates to a compound offormula (I-C), or a pharmaceutically acceptable salt thereof, In other embodiments, the disclosure relates to a compound ofacceptable salt thereof, . In other embodiments, the disclosure relates to a compound ofacceptable salt thereof, wherein. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, . In other embodiments, the disclosure relates to a compound ofacceptable salt thereof, . In other embodiments, the disclosure relates to a compound of salt thereof, wherein. In other embodiments, the disclosure relates to a compound offormula (I-C), or a pharmaceutically acceptable salt thereof, . In other embodiments, the disclosure relates to a compound ofacceptable salt thereof, . In other embodiments, the disclosure relates to a compound ofsalt thereof, wherein other embodiments, the disclosure relates to a compound offormula (I-C), or a pharmaceutically acceptable salt thereof, In other embodiments, the disclosure relates to a compound ofacceptable salt thereof, In other embodiments, the disclosure relates to aacceptable salt thereof, wherein. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, is OO . In other embodiments, the disclosure relates to a compound of formula (I-C), or apharmaceutically acceptable salt thereof, embodiments, the disclosure relates to a salt. In other embodiments, the disclosure relates to acompound of formula (I-C), or a pharmaceutically acceptable salt thereof, is. In other embodiments, the disclosure relates to a compound of formula (I-C), or aIn otheracceptable salt other embodiments, the disclosure relates to acompound of formula (I-C), or a pharmaceutically acceptable salt thereof, is. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, . In other embodiments, the disclosure relates to a compound of formula salt thereof,. In other embodiments, the disclosure relates to a compound offormula (I-C), or a pharmaceutically acceptable salt thereof, In other embodiments, the disclosure relates to a compound ofacceptable salt thereof, In other embodiments, the disclosure relates to a compound of salt thereof, wherein. In other embodiments, the disclosure relates to a compound offormula (I-C), or a pharmaceutically acceptable salt thereof, . In other embodiments, the disclosure relates to a compound ofacceptable salt thereof, . In other embodiments, the disclosure relates to a compound ofsalt thereof, wherein . In other embodiments, the disclosure relates to a compound offormula (I-C), or a pharmaceutically acceptable salt thereof, is. embodiments, the disclosure relates to a compound of formula (I-C), or aacceptable salt thereof, wherein L2is bond, –CH2–, –C(O)–, or –S(O)2–. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein L2is bond. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein L2is –CH2–. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein L2is –C(O)–. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein L2is –S(O)2–.

[0110] In some embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R2ais H or –CH3, and R2bis H. In some embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R2ais H and R2bis H. In some embodiments, the disclosure relates to a compound of formula (I- C), or a pharmaceutically acceptable salt thereof, wherein R2ais –CH3and R2bis H. In some embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R2aand R2btogether form oxo.

[0111] In some embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R5ais H or –CH3. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R5ais H. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R5ais –CH3.

[0112] In some embodiments, the disclosure relates to a compound selected from Table A, or a pharmaceutically acceptable salt thereof. In other embodiments, the disclosure relates to a compound selected from Table A, i.e., the compound in non-salt form.

[0113] Table A. Compound Structures and Names. -O2NO- -O N e - -n- 2- -e n- -1- - - 1-O O2N O N n- 1- 1-n- - -

[0114] In some embodiments, the disclosure relates to a compound selected from Table B, or a pharmaceutically acceptable salt thereof. In other embodiments, the disclosure relates to a compound selected from Table B, i.e., the compound in non-salt form.

[0115] Table B. Compound Structures and Names.Examples 1-98, or a pharmaceutically acceptable salt thereof. Such compound is considered to be a “compound of the disclosure,” as that term is used herein. Salts, Compositions, Uses, Formulation, Administration and Additional Agents Pharmaceutically acceptable salts and compositions

[0117] As discussed herein, the disclosure provides compounds, and pharmaceutically acceptable salts thereof, that are inhibitors of mycobacterial growth, and thus the present compounds, and pharmaceutically acceptable salts thereof, are useful for the treatment of diseases, disorders, and conditions including, but not limited to mycobacterial infection in a subject. Accordingly, in another aspect of the disclosure, pharmaceutical compositions are provided, wherein these compositions comprise a compound as described herein, or a pharmaceutically acceptable salt thereof, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, these compositions optionally further comprise one or more additional therapeutic agents. In some embodiments, the additional therapeutic agent is an anti-mycobacterial agent.

[0118] As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. A “pharmaceutically acceptable salt” of a compound of this disclosure includes any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure or an inhibitorily active metabolite or residue thereof. The salt may be in pure form, in a mixture (e.g., solution, suspension, or colloid) with one or more other substances, or in the form of a hydrate, solvate, or co-crystal. As used herein, the term “inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of mycobacterial growth.

[0119] Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19,incorporated herein by reference. Pharmaceutically acceptable salts of the compound of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0120] As described herein, the pharmaceutically acceptable compositions of the disclosure additionally comprise a pharmaceutically acceptable carrier, adjuvant, or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington’s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium is incompatible with the compounds of the disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this disclosure. Some examples of materials which can serve as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, or potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogenphosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such a propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer’s solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0121] In another aspect, the disclosure features a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0122] In another aspect, the disclosure features a pharmaceutical composition comprising a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles. Uses of Compounds and Pharmaceutically Acceptable Salts and Compositions

[0123] In another aspect, the disclosure features a method of inhibiting the growth of a mycobacterium comprising contacting the mycobacterium with a compound of the disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof. In some aspects, the Mycobacterium expresses Ddn and Fdg1. Without being bound to theory, Ddn and Fdg1 are enzymes capable of converting the compound of the disclosure to an active metabolite responsible for the anti- mycobacterial activity, i.e. the compounds of the disclosure may be prodrugs. In certain aspects, the Mycobacterium is Mycobacterium tuberculosis. In certain aspects, the Mycobacterium is Mycobacterium abscessus.

[0124] In yet another aspect, the disclosure features a method of treating a mycobacterium infection in a subject comprising administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to the subject. In some aspects, the Mycobacterium expresses Ddn and Fdg1. In certain aspects, the Mycobacterium is Mycobacterium tuberculosis. In certain aspects, the Mycobacterium is Mycobacterium abscessus.

[0125] In yet another aspect, the disclosure features a method of treating a Mycobacterium tuberculosis infection in a subject comprising administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to the subject. In some aspects, the Mycobacterium tuberculosis expresses Ddn and Fdg1.

[0126] In yet another aspect, the disclosure features a method of treating a Mycobacterium abscessus infection in a subject comprising administering an effective amount of a compound of the disclosure, a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to the subject. In some aspects, the Mycobacterium abscessus expresses Ddn and Fdg1.

[0127] In yet another aspect, the disclosure features a method wherein the subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with an effective amount of the compound, pharmaceutically acceptable salt or pharmaceutical composition. In some embodiments, the additional therapeutic agent is an anti-mycobacterial agent. Compounds, Pharmaceutically Acceptable Salts, and Compositions for Use

[0128] In another aspect, the disclosure features a compound of the disclosure, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use as a medicament.

[0129] In another aspect, the disclosure features a compound of the disclosure, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in inhibiting growth of a mycobacterium. In some aspects, the Mycobacterium expresses Ddn and Fdg1. Without being bound to theory, Ddn and Fdg1 are enzymes capable of converting the compound of the disclosure to an active metabolite responsible for the anti-mycobacterial activity, i.e. the compounds of the disclosure may be prodrugs. In certain aspects, the Mycobacterium is Mycobacterium tuberculosis. In certain aspects, the Mycobacterium is Mycobacterium abscessus.

[0130] In another aspect, the disclosure features a compound of the disclosure, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a mycobacterium infection in a subject. In some aspects, the Mycobacterium expresses Ddn and Fdg1. In certain aspects, the Mycobacterium is Mycobacterium tuberculosis. In certain aspects, the Mycobacterium is Mycobacterium abscessus.

[0131] In another aspect, the disclosure features a compound of the disclosure, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a Mycobacterium tuberculosis infection in a subject. In some aspects, the Mycobacterium tuberculosis expresses Ddn and Fdg1.

[0132] In another aspect, the disclosure features a compound of the disclosure, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method of treating a Mycobacterium abscessus infection in a subject. In some aspects, the Mycobacterium abscessus expresses Ddn and Fdg1.

[0133] In another aspect, the disclosure features a compound of the disclosure, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use in a method wherein the subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with an effective amount of the compound, pharmaceutically acceptable salt or pharmaceutical composition. In some embodiments, the additional therapeutic agent is an anti-mycobacterial agent. Manufacture of Medicaments

[0134] In another aspect, the disclosure provides the use of a compound of the disclosure, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for the manufacture of a medicament.

[0135] In another aspect, the disclosure provides the use of a compound of the disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in inhibiting the growth of a mycobacterium. In some aspects, the Mycobacterium expresses Ddn and Fdg1. Without being bound to theory, Ddn and Fdg1 are enzymes capable of converting the compound of the disclosure to an active metabolite responsible for the anti-mycobacterial activity, i.e. the compounds of the disclosure may be prodrugs. In certain aspects, the Mycobacterium is Mycobacterium tuberculosis. In certain aspects, the Mycobacterium is Mycobacterium abscessus.

[0136] In yet another aspect, the disclosure provides the use of a compound of the disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating a mycobacterium infection in a subject. In some aspects, the Mycobacterium expresses Ddn and Fdg1. In certain aspects, the Mycobacterium is Mycobacterium tuberculosis. In certain aspects, the Mycobacterium is Mycobacterium abscessus.

[0137] In yet another aspect, the disclosure provides the use of a compound of the disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating a Mycobacterium tuberculosis infection in a subject. In some aspects, the Mycobacterium tuberculosis expresses Ddn and Fdg1.

[0138] In yet another aspect, the disclosure provides the use of a compound of the disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in treating a Mycobacterium abscessus infection in a subject. In some aspects, the Mycobacterium abscessus expresses Ddn and Fdg1.

[0139] In yet another aspect, the disclosure provides the use of a compound of the disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the manufacture of a medicament for use in combination with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound or pharmaceutical composition. In some embodiments, the additional therapeutic agent is an anti-mycobacterial agent. Administration of Compounds, Pharmaceutically Acceptable Salts, and Compositions

[0140] In certain embodiments of the disclosure, an “effective amount” of a compound of the disclosure, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof is that amount effective for treating or lessening the severity of one or more of the conditions recited above.

[0141] The compounds, salts, and compositions, according to the method of the disclosure, may be administered using any amount and any route of administration effective for treating or lessening the severity of one or more of the indications recited herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition, the particular agent, its mode of administration, and the like. The compounds, salts, and compositions of the disclosure are preferably formulated in dosage unit form for ease of administration and uniformity of dosage. The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the subject to be treated. It will be understood, however, that the total daily usage of the compounds, salts, and compositions of the disclosure will be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject or organism will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound or salt employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound or salt employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound or salt employed, and like factors well known in the medical arts. The term “subject” or “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.

[0142] The pharmaceutically acceptable compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, as an oral or nasal spray, or the like, depending on the severity of the condition being treated. In certain embodiments, the compound, salts, and compositions of the disclosure may be administered orally or parenterally at dosage levels of about 0.001 mg / kg to about 1000 mg / kg, one or more times a day, effective to obtain the desired therapeutic effect.

[0143] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound or salt, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0144] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0145] The injectable formulations can be sterilized, for example, by filtration through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0146] In order to prolong the effect of the compounds of the disclosure, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0147] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compound or salt of this disclosure with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

[0148] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound or salt is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0149] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0150] The active compound or salt can also be in microencapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release-controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active compound or salt may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the caseof capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0151] Dosage forms for topical or transdermal administration of a compound or salt of this disclosure include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, eardrops, and eye drops are also contemplated as being within the scope of this disclosure. Additionally, the disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms are prepared by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel. Additional Therapeutic Agents

[0152] It will also be appreciated that the compounds, salts, and pharmaceutically acceptable compositions of the disclosure can be employed in combination therapies, that is, the compounds, salts, and pharmaceutically acceptable compositions can be administered concurrently with, prior to, or subsequent to, one or more other desired therapeutics or medical procedures. The particular combination of therapies (therapeutics or procedures) to employ in a combination regimen will take into account compatibility of the desired therapeutics and / or procedures and the desired therapeutic effect to be achieved. It will also be appreciated that the therapies employed may achieve a desired effect for the same disorder (for example, an inventive compound may be administered concurrently with another agent used to treat the same disorder), or they may achieve different effects (e.g., control of any adverse effects). As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease, or condition, are known as “appropriate for the disease, or condition, being treated.” Additional appropriate therapeutic agents or approaches are described generally in The Merck Manual, Nineteenth Edition, Ed. Robert S. Porter and Justin L. Kaplan, Merck Sharp &Dohme Corp., a subsidiary of Merck & Co., Inc., 2011, and the Food and Drug Administration website, www.fda.gov, the entire contents of which are hereby incorporated by reference.

[0153] The amount of additional therapeutic agent present in the compositions of this disclosure may be no more than the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. The amount of additional therapeutic agent in the presentlydisclosed compositions may range from about 10% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0154] The compounds and salts of this disclosure or pharmaceutically acceptable compositions thereof may also be incorporated into compositions for coating an implantable medical device, such as prostheses, artificial valves, vascular grafts, stents and catheters. Accordingly, the disclosure, in another aspect, includes a composition for coating an implantable device comprising a compound or salt of the disclosure as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. In still another aspect, the disclosure includes an implantable device coated with a composition comprising a compound or salt of the disclosure as described generally above, and in classes and subclasses herein, and a carrier suitable for coating said implantable device. The coatings are typically biocompatible polymeric materials such as a hydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof. The coatings may optionally be further covered by a suitable topcoat of fluorosilicone, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart controlled release characteristics in the composition. Synthesis of the Compounds of the Disclosure

[0155] The compounds of the disclosure can be prepared from known materials by the methods described in the Examples, other similar methods, and other methods known to one skilled in the art. As one skilled in the art would appreciate, the functional groups of the intermediate compounds in the methods described below may need to be protected by suitable protecting groups. Protecting groups may be added or removed in accordance with standard techniques, which are well-known to those skilled in the art. The use of protecting groups is described in detail in T.G.M. Wuts et al., Greene’s Protective Groups in Organic Synthesis (4th ed.2006). Radiolabeled Analogs of the Compounds of the Disclosure

[0156] In another aspect, the disclosure relates to radiolabeled analogs of the compounds of the disclosure. As used herein, the term “radiolabeled analogs of the compounds of the disclosure” refers to compounds that are identical to the compounds of the disclosure, as described herein, including all embodiments thereof, except that one or more atoms has been replaced with a radioisotope of the atom present in the compounds of the disclosure.

[0157] As used herein, the term “radioisotope” refers to an isotope of an element that is known to undergo spontaneous radioactive decay. Examples of radioisotopes include3H,14C,32P,35S,18F,36Cl, andthe like, as well as the isotopes for which a decay mode is identified in V.S. Shirley & C.M. Lederer, Isotopes Project, Nuclear Science Division, Lawrence Berkeley Laboratory, Table of Nuclides (January 1980).

[0158] The radiolabeled analogs can be used in a number of beneficial ways, including in various types of assays, such as substrate tissue distribution assays. For example, tritium (3H)- and / or carbon-14 (14C)-labeled compounds may be useful for various types of assays, such as substrate tissue distribution assays, due to relatively simple preparation and excellent detectability.

[0159] In another aspect, the disclosure relates to pharmaceutically acceptable salts of the radiolabeled analogs, in accordance with any of the embodiments described herein in connection with the compounds of the disclosure.

[0160] In another aspect, the disclosure relates to pharmaceutical compositions comprising the radiolabeled analogs, or pharmaceutically acceptable salts thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle, in accordance with any of the embodiments described herein in connection with the compounds of the disclosure.

[0161] In another aspect, the disclosure relates to radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for use, in accordance with any of the embodiments described herein in connection with the compounds of the disclosure.

[0162] In another aspect, the disclosure relates to the use of the radiolabeled analogs, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments, in accordance with any of the embodiments described herein in connection with the compounds of the disclosure.

[0163] In another aspect, the radiolabeled analogs, pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof, can be employed in combination therapies, in accordance with any of the embodiments described herein in connection with the compounds of the disclosure. EXAMPLES Abbreviations

[0164] Unless otherwise noted, or where the context dictates otherwise, the following abbreviations shall be understood to have the following meanings: Abbreviation Meaning Boc tert-butoxycarbonyl NMR Nuclear magnetic resonance ESI-MS Electrospray mass spectrometry LC / MS Liquid chromatography-mass spectrometry UPLC Ultra performance liquid chromatography HPLC / MS / MS High performance liquid chromatography / tandem mass spectrometryHRMS High-resolution mass spectrometry IS Internal standard HPLC High performance liquid chromatography SFC Supercritical fluid chromatography ESI Electrospray ionization kg Kilogram g Grams mg Milligrams L Liter(s) mL Milliliters μL Microliters nL Nanoliters mol Mole mmol Millimoles hr, h Hours min Minutes ms Millisecond mm Millimeters μm Micrometers nm Nanometer MHz Megahertz Hz Hertz N Normal (concentration) M Molar (concentration) mM Millimolar (concentration) μM Micromolar (concentration) ppm Parts per million % w / v Weight-volume concentration % w / w Weight-weight concentration Example 1 1-[(5-Nitrofuran-2-yl)methyl]-4-[4-(trifluoromethyl)phenyl]piperazine

[0165] To a 100 mL roundnitrofuran-2-carboxaldehyde (0.703 g, 4.98 mmol), dichloromethane (15.0 mL), 1-(4-trifluoromethylphenyl)piperazine (1.26 g, 5.50 mmol) and acetic acid (1.20 g, 20.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (3.17 g, 15.0 mmol) was added as a solid. The reaction vessel was sealed with a septum, flushed with argon, stirred for 20 hours at room temperature, quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate,filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the title product (0.408 g, 23% yield).

[0166] 1H NMR (500 MHz, cdcl3) δ 7.53 – 7.46 (m, 2H), 7.30 (d, J = 3.6 Hz, 1H), 6.94 – 6.89 (m, 2H), 6.52 (dd, J = 3.6, 0.7 Hz, 1H), 3.71 (s, 2H), 3.35 – 3.27 (m, 4H), 2.73 – 2.66 (m, 4H).

[0167] 19F NMR (470 MHz, cdcl3) δ -61.42.

[0168] HRMS ESI (+) calc’d for [M+H] = 356.1218, found =356.1236. Example 2 1-(4-Chlorophenyl)-4-[(5-nitrothiophen-3-yl)methyl]piperazine

[0169] To a 100 mL round 3-carboxaldehyde(0.403 g, 2.56 mmol), , piperazine (0.590 g, 3.00 mmol) and acetic acid (0.300 g, 5.00 mmol). The reaction mixture was stirred and after 10 minutes sodium triacetoxyborohydride (1.48 g, 7.00 mmol) was added as a solid, the reaction vessel was sealed with a septum, flushed with argon, and stirred for 20 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes) to yield the title product (0.292 g, 34 % yield).

[0170] 1H NMR (500 MHz, cdcl3) δ 7.91 (dd, J = 11.5, 1.9 Hz, 1H), 7.49 – 7.37 (m, 1H), 7.23 – 7.17 (m, 2H), 6.85 – 6.80 (m, 2H), 3.53 (d, J = 0.9 Hz, 2H), 3.22 – 3.12 (m, 4H), 2.65 – 2.54 (m, 4H).

[0171] HRMS ESI (+) calc’d for [M+H] = 338.0726, found = 338.0760. Example 3 1-[(4-Methoxyphenyl)methyl]-4-[(5-nitrofuran-2-yl)methyl]piperazine

[0172] To a 100 mL2-carboxaldehyde (0.652 g, 4.60 mmol), dichloromethane (12.0 mL), 1-(4-methoxybenzyl)piperazine (1.23 g, 6.00 mmol) and acetic acid (0.600 g, 10.0 mmol). After 10 minutes sodium triacetoxyborohydride (1.69 g, 8.00 mmol) was added as a solid and the reaction vessel was sealed with a septum, flushed with argon, and stirred for18 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes) to yield the title product (0.313 g, 21% yield).

[0173] 1H NMR (500 MHz, cdcl3) δ 7.27 (d, J = 3.5 Hz, 1H), 7.24 – 7.18 (m, 2H), 6.90 – 6.80 (m, 2H), 6.46 (d, J = 3.6 Hz, 1H), 3.80 (s, 3H), 3.64 (s, 2H), 3.46 (s, 2H), 2.56 (s, 8H).

[0174] HRMS ESI (-) calc’d for [M - H] = 330.1458, found = 330.1474. Example 4 1-[(5-Nitrofuran-2-yl)methyl]-4-{[4-(tert-butyl)phenyl]}piperazine

[0175] To a 100 mL 2-carboxaldehyde (0.814g, 5.70 mmol), dichloromethane (15.0 mL),1-(4-tert-butylbenzyl)piperazine (1.62 g, 7.00 mmol), and acetic acid (0.900 g, 15.0 mmol). After 10 minutes sodium triacetoxyborohydride (2.54 g, 12.0 mmol) was added as a solid and the reaction vessel was sealed with a septum, flushed with argon, and stirred for 19 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes) to yield the title product (0.263 g, 13 % yield).

[0176] 1H NMR (500 MHz, cdcl3) δ 7.35 – 7.29 (m, 2H), 7.26 (d, J = 3.7 Hz, 1H), 7.24 – 7.19 (m, 2H), 6.46 (d, J = 3.6 Hz, 1H), 3.64 (s, 2H), 3.48 (s, 2H), 2.56 (s, 8H), 1.31 (s, 9H).

[0177] HRMS ESI (+) calc’d for [M+H] = 358.2126, found = 358.2160. Example 5 1-(4-Chlorophenyl)-4-[(5-iodofuran-2-yl)methyl]piperazine

[0178] To a 100 mL round bottom flask was added a stir bar, 5-iodo-2-furan carboxaldehyde (1.06 g, 4.77 mmol), dichloromethane (20.0 mL), 1-(4-chloro)phenyl piperazine (1.14 g, 5.80 mmol) and acetic acid (0.600 g, 10.0 mmol). After 10 minutes sodium triacetoxyborohydride (1.69 g, 8.00 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 19 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes) to yield the title product (0.758 g, 40 % yield).

[0179] 1H NMR (500 MHz, cdcl3) δ 7.24 – 7.16 (m, 2H), 6.88 – 6.79 (m, 2H), 6.49 (d, J = 3.2 Hz, 1H), 6.18 (d, J = 3.2 Hz, 1H), 3.63 (s, 2H), 3.18 (dd, J = 6.1, 3.9 Hz, 4H), 2.64 (t, J = 5.0 Hz, 4H).

[0180] HRMS ESI (+) calc’d for [M+H] = 404.0070, found = 404.0112. Example 6 1-[(5-Nitrothiophen-2-yl)methyl]-4-[4-(tert-butyl)phenyl]piperazine

[0181] To a 100 mL round2-carboxaldehyde (0.314 g, 2.00 mmol), dichloromethane (10.0 mL), 1-(4-tert-butyl)phenyl piperazine (0.480 g, 2.20 mmol) and acetic acid (0.360 g, 6.00 mmol). After 10 minutes sodium triacetoxyborohydride (1.48 g, 7.00 mmol) was added as a solid and the reaction vessel was sealed with a septum, flushed with argon, and stirred for 20 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes) to yield the title product (0.069 g, 9.6% yield).

[0182] 1H NMR (500 MHz, cdcl3) δ 7.81 (d, J = 4.1 Hz, 1H), 7.33 – 7.28 (m, 2H), 6.97 – 6.79 (m, 3H), 3.77 (s, 2H), 3.21 (t, J = 5.0 Hz, 4H), 2.71 (t, J = 5.0 Hz, 4H), 1.30 (d, J = 1.2 Hz, 9H).

[0183] HRMS ESI (+) calc’d for [M+H] = 360.1741, found = 360.1774.Example 7 1-([1,1'-Biphenyl]-4-yl)-4-[(5-nitrofuran-2-yl)methyl]piperazine

[0184] To a 100 mL round 2-carboxaldehyde (0.315g, 2.20 mmol), dichloromethane , (0.620 g, 2.60 mmol) and acetic acid (0.600 g, 10.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (0.847 g, 4.00 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 19 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was concentrated in vacuo to a solid which was filtered, washed with ethyl acetate, dichloromethane, methanol and hexanes and dried to constant weight to yield the title product (0.159 g, 22 % yield).

[0185] 1H NMR (500 MHz, cdcl3) δ 7.54 (ddd, J = 17.6, 7.5, 1.8 Hz, 4H), 7.41 (t, J = 7.7 Hz, 2H), 7.33 – 7.28 (m, 2H), 7.06 – 6.96 (m, 2H), 6.54 (d, J = 3.6 Hz, 1H), 3.73 (s, 2H), 3.32 – 3.21 (m, 4H), 2.79 – 2.69 (m, 4H).

[0186] HRMS ESI (+) calc’d for [M+H] = 364.1657, found = 364.1689. Example 8 [4-(4-tert-Butylphenyl)piperazin-1-yl](5-nitrofuran-2-yl)methanone O O

[0187] To a 100 mL roundadded 5-nitrofuran-2-carboxylic acid (0.361 g, 2.30 mmol), N,N-dimethylformamide (2.00 mL), triethylamine (0.808 g, 8.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.893 g, 2.35 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred atroom temperature.1-4-(tert-Butyl)phenyl piperazine (0.539 g, 2.46 mmol) was dissolved in N,N- dimethylformamide (2.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 19 hours, diluted with ethyl acetate, transferred to a separatory funnel and washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes) to yield the title product (0.434 g, 42 % yield).

[0188] 1H NMR (500 MHz, cdcl3) δ 7.37 (dd, J = 3.8, 0.6 Hz, 1H), 7.34 – 7.30 (m, 2H), 7.22 (dd, J = 3.8, 0.7 Hz, 1H), 6.93 – 6.85 (m, 2H), 4.14 – 3.85 (m, 4H), 3.30 – 3.21 (m, 4H), 1.30 (d, J = 0.7 Hz, 9H).

[0189] HRMS ESI (+) calc’d for [M+H] = 358.1763, found = 358.1792. Example 9 4-(4-Chlorophenyl)-1-[(5-nitrofuran-2-yl)methyl]piperidine O2NON Cl

[0190] To a 100 mL round nitrofuran-2-carboxaldehyde (0.479g, 3.39 mmol), dichloromethane (10.0 mL), 4-(4-chloro)phenyl piperazine (0.740 g, 3.60 mmol) and acetic acid (0.420 g, 7.00 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (1.10 g, 5.00 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 23 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes) to yield the title product (0.337 g, 31% yield).

[0191] 1H NMR (500 MHz, cdcl3) δ 7.29 (d, J = 3.6 Hz, 1H), 7.28 – 7.24 (m, 3H), 7.17 – 7.11 (m, 2H), 6.50 (d, J = 3.7 Hz, 1H), 3.68 (s, 2H), 3.04 (dq, J = 10.5, 2.5 Hz, 2H), 2.47 (tt, J = 11.8, 4.2 Hz, 1H), 2.23 (td, J = 11.5, 2.9 Hz, 2H), 1.88 – 1.69 (m, 4H).

[0192] HRMS ESI (+) calc’d for [M+H] = 321.1002, found = 321.1002.Example 10 1-(4-Chlorophenyl)-4-[(3-nitrophenyl)methyl]piperazine

[0193] To a 100 mL round nitrobenzaldehyde (0.539 g, 3.56mmol), dichloromethane (12.0 , (0.747 g, 3.80 mmol) and acetic acid (0.600 g, 10.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (1.69 g, 8.00 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 22 hours at room temperature. The reaction was quenched by adding saturated aqueous sodium carbonate and transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes) to yield the title product (0.553 g, 47 %).

[0194] 1H NMR (500 MHz, cdcl3) δ 7.29 (d, J = 3.6 Hz, 1H), 7.28 – 7.24 (m, 3H), 7.17 – 7.11 (m, 2H), 6.50 (d, J = 3.7 Hz, 1H), 3.68 (s, 2H), 3.04 (dq, J = 10.5, 2.5 Hz, 2H), 2.47 (tt, J = 11.8, 4.2 Hz, 1H), 2.23 (td, J = 11.5, 2.9 Hz, 2H), 1.88 – 1.69 (m, 4H).

[0195] HRMS ESI (+) calc’d for [M+H] = 321.1002, found = 321.1002. Example 11 N1,N2-Dimethyl-N1-[(5-nitrofuran-2-yl)methyl]-N2-phenylethane-1,2-diamine O2NON N

[0196] To a 100 mL roundmethyl-N-[2- (methylamino)]ethylaniline (0.410 g, 2.50 mmol), dichloromethane (10.0 mL), 5-nitrofuran-2- carboxaldehyde (0.316 g, 2.23 mmol) and acetic acid (0.480 g, 8.00 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (1.05 g, 5.00 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 20 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo.The crude material was purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes) and fractions containing product were combined and concentrated in vacuo to yield the title product (0.337 g, 52% yield).

[0197] 1H NMR (500 MHz, cdcl3) δ 7.24 – 7.18 (m, 3H), 6.72 – 6.66 (m, 3H), 6.42 – 6.36 (m, 1H), 3.68 (s, 2H), 3.52 – 3.45 (m, 2H), 2.96 (s, 3H), 2.68 – 2.58 (m, 2H), 2.38 (s, 3H).

[0198] HRMS ESI (+) calc’d for [M+H] = 290.1500, found = 290.1531. Example 12 1-[(5-Nitrofuran-2-yl)methyl]-4-[3-(trifluoromethyl)phenyl]piperazine

[0199] To a 100 mL round (3-trifluoromethyl)phenyl]piperazine (1.15 g, 5.00 mmol), dichloromethane (15.0 mL), 5-nitrofuran-2- carboxaldehyde (0.316 g, 2.23 mmol) and acetic acid (0.480 g, 8.00 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (1.05 g, 5.00 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 20 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes) to yield the title product (0.636 g, 42 % yield).

[0200] 1H NMR (500 MHz, cdcl3) δ 7.36 (t, J = 7.9 Hz, 1H), 7.31 (d, J = 3.6 Hz, 1H), 7.15 – 7.08 (m, 2H), 7.06 (dd, J = 8.4, 2.4 Hz, 1H), 6.53 (d, J = 3.6 Hz, 1H), 3.72 (s, 2H), 3.32 – 3.23 (m, 4H), 2.72 (dd, J = 6.2, 3.9 Hz, 4H).

[0201] 19F NMR (470 MHz, cdcl3) δ -62.72.

[0202] HRMS ESI (+) calc’d for [M+H] = 356.1218, found = 356.1248.Example 13 1-(4-Bromophenyl)-4-[(5-nitrofuran-2-yl)methyl]piperazine

[0203] To a 100 mL round (4-bromo)phenyl piperazine (1.20 g, 5.00 mmol), dichloromethane, (0.575 g, 4.00 mmol) and acetic acid (0.720 g, 12.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (1.69 g, 8.00 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 20 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes) to yield the title product (0.619 g, 43% yield).

[0204] 1H NMR (500 MHz, cdcl3) δ 7.36 – 7.31 (m, 2H), 7.29 (d, J = 3.6 Hz, 1H), 6.83 – 6.70 (m, 2H), 6.51 (d, J = 3.5 Hz, 1H), 3.70 (s, 2H), 3.22 – 3.14 (m, 4H), 2.73 – 2.64 (m, 4H).

[0205] HRMS ESI (+) calc’d for [M+H] = 366.0449, found = 366.0476. Example 14 1-[(4-Fluorophenyl)methyl]-4-(5-nitrofuran-2-sulfonyl)piperazine

[0206] To a 100 mL roundfluoro)benzyl piperazine (0.291 g, 1.50 mmol), dichloromethane (5.00 mL) and triethylamine (0.303 g, 3.00 mmol). The reaction vessel was cooled to 0oC in an ice-water bath and 5-nitro-2-sulfonyl chloride (0.240, 1.13 mmol, dissolved in 5.00 mL dichlormethane) was added via syringe. The reaction mixture was stirred for 10 minutes at 0oC at which time it was concentrated in vacuo to a minimal volume and purified by silica gel chromatography (0 – 10 % methanol in dichloromethane) to yield the pure product (0.336 g, 81 % yield).

[0207] 1H NMR (500 MHz, cdcl3) δ 7.35 (d, J = 3.7 Hz, 1H), 7.28 – 7.20 (m, 2H), 7.12 (d, J = 3.7 Hz, 1H), 7.03 – 6.94 (m, 2H), 3.49 (s, 2H), 3.33 (t, J = 5.0 Hz, 4H), 2.59 – 2.44 (m, 4H).

[0208] 19F NMR (470 MHz, cdcl3) δ -115.13 (ddd, J = 14.1, 8.8, 5.3 Hz).

[0209] HRMS ESI (+) calc’d for [M+H] = 370.0869, found = 370.0896. Example 15 1-(3,4-Dichlorophenyl)-4-[(5-nitrofuran-2-yl)methyl]piperazine

[0210] To a 100 mL round (3,4-dichlorophenyl)piperazine(0.693 g, 3.00 mmol), , (0.342 g, 2.40 mmol) and acetic acid (0.720 g, 12.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (1.48 g, 7.00 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 22 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes) and fractions containing product were combined and concentrated in vacuo to yield the title product (0.277 g, 34% yield).

[0211] 1H NMR (500 MHz, cdcl3) δ 7.33 – 7.24 (m, 2H), 6.94 (d, J = 2.8 Hz, 1H), 6.73 (dd, J = 8.9, 2.9 Hz, 1H), 6.59 – 6.47 (m, 1H), 3.70 (s, 2H), 3.26 – 3.12 (m, 4H), 2.72 – 2.63 (m, 4H).

[0212] HRMS ESI (+) calc’d for [M+H] = 356.0564, found = 356.0595. Example 16 (5-Nitrofuran-2-yl){4-[4-(trifluoromethyl)benzene-1-sulfonyl]piperazin-1-yl}methanone Step 1: 1-[4-(Trifluoromethyl)

[0213] To a 100 mL round bottom flask was added a stir bar, piperazine (4.20 g, 50.0 mmol, dichloromethane (40.0 mL). The reaction vessel was sealed with a septum, flushed with argon, and cooled to 0oC.4-(Trifluoromethyl)phenyl sulfonyl chloride (1.16 g, 5.10 mmol, dissolved in 10.0 mL dichloromethane) was added via syringe. The reaction mixture was stirred at room temperature for 1 hour, transferred to a separatory funnel, washed with water and brine, the organic layer was dried over sodiumsulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 10% methanol in dichloromethane) to yield the title product (1.15 g, 78 % yield).

[0214] 1H NMR (500 MHz, cdcl3) δ 7.89 (d, J = 8.2 Hz, 2H), 7.82 (d, J = 8.3 Hz, 2H), 3.08 – 2.97 (m, 4H), 2.96 – 2.89 (m, 4H).

[0215] 19F NMR (470 MHz, cdcl3) δ -63.13. Step 2: (5-Nitrofuran-2-yl){4- piperazin-1-yl}methanone

[0216] To a 100 mL round a was added 5-nitrofuran-2-carboxylic acid (0.314 g, 2.00 mmol), N,N-dimethylformamide (2.00 mL), triethylamine (0.505 g, 5.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.779 g, 2.05 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature.1-[4-(Trifluoromethyl)benzene-1-sulfonyl]piperazine (0.626 g, 2.12 mmol) was dissolved in N,N-dimethylformamide (2.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 22 hours, diluted with ethyl acetate, transferred to a separatory funnel and washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the title product (0.422 g, 49% yield).

[0217] 1H NMR (500 MHz, cdcl3) δ 7.91 (d, J = 8.2 Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 3.8 Hz, 1H), 7.19 (d, J =3.8 Hz, 1H), 4.21 – 3.73 (m, 4H), 3.19 (t, J = 5.1 Hz, 4H).

[0218] 19F NMR (470 MHz, cdcl3) δ -63.19.

[0219] HRMS ESI (+) calc’d for [M+H] = 434.0629, found = 434.0650. Example 17 1-[(5-Nitrofuran-2-yl)methyl]-4-{4-[3-(trifluoromethyl)-3H-diazirin-3-yl]benzene-1-sulfonyl}piperazine Step 1: 1-{4-[3-(Trifluoromethyl)-

[0220] To a 100 mL round bottom flask was added a stir bar, dichloromethane (20.0 mL) and piperazine (2.05 g, 23.7 mmol). The reaction mixture was stirred, cooled to 0oC in an ice-water bath, and4-[3-(trifluoromethyl)-3H-diazirin-4-yl]benzoic acid (0.500 g, 1.76 mmol, added as a solution in 10.0 mL of dichloromethane) was added as via syringe. The reaction mixture was stirred at 0oC for 2 hours, water (30.0 mL) was added, the reaction mixture was partitioned, the aqueous layer was washed with dichloromethane, the organic layers were combined, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by silica gel chromatography (0 – 10 % methanol in dichloromethane) to yield the title product (0.360, 61% yield).

[0221] 1H NMR (500 MHz, cdcl3) δ 7.83 – 7.74 (m, 2H), 7.35 (d, J = 8.3 Hz, 2H), 2.99 (t, J = 4.7 Hz, 4H), 2.93 (dd, J = 5.5, 3.9 Hz, 4H).

[0222] 19F NMR (470 MHz, cdcl3) δ -64.84. Step 2: 1-[(5-Nitrofuran-2- 3-yl]benzene-1-sulfonyl}piperazine

[0223] To a 100 mL round bottom flask was added a stir bar, (1-{4-[3-(trifluoromethyl)-3H-diazirin- 3-yl]benzene-1-sulfonyl}piperazine (0.360 g, 1.07 mmol), dichloromethane (12.0 mL), 5-nitrofuran-2- carboxaldehyde (0.282 g, 2.00 mmol) and acetic acid (0.480 g, 8.00 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (0.847 g, 4.00 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 20 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 10 % methanol in dichloromethane) to yield the title product (0.388 g, 85%).

[0224] 1H NMR (Amide rotamers, 500 MHz, cdcl3) δ 7.83 – 7.73 (m, 2H), 7.34 (d, J = 8.2 Hz, 2H), 7.29 (d, J = 3.6 Hz, 0.5H), 7.24 (d, J = 3.6 Hz, 1H), 6.62 – 6.39 (m, 1.5H), 4.72 (s, 1H), 3.62 (s, 2H), 3.05 (s, 4H), 2.61 (t, J = 5.0 Hz, 4H).

[0225] 19F NMR (470 MHz, cdcl3) δ -64.81.

[0226] HRMS ESI (+) calc’d for [M+H] = 460.0898, found = 460.0990.Example 18 1-(4-Chlorobenzene-1-sulfonyl)-4-[(5-nitrofuran-2-yl)methyl]piperazine Step 1: 1-(4-

[0227] Tommol, dichloromethane (40.0 mL). The reaction vessel was sealed with a septum, flushed with argon, and cooled to 0oC.4-Chlorobenzenesulfonyl chloride (1.30 g, 6.18 mmol, dissolved in 10.0 mL dichloromethane) was added via syringe. The reaction mixture was stirred at room temperature for 1 hour, transferred to a separatory funnel, washed with water and brine, the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 10 % methanol in dichloromethane) to yield the title product (1.18 g, 73% yield).

[0228] 1H NMR (500 MHz, cdcl3) δ 7.71 – 7.66 (m, 2H), 7.57 – 7.43 (m, 2H), 2.98 (t, J = 4.8 Hz, 5H), 2.93 (dd, J = 5.6, 3.9 Hz, 5H). Step 2: 1-(4-Chlorobenzene-1-piperazine

[0229] To a 100 mL round bottom flask was added a stir bar, 1-(4-chlorobenzene-1- sulfonyl)piperazine (0.425 g, 1.61 mmol), dichloromethane (15.0 mL), 5-nitrofuran-2-carboxaldehyde (0.282 g, 2.00 mmol) and acetic acid (0.480 g, 8.00 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (1.27 g, 6.00 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 19 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes) to yield the title product (0.310 g, 50% yield).

[0230] 1H NMR (500 MHz, cdcl3) δ 7.75 – 7.63 (m, 2H), 7.60 – 7.42 (m, 2H), 7.30 – 7.22 (m, 1H), 6.63 – 6.35 (m, 1H), 3.62 (s, 2H), 3.06 (s, 4H), 2.61 (t, J = 5.0 Hz, 4H).

[0231] HRMS ESI (+) calc’d for [M+H] = 386.0573, found = 386.0599.Example 19 1-(3,4-Difluorobenzene-1-sulfonyl)-4-[(5-nitrofuran-2-yl)methyl]piperazine HN F Step 1: 1-

[0232] mmol, dichloromethane (40.0 mL). The reaction vessel was sealed with a septum, flushed with argon, and cooled to 0oC.3,4-difluorobenzenesulfonyl chloride (1.34 g, 6.30 mmol, dissolved in 10.0 mL dichloromethane) was added via syringe. The reaction mixture was stirred at room temperature for 1 hour, transferred to a separatory funnel, washed with water and brine, the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 10% methanol in dichloromethane) to yield the title product (1.43 g, 87% yield).

[0233] 1H NMR (500 MHz, cdcl3) δ 7.61 (ddd, J = 9.3, 7.2, 2.2 Hz, 1H), 7.55 (ddt, J = 8.0, 3.9, 1.8 Hz, 1H), 7.35 (ddd, J = 9.6, 8.6, 7.4 Hz, 1H), 3.08 – 2.97 (m, 5H), 2.97 – 2.88 (m, 5H).

[0234] 19F NMR (470 MHz, cdcl3) δ -129.10 – -129.35 (m), -133.52 (dt, J = 20.7, 8.4 Hz). Step 2: 1-(3,4-Difluorobenzene-piperazine

[0235] To a 100 mL round bottom flask was added a stir bar, 1-(3,4-difluorobenzene-1- sulfonyl)piperazine (0.459 g, 1.75 mmol), dichloromethane (15.0 mL), 5-nitrofuran-2-carboxaldehyde (0.317 g, 2.25 mmol) and acetic acid (0.480 g, 8.00 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (1.27 g, 6.00 mmol) was added as a solid and the reaction vessel sealed, flushed with argon, and stirred for 21 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the title product (0.376 g, 50 % yield).

[0236] 1H NMR (500 MHz, cdcl3) δ 7.66 – 7.45 (m, 2H), 7.38 – 7.28 (m, 1H), 7.25 (d, J = 3.6 Hz, 1H), 6.63 – 6.37 (m, 1H), 3.63 (s, 2H), 3.08 (s, 4H), 2.62 (t, J = 5.0 Hz, 4H).

[0237] 19F NMR (470 MHz, cdcl3) δ -128.83 (dddd, J = 20.9, 10.7, 7.2, 4.1 Hz), -133.21 (dt, J = 20.6, 8.2 Hz).

[0238] HRMS ESI (+) calc’d for [M+Na] = 410.0598, found = 410.0623. Example 20 1-(4-Chlorophenyl)-4-[(5-nitrothiophen-2-yl)methyl]piperazine

[0239] To a 100 mL round (4-chlorophenyl)piperazine (0.786 g,4.00 mmol), dichloromethane , (0.476 g, 3.00 mmol) and acetic acid (0.720 g, 12.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (1.69 g, 8.00 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 20 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the title product (0.461 g, 46% yield).

[0240] 1H NMR (500 MHz, cdcl3) δ 7.81 (dd, J = 8.9, 4.1 Hz, 1H), 7.23 – 7.18 (m, 2H), 6.95 – 6.81 (m, 3H), 3.76 (d, J = 1.0 Hz, 2H), 3.23 – 3.15 (m, 4H), 2.74 – 2.66 (m, 4H).

[0241] HRMS ESI (+) calc’d for [M+H] = 338.0726, found = 338.0762. Example 21 Ethyl 4-{4-[(5-nitrofuran-2-yl)methyl]piperazin-1-yl}benzoate

[0242] To a 100 mL4-(piperazin-1-yl) benzoate (0.561 g, 2.39 mmol), dichloromethane (15.0 mL), 5-nitrofuran-2-carboxaldehyde (0.423 g, 3.00 mmol) and acetic acid (0.720 g, 12.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes, sodium triacetoxyborohydride (1.69 g, 8.00 mmol) was added as a solid and the reaction vessel sealed, flushed with argon, and stirred for 20 hours at room temperature. The reaction mixture wasquenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the title product (0.298 g, 36% yield).

[0243] 1H NMR (500 MHz, cdcl3) δ 7.98 – 7.90 (m, 2H), 7.30 (d, J = 3.6 Hz, 1H), 6.93 – 6.81 (m, 2H), 6.54 (d, J = 3.6 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 3.74 (s, 2H), 3.42 – 3.33 (m, 4H), 2.72 (t, J = 5.0 Hz, 4H), 1.37 (t, J = 7.1 Hz, 3H).

[0244] HRMS ESI (+) calc’d for [M+H] = 360.1555, found = 360.1593. Example 22 2-Methyl-1-[(5-nitrofuran-2-yl)methyl]-4-phenylpiperazine

[0245] To a 100 (0.231 g,1.80 mmol), dichloromethane (15.0 mL), 5-nitrofuran-2-carboxaldehyde (0.253 g, 1.80 mmol) and acetic acid (0.720 g, 12.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (0.846 g, 4.00 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 20 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the title product (0.221 g, 56% yield).

[0246] 1H NMR (500 MHz, cdcl3) δ 7.33 – 7.20 (m, 3H), 6.91 (dt, J = 8.0, 1.1 Hz, 2H), 6.86 (tt, J = 7.3, 1.0 Hz, 1H), 6.57 – 6.48 (m, 1H), 4.71 (s, 1H), 3.95 (d, J = 15.5 Hz, 1H), 3.80 (d, J = 15.5 Hz, 1H), 3.52 – 3.38 (m, 2H), 2.92 (tdd, J = 11.8, 9.3, 3.1 Hz, 2H), 2.69 – 2.52 (m, 3H), 1.24 (d, J = 5.4 Hz, 3H).

[0247] HRMS ESI (+) calc’d for [M+H] = 302.1500, found = 302.1536.Example 23 2-Methyl-4-[(5-nitrofuran-2-yl)methyl]-1-phenylpiperazine

[0248] To a 100 mL round methyl-1-phenylpiperazine (0.243 g, 1.37 mmol), dichloromethane (8.00, (0.268 g, 1.90 mmol) and acetic acid (0.480 g, 8.00 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (0.844 g, 4.00 mmol) was added as a solid and the reaction vessel sealed, flushed with argon, and stirred for 20 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the title product (0.244 g, 59% yield).

[0249] 1H NMR (500 MHz, cdcl3) δ 7.31 (d, J = 3.6 Hz, 1H), 7.30 – 7.25 (m, 4H), 6.93 (d, J = 8.1 Hz, 2H), 6.88 (t, J = 7.3 Hz, 1H), 6.52 (d, J = 3.6 Hz, 1H), 3.85 (tt, J = 6.6, 3.8 Hz, 1H), 3.76 – 3.63 (m, 2H), 3.24 (dt, J = 11.9, 3.9 Hz, 1H), 3.16 (ddd, J = 12.0, 9.4, 3.3 Hz, 1H), 2.87 (dt, J = 10.8, 3.8 Hz, 1H), 2.65 (d, J = 3.7 Hz, 2H), 2.51 (td, J = 10.1, 3.5 Hz, 1H), 1.08 (d, J = 6.5 Hz, 3H).

[0250] HRMS ESI (+) calc’d for [M+H] = 302.1500, found = 302.1534. Example 24 1-[(5-Nitrofuran-2-yl)methyl]-4-[4-(trifluoromethyl)phenoxy]piperidine O2NON CF3

[0251] To a 100 mL round(trifluoromethyl)phenoxy]piperidine (0.326 g, 1.32 mmol), dichloromethane (10.0 mL), 5-nitrofuran-2- carboxaldehyde (0.255 g, 1.60 mmol) and acetic acid (0.360 g, 6.00 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (0.844 g, 4.00 mmol) added as a solid and the reaction vessel sealed, flushed with argon, and stirred for 22 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo.The crude material was purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the title product (0.282 g, 54%).

[0252] 1H NMR (500 MHz, cdcl3) δ 7.57 – 7.52 (m, 1H), 7.29 (d, J = 3.6 Hz, 1H), 6.97 – 6.91 (m, 2H), 6.58 – 6.46 (m, 1H), 4.73 (s, 1H), 4.41 (tt, J = 7.3, 3.7 Hz, 1H), 3.67 (s, 2H), 2.78 (ddd, J = 11.7, 7.5, 3.3 Hz, 2H), 2.47 (ddd, J = 11.6, 8.2, 3.3 Hz, 2H), 2.05 – 1.98 (m, 2H), 1.87 (dtd, J = 11.0, 7.5, 3.5 Hz, 2H).19F NMR (470 MHz, cdcl3) δ -61.53.

[0253] HRMS ESI (+) calc’d for [M+H] = 371.1214, found = 371.1246. Example 25 3-(4-tert-Butylphenyl)-1-[(5-nitrofuran-2-yl)methyl]pyrrolidine

[0254] To a 100 mL round (4-tertbutyl)phenyl pyrrolidine(0.218 g, 1.07 mmol), dichloromethane (10.0 mL), 5-nitrofuran-2-carboxaldehyde (0.185 g, 1.30 mmol) and acetic acid (0.360 g, 6.00 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (1.69 g, 10.30 mmol) was added as a solid and the reaction vessel sealed, flushed with argon, and stirred for 22 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the title product (0.078 g, 22%).

[0255] 1H NMR (500 MHz, cdcl3) δ 7.36 – 7.31 (m, 2H), 7.29 (d, J = 3.6 Hz, 1H), 7.23 – 7.19 (m, 2H), 6.50 (d, J = 3.5 Hz, 1H), 3.81 (q, J = 14.9 Hz, 2H), 3.39 (dq, J = 9.8, 7.8 Hz, 1H), 3.12 (dd, J = 9.1, 7.8 Hz, 1H), 2.99 – 2.86 (m, 1H), 2.81 (td, J = 8.9, 5.5 Hz, 1H), 2.63 (dd, J = 9.1, 7.9 Hz, 1H), 2.41 – 2.28 (m, 1H), 1.94 (dddd, J = 12.8, 8.7, 7.5, 6.3 Hz, 1H), 1.32 (s, 9H).

[0256] HRMS ESI (+) calc’d for [M+H] = 329.1861, found = 329.1883.Example 26 4-{4-[(5-Nitrofuran-2-yl)methyl]piperazin-1-yl}benzonitrile

[0257] To a 100 mL round 1-yl benzonitrile (0.436 g, 2.32 mmol), dichloromethane (15.0, g, 2.80 mmol) and acetic acid (0.900 g, 15.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (2.11 g, 10.0 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 19 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the title product (0.129 g, 18%).

[0258] 1H NMR (500 MHz, cdcl3) δ 7.54 – 7.46 (m, 2H), 7.29 (d, J = 3.6 Hz, 1H), 6.89 – 6.83 (m, 2H), 6.51 (dd, J = 3.7, 0.7 Hz, 1H), 3.70 (s, 2H), 3.40 – 3.31 (m, 4H), 2.73 – 2.63 (m, 4H).

[0259] HRMS ESI (+) calc’d for [M+H] = 313.1296, found = 313.1320. Example 27 1-(3-Bromophenyl)-4-[(5-nitrofuran-2-yl)methyl]piperazine

[0260] To a 100 mL roundbromophenyl)piperazine (0.438 g, 1.81 mmol), dichloromethane (10.0 mL), 5-nitrofuran-2-carboxaldehyde (0.282 g, 2.00 mmol) and acetic acid (0.600 g, 10.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (1.27 g, 6.00 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 23 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes) to yield the title product (0.257 g, 39% yield).

[0261] 1H NMR (500 MHz, cdcl3) δ 7.30 (t, J = 3.7 Hz, 1H), 7.11 (t, J = 8.1 Hz, 1H), 7.03 (t, J = 2.1 Hz, 1H), 7.02 – 6.94 (m, 1H), 6.85 – 6.80 (m, 1H), 6.59 – 6.51 (m, 1H), 3.71 (s, 2H), 3.28 – 3.17 (m, 4H), 2.74 – 2.66 (m, 4H).

[0262] HRMS ESI (+) calc’d for [M+H] = 366.0449, found = 366.0470. Example 28 1-(3,5-Dichlorophenyl)-4-[(5-nitrofuran-2-yl)methyl]piperazine

[0263] To a 100 mL round (3,5-dichlorophenyl)piperazine(0.358 g, 1.54 mmol), , (0.246 g, 1.75 mmol) and acetic acid (0.600 g, 10.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (1.27 g, 6.00 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 20 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) and fractions containing product were combined and concentrated in vacuo to yield the title product (0.220 g, 40% yield).

[0264] 1H NMR (500 MHz, cdcl3) δ 7.31 (d, J = 3.5 Hz, 1H), 6.81 (t, J = 1.7 Hz, 1H), 6.74 (d, J = 1.7 Hz, 2H), 6.60 – 6.47 (m, 1H), 3.70 (s, 2H), 3.27 – 3.18 (m, 4H), 2.72 – 2.64 (m, 4H).

[0265] HRMS ESI (+) calc’d for [M+H] = 356.0564, found = 356.0586. Example 29 (5-Nitro-1H-pyrazol-3-yl){4-[4-(trifluoromethyl)phenyl]piperazin-1-yl}methanone

[0266] To a 100 mL roundadded 3-nitro-1H-pyrazole-5- carboxylic acid (0.314 g, 2.00 mmol), N,N-dimethylformamide (2.00 mL), triethylamine (0.303 g, 3.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.779 g, 2.05 mmol). The reaction vessel was sealed with a septum, flushed withargon, and stirred at room temperature.1-(4-(Trifluoromethyl)phenylpiperazine (0.529 g, 2.30 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 22 hours, diluted with ethyl acetate, transferred to a separatory funnel and washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and filtered through silica with 10% methanol in dichloromethane. The filtrate was concentrated in vacuo to yield the product (0.601 g, 82%).

[0267] 1H NMR (500 MHz, dmso-d6) δ 7.53 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 4.00 – 3.68 (m, 4H), 3.41 (t, J = 5.1 Hz, 4H), 2.68 (s, 1H).

[0268] 19F NMR (470 MHz, dmso-d6) δ -59.46, -70.89.

[0269] HRMS ESI (+) calc’d for [M+H] = 370.1123, found = 370.1122. Example 30 (5-Nitrofuran-2-yl){4-[4-(trifluoromethyl)phenyl]piperazin-1-yl}methanone O NN

[0270] To a 100 mL round added 5-nitrofuran-2-carboxylicacid (0.582 g, 3.70 mmol), N,N-dimethylformamide (3.00 mL), triethylamine (0.808 g, 8.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1.44 g, 3.80 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature.1-(4-(Trifluoromethyl)phenyl piperazine (0.897 g, 3.90 mmol) was dissolved in N,N- dimethylformamide (2.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 20 hours, diluted with ethyl acetate, transferred to a separatory funnel and washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and filtered through silica with 10% methanol in dichloromethane. The filtrate was concentrated in vacuo to yield the product (0.812 g, 59% yield).

[0271] 1H NMR (500 MHz, dmso-d6) δ 7.79 (d, J = 3.9 Hz, 1H), 7.57 – 7.47 (m, 2H), 7.33 (d, J = 3.9 Hz, 1H), 7.08 (d, J = 8.7 Hz, 2H), 3.96 – 3.69 (m, 4H), 3.41 (dd, J = 6.5, 4.1 Hz, 4H).

[0272] 19F NMR (470 MHz, dmso-d6) δ -59.47.

[0273] HRMS ESI (+) calc’d for [M+H] = 370.1010, found = 370.1006.Example 31 2-Methyl-4-[(5-nitrofuran-2-yl)methyl]-1-[4-(trifluoromethyl)phenyl]piperazine

[0274] , , nitrofuran-2- carboxaldehyde (0.183 g, 1.30 mmol) and acetic acid (0.360 g, 6.00 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (0.847 g, 4.00 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 20 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes) and fractions containing product were combined and concentrated in vacuo to yield the title product (0.201 g, 56% yield).

[0275] 1H NMR (500 MHz, cdcl3) δ 7.48 (d, J = 8.7 Hz, 2H), 7.31 (d, J = 3.6 Hz, 1H), 6.88 (d, J = 8.7 Hz, 2H), 6.52 (d, J = 3.6 Hz, 1H), 4.11 – 4.02 (m, 1H), 3.75 – 3.61 (m, 2H), 3.40 (dt, J = 12.1, 3.2 Hz, 1H), 3.19 (td, J = 11.7, 3.5 Hz, 1H), 2.97 (dq, J = 9.2, 2.8 Hz, 1H), 2.78 (dt, J = 10.9, 2.4 Hz, 1H), 2.55 (dd, J = 10.9, 3.6 Hz, 1H), 2.41 (td, J = 11.1, 3.5 Hz, 1H), 1.17 (d, J = 6.6 Hz, 3H).

[0276] 19F NMR (470 MHz, cdcl3) δ -61.28.

[0277] HRMS ESI (+) calc’d for [M+H] = 370.1374, found = 370.1390. Example 32 1-[(5-Nitrofuran-2-yl)methyl]-4-[2-nitro-4-(trifluoromethyl)phenyl]piperazine

[0278] To a 100 mL roundnitro-4- (trifluoromethyl)phenyl]piperazine (0.539 g, 1.95 mmol), dichloromethane (10.0 mL), 5-nitrofuran-2- carboxaldehyde (0.338 g, 2.40 mmol) and acetic acid (0.720 g, 12.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (1.69 g, 8.00 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 20 hours at roomtemperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes) to yield the title product (0.417 g, 53 % yield).

[0279] 1H NMR (500 MHz, cdcl3) δ 8.06 (d, J = 2.2 Hz, 1H), 7.68 (dd, J = 8.7, 2.3 Hz, 1H), 7.30 (d, J = 3.6 Hz, 1H), 7.17 (d, J = 8.7 Hz, 1H), 6.51 (d, J = 3.6 Hz, 1H), 3.72 (s, 2H), 3.23 – 3.13 (m, 4H), 2.76 – 2.65 (m, 4H).

[0280] 19F NMR (470 MHz, cdcl3) δ -60.14.

[0281] HRMS ESI (+) calc’d for [M+H] = 401.1069, found = 401.1103. Example 33 1-[(5-Nitrofuran-2-yl)methyl]-4-[4-nitro-2-(trifluoromethyl)phenyl]piperazine

[0282] To a 100 mL nitro-2-(trifluoromethyl)phenyl]piperazine (0.651 g, 2.36 mmol), dichloromethane (12.0 mL), 5-nitrofuran-2- carboxaldehyde (0.395 g, 2.80 mmol) and acetic acid (0.900 g, 15.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (2.11 g, 10.0 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 25 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes) to yield the title product (0.361 g, 38% yield).

[0283] 1H NMR (500 MHz, cdcl3) δ 8.51 (d, J = 2.7 Hz, 1H), 8.34 (dd, J = 9.0, 2.7 Hz, 1H), 7.34 – 7.27 (m, 2H), 6.52 (d, J = 3.7 Hz, 1H), 3.72 (s, 2H), 3.22 – 3.13 (m, 4H), 2.72 (t, J = 4.8 Hz, 4H).

[0284] 19F NMR (470 MHz, cdcl3) δ -60.14.

[0285] HRMS ESI (+) calc’d for [M+H] = 401.1069, found = 401.1062.Example 34 1-(2,4-Dichlorophenyl)-4-[(5-nitrofuran-2-yl)methyl]piperazine

[0286] To a 100 mL round dichlorophenyl]piperazine (0.244 g, 1.05 mmol),, (0.169 g, 1.20 mmol) and acetic acid (0.360 g, 6.00 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (0.847 g, 4.00 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 20 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes) to yield the title product (0.053 g, 14% yield).

[0287] 1H NMR (500 MHz, cdcl3) δ 7.37 (d, J = 2.4 Hz, 1H), 7.31 (d, J = 3.6 Hz, 1H), 7.20 (dd, J = 8.7, 2.5 Hz, 1H), 6.96 (d, J = 8.6 Hz, 1H), 6.52 (d, J = 3.6 Hz, 1H), 3.72 (s, 2H), 3.07 (s, 4H), 2.74 (d, J = 6.2 Hz, 4H).

[0288] HRMS ESI (+) calc’d for [M+H] = 356.0564, found = 356.0579. Example 35 1-[(5-Nitrofuran-2-yl)methyl]-4-[6-(trifluoromethyl)pyridin-2-yl]piperazine

[0289] To a 100 mL round[6-(trifluoromethyl)pyridine-2-yl] piperazine (0.618 g, 2.67 mmol), dichloromethane (12.0 mL), 5-nitrofuran-2-carboxaldehyde (0.423 g, 3.00 mmol) and acetic acid (0.900 g, 15.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (2.11 g, 10.0 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 20 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using 0 – 100% ethyl acetate in hexanes and further purified by silica gelchromatography using 0 – 1% methanol in dichloromethane to yield the title product (0.204 g, 21% yield).

[0290] 1H NMR (500 MHz, cdcl3) δ 7.59 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 3.6 Hz, 1H), 6.96 (d, J = 7.3 Hz, 1H), 6.77 (d, J = 8.7 Hz, 1H), 6.52 (d, J = 3.6 Hz, 1H), 3.71 (s, 2H), 3.65 (t, J = 5.1 Hz, 4H), 2.65 (t, J = 5.1 Hz, 4H).

[0291] 19F NMR (470 MHz, cdcl3) δ -68.81.

[0292] HRMS ESI (+) calc’d for [M+H] = 357.1170, found = 357.1198. Example 36 1-(4-Iodophenyl)-4-[(5-nitrofuran-2-yl)methyl]piperazine

[0293] To a 100 piperazine (0.404 g,1.40 mmol), , g, 1.60 mmol) and acetic acid (0.480 g, 8.00 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (1.27 g, 6.00 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 20 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes) to yield the title product (0.185 g, 32% yield).

[0294] 1H NMR (500 MHz, cdcl3) δ 7.57 – 7.50 (m, 2H), 7.30 (d, J = 3.6 Hz, 2H), 6.73 – 6.63 (m, 2H), 6.61 – 6.49 (m, 2H), 4.74 (s, 2H), 3.71 (s, 2H), 3.23 – 3.15 (m, 4H), 2.69 (dd, J = 6.2, 3.9 Hz, 4H).

[0295] HRMS ESI (+) calc’d for [M+H] = 414.0310, found = 414.0329. Example 37 1-[(5-Nitrofuran-2-yl)methyl]-4-(pyridin-3-yl)piperazine

[0296] To a 100piperazine (0.359 g, 2.19 mmol), dichloromethane (12.0 mL), 5-nitrofuran-2-carboxaldehyde (0.353 g, 2.50 mmol) and acetic acid (0.720 g, 12.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (1.69 g, 8.00 mmol) was added as a solid and the reaction vessel was sealed,flushed with argon, and stirred for 23 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes) to yield the title product (0.245 g, 39 % yield).

[0297] 1H NMR (500 MHz, cdcl3) δ 8.31 (dd, J = 2.4, 1.3 Hz, 1H), 8.12 (dd, J = 3.7, 2.2 Hz, 1H), 7.30 (d, J = 3.6 Hz, 1H), 7.20 – 7.15 (m, 2H), 6.52 (d, J = 3.6 Hz, 1H), 3.71 (s, 2H), 3.29 – 3.22 (m, 4H), 2.76 – 2.66 (m, 4H).

[0298] HRMS ESI (+) calc’d for [M+H] = 289.1296, found = 289.1296. Example 38 Ethyl 3-{4-[(5-nitrofuran-2-yl)methyl]piperazin-1-yl}benzoate Step 1: Ethyl 3-(piperazin-1-yl)

[0299] To a 100 mL round bottom flask was added a stir bar 3-(piperazin-1-yl)benzoic acid bis hydrochloric acid salt (0.498 g, 1.78 mmol) and ethanol (25.0 mL). The reaction mixture was heated to 70oC for 22 hours at which time it was concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield the product (0.414 g, 99 % yield).

[0300] 1H NMR (500 MHz, cdcl3) δ 7.61 (t, J = 2.1 Hz, 1H), 7.53 (dt, J = 7.6, 1.2 Hz, 1H), 7.32 (t, J = 7.9 Hz, 1H), 7.11 (dd, J = 8.3, 2.7 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 3.25 – 3.15 (m, 4H), 3.05 (dd, J = 6.3, 3.7 Hz, 4H), 1.40 (t, J = 7.1 Hz, 3H). O Step 2: Ethyl 3-{4-[(5-

[0301] To a 100 mL round bottom flask was added a stir bar and ethyl 3-(piperazin-1-yl)benzoate (0.414 g, 1.76 mmol), dichloromethane (10.0 mL), 5-nitrofuran-2-carboxaldehyde (0.282 g, 2.00 mmol) and acetic acid (0.720 g, 12.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (1.69 g, 8.00 mmol) was added as a solid and the reaction vesselwas sealed, flushed with argon, and stirred for 23 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using 0 – 100% ethyl acetate in hexanes and further purified by silica gel chromatography using 0 – 10 % methanol in dichloromethane to yield the title product (0.233 g, 37%).

[0302] 1H NMR (500 MHz, cdcl3) δ 7.59 (t, J = 2.1 Hz, 1H), 7.54 (dt, J = 7.6, 1.2 Hz, 1H), 7.35 – 7.29 (m, 2H), 7.09 (dd, J = 8.2, 2.7 Hz, 1H), 6.52 (d, J = 3.6 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 3.72 (s, 2H), 3.30 – 3.24 (m, 4H), 2.74 – 2.69 (m, 4H), 1.39 (t, J = 7.1 Hz, 3H).

[0303] HRMS ESI (+) calc’d for [M+H] = 360.1555, found = 360.1556. Example 39 2-{4-[(5-Nitrofuran-2-yl)methyl]piperazin-1-yl}-5-(trifluoromethyl)pyrimidine

[0304] (trifluoromethyl)pyrimidine (0.267 g, 1.14 mmol), dichloromethane (10.0 mL), 5-nitrofuran-2- carboxaldehyde (0.183 g, 1.30 mmol) and acetic acid (0.480 g, 8.00 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (1.27 g, 6.00 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 23 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using 0 – 100% ethyl acetate in hexanes and further purified by silica gel chromatography using 0 – 10% methanol in dichloromethane to yield the title product (0.277 g, 68 % yield).

[0305] 1H NMR (500 MHz, cdcl3) δ 8.47 (s, 2H), 7.29 (d, J = 3.6 Hz, 1H), 6.58 – 6.50 (m, 2H), 4.73 (s, 2H), 3.99 – 3.89 (m, 4H), 3.70 (s, 2H), 2.64 – 2.55 (m, 4H).

[0306] 19F NMR (470 MHz, cdcl3) δ -61.09.

[0307] HRMS ESI (+) calc’d for [M+H] = 358.1123, found = 358.1129.Example 40 1-(5-Nitrofuran-2-yl)-4-[4-(trifluoromethyl)phenyl]piperazine

[0308] To a 100 (0.959 g, 5.00 mmol), n-butanol. mixture was heated to 50oC and 1-[(4-trifluoromethyl)phenyl]piperazine (1.38 g, 6.00 mmol, added as a solution in 6.00 mL n- butanol). It was stirred for 20 minutes at 50oC during which time a precipitate formed. The reaction mixture was stirred at 0oC for 30 minutes, filtered, washed with n-butanol and hexanes and dried in vacuo to yield the pure product (1.13 g, 66 % yield).

[0309] 1H NMR (500 MHz, dmso-d6) δ 7.84 (d, J = 4.4 Hz, 1H), 7.54 (d, J = 8.8 Hz, 2H), 7.13 (d, J = 8.7 Hz, 2H), 6.00 (d, J = 4.4 Hz, 1H), 3.71 – 3.57 (m, 4H), 3.54 – 3.39 (m, 4H).

[0310] 19F NMR (470 MHz, dmso) δ -59.51.

[0311] HRMS ESI (+) calc’d for [M+H] = 342.1061, found = 342.1081. Example 41 5-Nitro-N-{1-[4-(trifluoromethyl)phenyl]pyrrolidin-3-yl}furan-2-carboxamide Step 1: tert-

[0312] To a 100 mL round bottom flask was added a stir bar, 4-fluorobenzotrifluoride (2.33 g, 14.1 mmol), potassium carbonate (3.04 g, 22.0 mmol) and dimethylsulfoxide (10.0 mL).3-(tert- Butoxycarbonylamino)pyrrolidine (3.72 g, 20.0 mmol, dissolved in 10.0 mL dimethylsulfoxide) was added and the reaction mixture was stirred under argon at 100oC for 22 hours, after which the reaction mixture was cooled to room temperature, partitioned between ethyl acetate and water, washed with water, 5% w / v aqueous lithium chloride, and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes) to yield the product (1.80 g, 39% yield).

[0313] 1H NMR (500 MHz, dmso-d6) δ 7.43 (d, J = 8.5 Hz, 2H), 6.59 (d, J = 8.6 Hz, 2H), 4.14 (q, J = 6.1 Hz, 1H), 3.49 (dd, J = 10.0, 6.5 Hz, 1H), 3.39 (dt, J = 9.4, 7.0 Hz, 1H), 3.28 (ddd, J = 9.7, 7.8, 5.9 Hz, 1H), 3.08 (dd, J = 10.0, 4.9 Hz, 1H), 2.19 – 2.10 (m, 1H), 1.89 (dq, J = 12.9, 6.5 Hz, 1H), 1.38 (s, 9H).

[0314] 19F NMR (470 MHz, dmso-d6) δ -58.72.Step 2: 5-Nitro-N-{1-[4-(triflu -2-carboxamide

[0315] To a 100 mL round bottom as conta n ng a st r bas was added tert-butyl {1-[4- (trifluoromethyl)phenyl] pyrrolidin-3-yl}carbamate (0.172 g, 0.567 mmol) followed by dichloromethane (5.00 mL) and trifluoroacetic acid (0.707 g, 6.20 mmol). The reaction mixture was stirred at room temperature for 2 hours at which time it was cooled to 0oC, triethylamine was added (1.01 g, 10.0 mmol). The reaction mixture was concentrated in vacuo and the deprotected amine was used without purification in the next step. To a 100 mL round bottom flask containing a stir bar was added 5- nitrofuran-2-carboxylic acid (0.075 g, 0.480 mmol), N,N-dimethylformamide (2.00 mL), triethylamine (0.202 g, 2.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.193 g, 0.510 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature.1-[4-(Trifluoromethyl)phenyl]pyrrolidin-3-amine (0.119 g, 0.567 mmol) was dissolved in N,N-dimethylformamide (1.00 mL), triethylamine (0.505 g, 5.00 mmol) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 24 hours, diluted with ethyl acetate, transferred to a separatory funnel and washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes) and further purified by reverse phase medium pressure liquid chromatography (using 0 – 100% methanol in 25.0 M aqueous ammonium formate). Fractions were combined, concentrated in vacuo, dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate, brine, the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield the pure product (0.010 g, 5.6% yield).

[0316] 1H NMR (500 MHz, cdcl3) δ 7.54 – 7.46 (m, 2H), 7.38 (d, J = 3.8 Hz, 1H), 7.30 (d, J = 3.8 Hz, 1H), 6.65 (d, J = 7.3 Hz, 1H), 6.61 (d, J = 8.6 Hz, 2H), 4.83 (h, J = 6.0 Hz, 1H), 3.75 (dd, J = 10.2, 6.2 Hz, 1H), 3.65 – 3.57 (m, 1H), 3.48 (td, J = 8.9, 5.3 Hz, 1H), 3.40 (dd, J = 10.2, 4.1 Hz, 1H), 2.48 (ddt, J = 12.9, 8.2, 6.5 Hz, 1H), 2.25 – 2.11 (m, 1H).

[0317] 19F NMR (470 MHz, cdcl3) δ -60.89.

[0318] HRMS ESI (+) calc’d for M+H] = 370.1010, found = 370.1038.Example 42 Ethyl 4-[4-(5-nitrofuran-2-carbonyl)piperazin-1-yl]benzoate O O2NON

[0319] To a 100 mL 5-nitrofuran-2-carboxylicacid (0.323 g, 2.05 mmol), , (0.404 g, 4.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.798 g, 2.10 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature. Ethyl-4-(piperazin-1-yl)benzoate (0.515 g, 2.20 mmol) was dissolved in N,N- dimethylformamide (2.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 22 hours during which time a precipitate formed. Ethyl acetate was added, the solid was filtered and washed with ethyl acetate and hexanes. The crude material was dissolved in 10 % methanol in dichloromethane and filtered through a plug of silica (eluted in 10% methanol in dichloromethane) and concentrated in vacuo to yield the product (0.342 g, 45% yield).

[0320] 1H NMR (500 MHz, dmso-d6) δ 7.82 – 7.73 (m, 3H), 7.33 (d, J = 3.9 Hz, 1H), 7.04 – 6.94 (m, 2H), 4.23 (q, J = 7.1 Hz, 2H), 3.93 – 3.70 (m, 4H), 3.46 (t, J = 5.3 Hz, 4H), 1.28 (t, J = 7.1 Hz, 3H).

[0321] HRMS ESI (+) calc’d for [M+H] = 374.1348, found = 374.1367. Example 43 (5-Nitrofuran-2-yl){4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}methanone

[0322] To a 100 mL roundadded 5-nitrofuran-2-carboxylic acid (0.314 g, 2.00 mmol), N,N-dimethylformamide (1.50 mL), triethylamine (0.404 g, 4.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1.44 g, 3.80 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature.1-[(5-(Trifluoromethyl)pyridine-2-yl] piperazine (0.798 g, 2.30 mmol) was dissolved inN,N-dimethylformamide (2.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 22 hours, diluted with ethyl acetate, transferred to a separatory funnel and washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and filtered through silica with 5 % methanol in dichloromethane. This material was recrystallized from dichloromethane and hexanes to yield the title product (0.572 g, 77% yield).

[0323] 1H NMR (500 MHz, dmso-d6) δ 8.44 (d, J = 2.5 Hz, 1H), 7.84 (dd, J = 9.1, 2.6 Hz, 1H), 7.79 (d, J = 3.8 Hz, 1H), 7.33 (d, J = 3.9 Hz, 1H), 6.99 (d, J = 9.1 Hz, 1H), 3.85 (s, 2H), 3.80 – 3.67 (m, 6H).

[0324] 19F NMR (470 MHz, dmso-d6) δ -59.33, -69.38, -70.89.

[0325] HRMS ESI (+) calc’d for [M+H] = 371.0963, found = 371.0979. Example 44 (5-Nitrofuran-2-yl){4-[5-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl}methanone

[0326] To a 100 mL round added 5-nitrofuran-2-carboxylicacid (0.141 g, 0.900 mmol), N,N-dimethylformamide (0.800 mL), triethylamine (0.202 g, 2.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.380 g, 1.00 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature, 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (0.257 g, 1.10 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at 40oC for 22 hours, during which time a precipitate formed, cooled to room temperature, diluted with ethyl acetate, filtered and washed with ethyl acetate and hexanes. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and recrystallized from dichloromethane and hexanes to yield the title product (0.173 g, 52% yield).

[0327] 1H NMR (500 MHz, dmso-d6) δ 8.76 (s, 2H), 7.80 (d, J = 3.9 Hz, 1H), 7.33 (d, J = 3.9 Hz, 1H), 4.14 – 3.62 (m, 8H).

[0328] 19F NMR (470 MHz, dmso) δ -59.31.

[0329] HRMS ESI (+) calc’d for [M+H] = 372.0916, found = 372.0935.Example 45 (4-{4-[(5-Nitrofuran-2-yl)methyl]piperazin-1-yl}phenyl)(phenyl)methanone

[0330] To a 100 mL (4-piperazin-1-yl)phenylmethanone (0.405 g, 1.50 , , 2-carboxaldehyde (0.282 g, 5.00 mmol) and acetic acid (0.900 g, 15.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (2.11 g, 10.0 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 23 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using 0 – 10% ethyl acetate in hexanes to yield the product (0.093 g, 16%).

[0331] 1H NMR (500 MHz, dmso-d6) δ 7.67 (d, J = 3.7 Hz, 1H), 7.65 – 7.58 (m, 5H), 7.55 – 7.48 (m, 2H), 7.05 – 6.99 (m, 2H), 6.80 (d, J = 3.7 Hz, 1H), 3.72 (s, 2H), 3.38 (t, J = 5.1 Hz, 4H), 2.58 (t, J = 5.1 Hz, 4H).

[0332] HRMS ESI (+) calc’d for [M+H] = 392.1606, found = 392.1619. Example 46 [4-(4-Benzoylphenyl)piperazin-1-yl](5-nitrofuran-2-yl)methanone

[0333] To a 100 mL5-nitrofuran-2-carboxylic acid (0.376 g, 2.40 mmol), N,N-dimethylformamide (2.00 mL), triethylamine (0.808 g, 8.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.893 g, 2.35 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature. Phenyl (4-piperazin-1-yl)phenyl methanone (0.693 g, 2.60 mmol) was dissolved inN,N-dimethylformamide (2.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 19 hours, diluted with ethyl acetate, transferred to a separatory funnel and washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes). This material was recrystallized from dichloromethane and hexanes to yield the title product (0.440 g, 42% yield).

[0334] 1H NMR (500 MHz, dmso-d6) δ 7.79 (d, J = 3.8 Hz, 1H), 7.70 – 7.59 (m, 5H), 7.56 – 7.49 (m, 2H), 7.33 (d, J = 3.9 Hz, 1H), 7.10 – 6.97 (m, 2H), 4.01 – 3.70 (m, 4H), 3.51 (t, J = 5.3 Hz, 4H).

[0335] HRMS ESI (+) calc’d for [M+H] = 406.1399, found = 406.1416. Example 47 4-(5-Nitrofuran-2-carbonyl)-1-(4-nitrophenyl)piperazin-2-one

[0336] To a 100 mL round added 5-nitrofuran-2-carboxylicacid (0.268 g, 1.69 mmol), N,N-dimethylformamide (2.00 mL), triethylamine (0.303 g, 3.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.665 g, 1.75 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature.1-(4-Nitrophenyl )piperazin-2-one (0.398 g, 1.80 mmol) was dissolved in N,N- dimethylformamide (2.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 19 hours, diluted with ethyl acetate, transferred to a separatory funnel and washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the title product (0.191 g, 31% yield).

[0337] 1H NMR (500 MHz, dmso-d6) δ 8.36 – 8.20 (m, 2H), 7.80 (s, 1H), 7.77 – 7.63 (m, 2H), 7.41 (s, 1H), 4.64 (s, 1H), 4.39 (s, 1H), 4.15 (s, 1H), 4.06 – 3.80 (m, 3H).

[0338] HRMS ESI (+) calc’d for [M+H] = 361.0780, found = 361.0796.Example 48 Ethyl 4-{[4-(5-nitrofuran-2-carbonyl)piperazin-1-yl]methyl}benzoate

[0339] To a 100 mL 1-yl methyl)benzoic acid bis hydrochloric acid salt. reaction mixture was heated to 70oC for 22 hours at which time it was concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield the ethyl 4-(piperazin-1-ylmethyl)benzoate (0.254 g, 95 % yield). This material was used without further purification.

[0340] To a 100 mL round bottom flask containing a stir bar was added 5-nitrofuran-2-carboxylic acid (0.113 g, 0.85 mmol), N,N-dimethylformamide (1.00 mL), triethylamine (0.202 g, 2.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.342 g, 0.900 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature. Ethyl 4-[(piperazin-1-yl)methyl]benzoate (0.254 g, 1.01 mmol) was dissolved in N,N- dimethylformamide (1.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 22 hours, diluted with ethyl acetate, transferred to a separatory funnel and washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the title product (0.095 g, 29% yield).

[0341] 1H NMR (500 MHz, cdcl3) δ 8.08 – 7.95 (m, 2H), 7.47 – 7.37 (m, 2H), 7.35 (d, J = 3.7 Hz, 1H), 7.17 (d, J = 3.7 Hz, 1H), 4.39 (q, J = 7.2 Hz, 2H), 3.98 – 3.74 (m, 4H), 3.63 (s, 2H), 2.57 (t, J = 5.0 Hz, 4H), 1.45 – 1.37 (m, 4H).

[0342] HRMS calc’d for ESI (+) = 374.1710, found = 374.1724.Example 49 (5-Nitrofuran-2-yl){4-[4-(trimethylsilyl)phenyl-2-yl]piperazin-1-yl}methanone

[0343] To a 100 mL round added 5-nitrofuran-2-carboxylicacid (0.157 g, 1.00 mmol), N,N- , (0.202 g, 2.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.399 g, 1.05 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature.1-[4-(Trimethylsilyl)phenyl]piperazine (0.259 g, 1.10 mmol) was dissolved in N,N- dimethylformamide (2.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 20 hours, diluted with ethyl acetate, transferred to a separatory funnel and washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography with 0 – 100 % ethyl acetate in hexanes and additionally purified by silica gel chromatography using 0 – 10% methanol in dichloromethane to yield the title product (0.189 g, 51% yield).

[0344] 1H NMR (500 MHz, dmso-d6) δ 7.78 (d, J = 3.9 Hz, 1H), 7.39 – 7.33 (m, 2H), 7.31 (d, J = 3.9 Hz, 1H), 6.99 – 6.76 (m, 2H), 3.91 – 3.69 (m, 4H), 3.24 (dt, J = 14.6, 5.3 Hz, 4H), 0.19 (s, 9H).

[0345] HRMS ESI (+) calc’d for [M+H] = 374.1532, found = 374.1550. Example 50 (1-Methyl-4-nitro-1H-pyrrol-2-yl){4-[4-(trifluoromethyl)phenyl]piperazin-1-yl}methanone

[0346] carboxylic acid (0.235 g, 1.38 mmol), N,N-dimethylformamide (1.00 mL), triethylamine (0.202 g, 2.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.551 g, 1.45 mmol). The reaction vessel was sealed with a septum, flushed withargon, and stirred at room temperature.4-(Trifluoromethyl)phenyl piperazine (0.356 g, 1.55 mmol) was dissolved in N,N-dimethylformamide (2.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 20 hours, diluted with ethyl acetate, transferred to a separatory funnel and washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo to a solid which was filtered and washed with ethyl acetate, dichloromethane, and hexanes to yield the pure product (0.349 g, 66% yield).

[0347] 1H NMR (500 MHz, dmso-d6) δ 8.15 (d, J = 1.9 Hz, 1H), 7.53 (d, J = 8.7 Hz, 2H), 7.07 (d, J = 8.7 Hz, 2H), 7.00 (d, J = 2.0 Hz, 1H), 3.74 (d, J = 3.1 Hz, 7H), 3.38 (t, J = 5.3 Hz, 4H).

[0348] 19F NMR (470 MHz, dmso-d6) δ -59.46.

[0349] HRMS ESI (+) calc’d for [M+H] = 383.1327, found = 383.1348. Example 51 (1-Methyl-4-nitro-1H-pyrazol-3-yl){4-[4-(trifluoromethyl)phenyl]piperazin-1-yl}methanone

[0350] To a 100 mL roundadded 1-methyl-4-nitro-1H- pyrazole-3-carboxylic acid (0.182 g, 1.06 mmol), N,N-dimethylformamide (1.00 mL), triethylamine (0.202 g, 2.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.418 g, 1.10 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature.4-(Trifluoromethyl)phenyl piperazine (0.276 g, 1.20 mmol) was dissolved in N,N-dimethylformamide (2.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 20 hours, diluted with ethyl acetate, transferred to a separatory funnel and washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the product (0.229 g, 56%).

[0351] 1H NMR (500 MHz, cdcl3) δ 8.18 (s, 1H), 7.55 – 7.43 (m, 2H), 6.94 (d, J = 8.6 Hz, 2H), 4.03 – 3.94 (m, 5H), 3.50 (dd, J = 6.3, 4.1 Hz, 2H), 3.45 – 3.37 (m, 2H), 3.29 – 3.23 (m, 2H).

[0352] 19F NMR (470 MHz, cdcl3) δ -61.52.

[0353] HRMS ESI (+) calc’d for [M+H] = 384.1279, found = 384.1298.Example 52 (5-Nitrofuran-2-yl){4-[4-(trifluoromethyl)pyrimidin-2-yl]piperazin-1-yl}methanone

[0354] To a 100 mL round added 5-nitrofuran-2 carboxylic acid (0.268 g, 1.70 mmol), N,N-, (0.303 g, 3.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.684 g, 1.80 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature.2-(Piperiain-1-yl)-4-(trifluoromethyl)pyrimidine (0.441 g, 1.90 mmol) was dissolved in N,N-dimethylformamide (2.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 20 hours during which a solid precipitated. The reaction mixture was diluted with ethyl acetate, filtered and washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the product (0.585 g, 93% yield).

[0355] 1H NMR (500 MHz, dmso-d6) δ 8.73 (d, J = 4.8 Hz, 1H), 7.80 (d, J = 3.9 Hz, 1H), 7.32 (d, J = 3.9 Hz, 1H), 7.09 (d, J = 4.8 Hz, 1H), 3.92 – 3.71 (m, 8H).

[0356] 19F NMR (470 MHz, dmso-d6) δ -69.45.

[0357] HRMS ESI (+) calc’d for [M+H] = 372.0915, found = 372.0932. Example 53 1-[(5-Nitrofuran-2-yl)methyl]-4-[5-(trifluoromethyl)pyridin-2-yl]piperazine

[0358] To a 100 mL round[5-(trifluoromethyl)pyridine-2- yl]piperazine (0.342 g, 1.47 mmol), dichloromethane (20.0 mL), 5-nitrofuran-2-carboxaldehyde (0.352 g, 2.50 mmol) and acetic acid (0.605 g, 10.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (1.69 g, 8.00 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 20 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel,partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography using 0 – 100% ethyl acetate in hexanes to yield the product (0.195 g, 37%).

[0359] 1H NMR (500 MHz, dmso-d6) δ 8.39 (dt, J = 2.0, 1.0 Hz, 1H), 7.78 (dd, J = 9.2, 2.6 Hz, 1H), 7.66 (d, J = 3.7 Hz, 1H), 6.95 (d, J = 9.1 Hz, 1H), 6.79 (d, J = 3.7 Hz, 1H), 3.70 (s, 2H), 3.63 (t, J = 5.1 Hz, 4H), 2.53 (t, J = 5.1 Hz, 4H).

[0360] 19F NMR (470 MHz, dmso) δ -59.31.

[0361] HRMS ESI (+) calc’d for [M+H] = 357.1170, found = 357.1195. Example 54 3-Nitro-5-{4-[4-(trifluoromethyl)phenyl]piperazin-1-yl}pyrazolo[1,5-a]pyrimidine

[0362] To a 100 mL round 3-nitropyrazol[1,5]pyrimidine(1.02 g, 5.00 mmol), n-butanol (25.0 mL), and triethylamine (1.01 g, 10.0 mmol). The reaction mixture was stirred and heated to 50oC. In a vial 1-(4-trifluoromethyl)phenyl piperazine (1.15 g, 6.00 g) was dissolved in n-butanol (5.00 mL) and added to the heated solution by syringe. The reaction mixture was stirred at 50oC for 2 hours, during which time a precipitate formed. The precipitate was filtered, washed with n-butanol, hexanes, and dried in vacuo to yield the pure product (1.79 g, 91% yield).

[0363] 1H NMR (500 MHz, dmso-d6) δ 8.85 (dd, J = 7.9, 0.9 Hz, 1H), 8.63 (d, J = 0.8 Hz, 1H), 7.54 (d, J = 8.7 Hz, 2H), 7.12 (d, J = 8.6 Hz, 2H), 7.06 (d, J = 8.0 Hz, 1H), 4.00 (s, 4H), 3.49 (t, J = 5.3 Hz, 4H).

[0364] 19F NMR (470 MHz, dmso-d6) δ -59.42.

[0365] HRMS ESI (+) calc’d for [M+H] = 393.1283, found = 393.1297.Example 55 (1-Methyl-4-nitro-1H-pyrazol-5-yl){4-[4-(trifluoromethyl)phenyl]piperazin-1-yl}methanone

[0366] To a 100 mL round was added 1-methyl-4-nitro-1H- pyrazole-5-carboxylic acid (0.268 g,, (2.00 mL), triethylamine (0.303 g, 3.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.684 g, 1.80 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature.4-(Trifluoromethyl)phenyl piperazine (0.441 g, 1.90 mmol) was dissolved in N,N-dimethylformamide (2.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 20 hours during which a solid precipitated. The reaction mixture was diluted with ethyl acetate, filtered and washed with saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the product (0.332 g, 51% yield).

[0367] 1H NMR (500 MHz, cdcl3) δ 8.09 (s, 1H), 7.62 – 7.38 (m, 2H), 7.11 – 6.85 (m, 2H), 4.10 (ddd, J = 13.2, 6.7, 3.5 Hz, 1H), 3.96 (ddd, J = 13.2, 7.2, 3.6 Hz, 1H), 3.91 (s, 3H), 3.54 – 3.32 (m, 5H), 3.23 – 3.15 (m, 1H).

[0368] 19F NMR (470 MHz, cdcl3) δ -61.63.

[0369] HRMS ESI (+) calc’d for [M+H] = 384.1279, found = 384.1299. Example 56 N,N-Dimethyl-4-[4-(5-nitrofuran-2-carbonyl)piperazin-1-yl]benzamide

[0370] To a 100 mL roundadded 5-nitrofuran-2 carboxylic acid (0.141 g, 0.900 mmol), N,N-dimethylformamide (2.00 mL), triethylamine (0.303 g, 3.00 mmol) and1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.361 g, 0.950 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature. N,N-dimethyl-4-(1-piperazinyl) benzamide bis-hydrochloric acid salt (0.306 g, 1.0 mmol) was dissolved in N,N-dimethylformamide (2.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 20 hours, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (0 – 10% methanol in dichloromethane) to yield the product (0.100 g, 30% yield).

[0371] 1H NMR (500 MHz, cdcl3) δ 7.45 – 7.35 (m, 3H), 7.25 (d, J = 3.8 Hz, 1H), 6.97 – 6.88 (m, 2H), 4.15 – 3.89 (m, 4H), 3.37 (t, J = 5.3 Hz, 4H), 3.07 (s, 6H).

[0372] HRMS ESI (+) calc’d for [M+H] = 373.1508, found = 373.1528. Example 57 N,N-Dimethyl-4-{4-[(5-nitrofuran-2-yl)methyl]piperazin-1-yl}benzamide

[0373] To a 100 mL round dimethyl-4-(1-piperazinyl)benzamide bis-hydrochloric acid salt (0.273 g, 0.890 mmol), n-butanol (4.00 mL), and triethylamine (0.707 g, 7.00 mmol). The reaction mixture was stirred and heated to 50oC and 2-(bromomethyl)-5- nitrofuran (0.263 g, 1.27 mmol, as a solution in 2.00 mL n-butanol) was added via syringe. The reaction mixture was stirred at 50oC for 2 hours, at which time it was cooled to room temperature, washed with saturated aqueous sodium bicarbonate, water, and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the pure product (0.116 g, 36% yield).

[0374] 1H NMR (500 MHz, cdcl3) δ 7.41 – 7.36 (m, 2H), 7.30 (d, J = 3.6 Hz, 1H), 6.92 – 6.83 (m, 2H), 6.52 (d, J = 3.6 Hz, 1H), 3.71 (s, 2H), 3.28 (dd, J = 6.2, 3.8 Hz, 4H), 3.06 (s, 6H), 2.74 – 2.65 (m, 4H).

[0375] HRMS ESI (+) calc’d for [M+H] = 359.1715, found = 359.1739.Example 58 1-(4-Trimethylsilyl)-4-[(5-nitrofuran-2-yl)methyl]piperazine

[0376] To a 100 mL round [4-(trimethylsilyl)phenyl]piperazine (0.255 g, 1.08 mmol),, (0.300 g, 2.12 mmol) and acetic acid (0.909 g, 15.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (2.11 g, 10.0 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 22 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the product as the monohydrate (0.248 g, 61 % yield).

[0377] 1H NMR (500 MHz, cdcl3) δ 7.43 (d, J = 8.1 Hz, 1H), 7.34 – 7.27 (m, 2H), 6.92 (t, J = 8.8 Hz, 2H), 6.62 – 6.45 (m, 1H), 4.73 (s, 1H), 3.72 (s, 2H), 3.26 (s, 4H), 2.72 (s, 4H), 1.58 (s, 1H), 0.24 (s, 9H).

[0378] HRMS ESI (+) calc’d for [M+H] = 360.1739, found = 360.1760. Example 59 2-{4-[(5-Nitrofuran-2-yl)methyl]piperazin-1-yl}-4-(trifluoromethyl)pyrimidine

[0379] To a 100 mL round1-yl)-4- (trifluoromethyl)pyrimidine (0.599 g, 2.50 mmol), dichloromethane (20.0 mL), 5-nitrofuran-2- carboxaldehyde (0.634 g, 4.50 mmol) and acetic acid (1.20 g, 20.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (2.11 g, 10.0 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 22 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organiclayers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes; the product eluted in 1:9 methanol: ethyl acetate) to yield the product as the monohydrate (0.172 g, 18% yield).

[0380] 1H NMR (500 MHz, cdcl3) δ 8.48 (d, J = 4.8 Hz, 1H), 7.30 (dd, J = 3.7, 2.1 Hz, 2H), 6.76 (d, J = 4.8 Hz, 1H), 6.56 (dd, J = 3.6, 0.8 Hz, 1H), 6.52 (d, J = 3.6 Hz, 1H), 4.73 (s, 2H), 3.96 – 3.86 (m, 4H), 3.71 (s, 2H), 2.65 – 2.57 (m, 4H).19F NMR (470 MHz, cdcl3) δ -70.85.

[0381] HRMS ESI (+) calc’d for [M+H] =358.1123. found = 358.1144. Example 60 [5-(4-Nitrophenyl)furan-2-yl]{4-[4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazin-1- yl}methanone

[0382] To a 100 mL round 5-nitrofuran-2 carboxylicacid (0.314 g, 2.00 mmol), N,N-dimethylformamide (2.00 mL), triethylamine (0.303 g, 3.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.779 g, 2.05 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature.1-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl piperazine (0.605 g, 2.10 mmol) was dissolved in N,N-dimethylformamide (2.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 20 hours, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography with 0 – 100 % ethyl acetate in hexanes and further purified by silica gel chromatography in 0 – 10% methanol in dichloromethane to yield the product (0.161 g, 19% yield).

[0383] 1H NMR (500 MHz, cdcl3) δ 7.80 – 7.71 (m, 2H), 7.37 (d, J = 3.8 Hz, 1H), 7.24 (d, J = 3.8 Hz, 1H), 6.98 – 6.87 (m, 2H), 4.16 – 3.86 (m, 4H), 3.39 (t, J = 5.2 Hz, 4H), 1.34 (s, 12H).

[0384] HRMS ESI (+) calc’d for [M+H] = 428.1989, found = 428.2003.Example 61 1-{4-[4-(5-Nitrofuran-2-carbonyl)piperazin-1-yl]phenyl}ethan-1-one

[0385] To a 100 mL round added 5-nitrofuran-2 carboxylicacid (0.315 g, 2.00 mmol), N,N- , (0.303 g, 3.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.779 g, 2.05 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature.1-[4-(acetylphenyl) piperazine (0.605 g, 2.10 mmol) was dissolved in N,N- dimethylformamide (2.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 20 hours, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and filtered through a plug of silica gel (eluting with neat ethyl acetate). The filtrate was concentrated in vacuo to a minimum volume and hexanes were added to precipitate the product, which was filtered, washed with hexanes and dried to give the pure product (0.189 g, 28% yield).

[0386] 1H NMR (500 MHz, cdcl3) δ 8.01 – 7.85 (m, 2H), 7.38 (dd, J = 3.8, 0.8 Hz, 1H), 7.27 (d, J = 2.2 Hz, 1H), 7.00 – 6.84 (m, 2H), 4.20 – 3.86 (m, 4H), 3.50 (t, J = 5.4 Hz, 4H), 2.55 (d, J = 0.9 Hz, 3H).

[0387] HRMS ESI (+) calc’d for [M+H] = 344.1242, found = 344.1262. Example 62 1-(4-{4-[(5-Nitrofuran-2-yl)methyl]piperazin-1-yl}phenyl)ethan-1-one

[0388] To a 100 mL roundnitrofuran-2-carboxaldehyde (0.705 g, 5.00 mmol), dichloromethane (25.0 mL), 1-(4-Acetylphenyl)piperazine (0.291 g, 2.80 mmol) and acetic acid (1.20 g, 20.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (2.53 g, 12.0 mmol) was added as a solid. The reaction vessel wassealed with a septum, flushed with argon, stirred for 24 hours at room temperature, quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes) to yield the title product (0.333 g, 36% yield).

[0389] 1H NMR (500 MHz, cdcl3) δ 7.97 – 7.74 (m, 2H), 7.30 (d, J = 3.6 Hz, 1H), 6.90 – 6.79 (m, 2H), 6.52 (d, J = 3.6 Hz, 1H), 3.71 (s, 2H), 3.43 – 3.32 (m, 4H), 2.73 – 2.65 (m, 4H), 2.53 (d, J = 0.9 Hz, 3H).

[0390] HRMS ESI (+) calc’d for [M+H] = 330.1450, found = 330.1472. Example 63 1-[3,5-Bis(trifluoromethyl)phenyl]-4-[(5-nitrofuran-2-yl)methyl]piperazine

[0391] To a 100 mL round 2-carboxaldehyde (0.423g, 3.00 mmol), dichloromethane (20.0 mL), 3,5-di(trifluoromethyl)phenyl piperazine (0.396 g, 1.30 mmol) and acetic acid (0.600 g, 10.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (1.69 g, 8.00 mmol) was added as a solid. The reaction vessel was sealed with a septum, flushed with argon, stirred for 24 hours at room temperature, quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the title product (0.355 g, 65% yield).

[0392] 1H NMR (500 MHz, cdcl3) δ 7.30 (dd, J = 6.5, 2.5 Hz, 2H), 7.23 (s, 2H), 6.59 – 6.46 (m, 1H), 3.73 (s, 2H), 3.36 – 3.29 (m, 4H), 2.76 – 2.66 (m, 4H).

[0393] 19F NMR (470 MHz, cdcl3) δ -63.06.

[0394] HRMS ESI (+) calc’d for [M+H] = 424.1092, found = 424.1120.Example 64 tert-Butyl-4-[5-(4-nitrophenyl)furan-2-carbonyl]piperazine-1-carboxylate

[0395] A 100 mL round 5-(4-nitrophenyl)furan-2 carboxylic acid (0.541 g, 2.30, , triethylamine (0.303 g, 3.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.912 g, 2.40 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature. N-boc piperazine (0.465 g, 2.50 mmol) was dissolved in N,N- dimethylformamide (2.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 22 hours, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the title product (0.552 g, 59% yield).

[0396] 1H NMR (500 MHz, cdcl3) δ 8.33 – 8.26 (m, 2H), 7.85 – 7.80 (m, 2H), 7.13 (d, J = 3.7 Hz, 1H), 6.95 (d, J = 3.6 Hz, 1H), 3.84 (s, 4H), 3.57 (t, J = 5.3 Hz, 4H), 1.50 (s, 9H).

[0397] HRMS ESI (+) calc’d for [M+H-Boc] = 302.1135, found = 302.1161. Example 65 [5-(4-Nitrophenyl)furan-2-yl]{4-[4-(trifluoromethyl)phenyl]piperazin-1-yl}methanone

[0398] To a 100 mL5-(4-nitrophenyl)furan-2 carboxylic acid (0.500 g, 2.29 mmol), N,N-dimethylformamide (3.60 mL), triethylamine (0.303 g, 3.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.912 g, 2.40 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature.4-(Trifluoromethyl)phenyl piperazine (0.575 g, 2.50 mmol) was dissolved in N,N-dimethylformamide (2.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 22 hours, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate,filtered, concentrated in vacuo and purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the title product (0.675 g, 64% yield).

[0399] 1H NMR (500 MHz, cdcl3) δ 8.34 – 8.25 (m, 2H), 7.91 – 7.80 (m, 2H), 7.53 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 3.6 Hz, 1H), 7.03 – 6.92 (m, 3H), 4.05 (s, 4H), 3.46 – 3.38 (m, 4H).19F NMR (470 MHz, cdcl3) δ -61.50.

[0400] HRMS ESI (+) calc’d for [M+H] = 446.1323, found = 446.1338. Example 66 1-[2-Fluoro-4-(trifluoromethyl)phenyl]-4-[(5-nitrofuran-2-yl)methyl]piperazine

[0401] To a 100 mL round nitrofuran-2-carboxaldehyde (0.632g, 4.48 mmol), dichloromethane (20.0 mL), 1-(2-fluoro)-4-(trifluoromethylphenyl) piperazine (0.499 g, 2.00 mmol) and acetic acid (0.900 g, 15.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (2.11 g, 10.0 mmol) was added as a solid. The reaction vessel was sealed with a septum, flushed with argon, stirred for 20 hours at room temperature, quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography using 0 – 100 % ethyl acetate in hexanes then additionally using 0 – 10% methanol in dichloromethane to yield the title product (0.611 g, 82% yield).

[0402] 1H NMR (500 MHz, cdcl3) δ 7.35 – 7.28 (m, 2H), 6.97 (t, J = 8.5 Hz, 1H), 6.52 (d, J = 3.6 Hz, 1H), 3.72 (s, 2H), 3.23 – 3.16 (m, 4H), 2.76 – 2.69 (m, 4H).

[0403] 19F NMR (470 MHz, cdcl3) δ -61.85, -61.87, -120.26 (dd, J = 12.7, 8.4 Hz).

[0404] HRMS ESI (+) calc’d for [M+H] = 374.1124, found = 374.1144.Example 67 {4-[2-Fluoro-4-(trifluoromethyl)phenyl]piperazin-1-yl}(5-nitrofuran-2-yl)methanone

[0405] To a 100 mL round added 5-nitrofuran-2 carboxylicacid (0.259 g, 1.65 mmol), N,N- , (0.303 g, 3.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.646 g, 1.70 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature.1-(2-Fluoro)-4-(trifluoromethylphenyl) piperazine (0.440 g, 1.70 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 22 hours, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the title product (0.412 g, 65% yield).

[0406] 1H NMR (500 MHz, cdcl3) δ 7.42 – 7.30 (m, 3H), 7.25 (d, J = 3.8 Hz, 1H), 7.01 (t, J = 8.4 Hz, 1H), 4.16 – 3.84 (m, 4H), 3.28 (s, 4H).

[0407] 19F NMR (470 MHz, cdcl3) δ -62.00, -120.30 (dd, J = 12.5, 8.3 Hz).

[0408] HRMS ESI (+) calc’d for [M+H] =388.0916, found = 388.0934. Example 68 (5-Nitrofuran-2-yl)[4-(4-nitrophenyl)piperazin-1-yl]methanone

[0409] To a 100 mL roundadded 5-nitrofuran-2 carboxylic acid (0.259 g, 1.65 mmol), N,N-dimethylformamide (2.00 mL), triethylamine (0.303 g, 3.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.779 g, 2.05 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature.1-(4-Nitrophenyl) piperazine (0.445 g, 2.15 mmol) was dissolved in N,N-dimethylformamide (2.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 22 hours, during which time a solid precipitated. Ethyl acetate was added to the reaction mixture and the solid was filtered, washed with ethyl acetate and hexanes. The solid was dried in vacuo to yield the title product (0.517 g, 75% yield).

[0410] 1H NMR (500 MHz, dmso-d6) δ 8.13 – 8.03 (m, 2H), 7.79 (d, J = 3.9 Hz, 1H), 7.34 (d, J = 3.9 Hz, 1H), 7.07 – 6.99 (m, 2H), 3.85 (d, J = 70.7 Hz, 4H), 3.62 (dd, J = 6.8, 4.1 Hz, 4H).

[0411] HRMS ESI (+) calc’d for [M+H] = 347.0987, found = 347.1008. Example 69 1-[4-Chloro-3-(trifluoromethyl)phenyl]-4-[(5-nitrofuran-2-yl)methyl]piperazine

[0412] To a 100 mL round 2-carboxaldehyde (0.705g, 5.00 mmol), dichloromethane (20.0 mL), 1-(4-chloro-3-trifluoromethyl)phenyl piperazine (0.783 g, 2.96 mmol) and acetic acid (0.900 g, 15.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (2.54 g, 12.0 mmol) was added as a solid. The reaction vessel was sealed with a septum, flushed with argon, stirred for 20 hours at room temperature, quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography using 0 – 100% ethyl acetate in hexanes then additionally using 0 – 10% methanol in dichloromethane to yield the title product (0.367 g, 32% yield).

[0413] 1H NMR (500 MHz, cdcl3) δ 7.34 (d, J = 8.9 Hz, 1H), 7.30 (d, J = 3.6 Hz, 1H), 7.16 (d, J = 3.0 Hz, 1H), 6.95 (dd, J = 8.9, 3.0 Hz, 1H), 6.52 (d, J = 3.6 Hz, 1H), 3.71 (s, 2H), 3.30 – 3.19 (m, 4H), 2.75 – 2.67 (m, 4H).

[0414] 19F NMR (470 MHz, cdcl3) δ -62.73.

[0415] HRMS ESI (+) calc’d for [M+H] = 390.0828, found = 390.0844.Example 70 {4-[4-Chloro-3-(trifluoromethyl)phenyl]piperazin-1-yl}(5-nitrofuran-2-yl)methanone

[0416] To a 100 mL round added 5-nitrofuran-2 carboxylicacid (0.219 g, 1.40 mmol), N,N- , (0.303 g, 3.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.551 g, 1.45 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature.1-(4-Chloro-3-trifluoromethyl)phenyl piperazine (0.393 g, 1.48 mmol) was dissolved in N,N-dimethylformamide (2.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 22 hours, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the title product (0.552 g, 98% yield).

[0417] 1H NMR (500 MHz, cdcl3) δ 7.43 – 7.36 (m, 2H), 7.26 (d, J = 3.7 Hz, 1H), 7.21 (d, J = 3.0 Hz, 1H), 7.01 (dd, J = 8.9, 3.0 Hz, 1H), 4.19 – 3.85 (m, 4H), 3.34 (t, J = 5.3 Hz, 4H).

[0418] 19F NMR (470 MHz, cdcl3) δ -62.77.

[0419] HRMS ESI (+) calc’d for [M+H] = 404.0621, found = 404.0642. Example 71 (5-Nitrofuran-2-yl)[4-(pyridin-3-yl)piperazin-1-yl]methanone

[0420] To a 100 mL roundadded 5-nitrofuran-2 carboxylic acid (0.549 g, 3.80 mmol), N,N-dimethylformamide (4.00 mL), triethylamine (0.606 g, 6.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (1.50 g, 3.60 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature.1-(Pyrid-3-yl) piperazine (0.623 g, 3.80 mmol) was dissolved in N,N-dimethylformamide(4.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 20 hours, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the title product (0.437 g, 38% yield).

[0421] 1H NMR (500 MHz, dmso-d6) δ 8.33 (d, J = 3.0 Hz, 1H), 8.03 (dd, J = 4.5, 1.3 Hz, 1H), 7.78 (d, J = 3.9 Hz, 1H), 7.36 (ddd, J = 8.5, 3.0, 1.3 Hz, 1H), 7.32 (d, J = 3.8 Hz, 1H), 7.24 (dd, J = 8.5, 4.6 Hz, 1H), 3.94 – 3.72 (m, 4H), 3.31 – 3.28 (m, 4H).

[0422] HRMS ESI (+) calc’d for [M+H] = 303.1089, found = 303.1118. Example 72 1-[4-(Methanesulfonyl)phenyl]-4-[(5-nitrofuran-2-yl)methyl]piperazine

[0423] To a 100 mL round added 1-(4-methylsulfonyl)phenylpiperazine, n-butanol (2.50 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction mixture was heated to 50oC and 5-bromomethyl-2-nitrofuran (0.406 g, 2.00 mmol, dissolved in 3.00 mL n-butanol) was added via syringe. The reaction mixture was stirred for 30 minutes at 50oC during which time a solid precipitated. The solid was filtered, washed with n-butanol and hexanes and dried to yield the title product (0.311 g, 47% yield).

[0424] 1H NMR (500 MHz, dmso-d6) δ 7.69 – 7.62 (m, 3H), 7.09 – 7.03 (m, 2H), 6.80 (d, J = 3.7 Hz, 1H), 3.71 (s, 2H), 3.34 (t, J = 5.0 Hz, 4H), 3.07 (s, 3H), 2.57 (t, J = 5.0 Hz, 4H).

[0425] HRMS ESI (+) calc’d for [M+H] = 366.1119, found = 366.1140.Example 73 {4-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}(5-nitrofuran-2-yl)methanone

[0426] To a 100 mL round added 5-nitrofuran-2 carboxylicacid (0.219 g, 1.40 mmol), N,N- , (0.303 g, 3.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.551 g, 1.45 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature.1-[3-(Chloro)-5-(trifluoromethyl)pyrid-2-yl] piperazine (0.400 g, 1.50 mmol) was dissolved in N,N-dimethylformamide (2.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 24 hours, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the title product (0.358 g, 62% yield).

[0427] 1H NMR (500 MHz, cdcl3) δ 8.43 (dq, J = 1.8, 0.9 Hz, 1H), 7.82 (d, J = 2.1 Hz, 1H), 7.38 (d, J = 3.8 Hz, 1H), 7.24 (d, J = 3.8 Hz, 1H), 4.00 (br d, 4H), 3.68 – 3.58 (m, 4H).

[0428] 19F NMR (470 MHz, cdcl3) δ -61.55.

[0429] HRMS ESI (+) calc’d for [M+H] = 405.0573, found = 405.0590. Example 74 1-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-4-[(5-nitrofuran-2-yl)methyl]piperazine

[0430] To a 100 mL round[3-(chloro)-5-(trifluoromethyl)pyrid- 2-yl] piperazine (0.635 g, 2.39 mmol), n-butanol (5.00 mL), triethylamine (0.606 g, 6.00 mmol). The reaction mixture was stirred, heated to 50oC, and 5-bromomethyl-2-nitrofuran (0.500 g, 2.50 mmol, as a solution dissolved in 3.00 mL n-butanol) was added. The reaction mixture was stirred at 50oC for 1 hour during which time a precipitate formed. The solid was filtered, washed with n-butanol and hexanes andpurified by silica gel chromatography using 0 – 100% ethyl acetate. Fractions containing product were combined and concentrated in vacuo to yield the title product (0.195 g, 21% yield).

[0431] 1H NMR (500 MHz, cdcl3) δ 8.39 (dt, J = 1.9, 0.9 Hz, 1H), 7.75 (d, J = 2.2 Hz, 1H), 7.30 (d, J = 3.6 Hz, 1H), 6.52 (d, J = 3.6 Hz, 1H), 3.72 (s, 2H), 3.61 – 3.48 (m, 4H), 2.70 (t, J = 4.9 Hz, 4H).

[0432] 19F NMR (470 MHz, cdcl3) δ -61.47.

[0433] HRMS ESI (+) calc’d for [M+H] = 391.0781, found = 391.0804. Example 75 (5-Nitrofuran-2-yl){4-[6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-yl}methanone

[0434] To a 100 mL round added 5-nitrofuran-2 carboxylicacid (0.180 g, 1.15 mmol), N,N-dimethylformamide (2.00 mL), triethylamine (0.303 g, 3.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.456 g, 1.20 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature.4-(1-Piperazinyl)-6-trifluoromethyl pyrimidine (0.293 g, 1.26 mmol) was dissolved in N,N-dimethylformamide (1.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 24 hours, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered and hexanes was added to cause a product to precipitate. This material was isolated by filtration and dried in vacuo to yield the pure product (0.269 g, 48% yield).

[0435] 1H NMR (500 MHz, dmso-d6) δ 8.67 (s, 1H), 7.79 (dd, J = 3.9, 0.8 Hz, 1H), 7.37 – 7.28 (m, 2H), 3.81 (d, J = 61.1 Hz, 8H).

[0436] 19F NMR (470 MHz, dmso-d6) δ -69.03.

[0437] HRMS ESI (+) calc’d for [M+H] = 372.0915, found = 372.0935.Example 76 (5-Nitrofuran-2-yl)[4-(pyridin-2-yl)piperazin-1-yl]methanone

[0438] To a 100 mL round was added 5-nitrofuran-2 carboxylicacid (0.314 g, 2.00 mmol), N,N- , (0.404 g, 4.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.798 g, 2.10 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature.1-(Pyrid-2-yl) piperazine (0.359 g, 2.20 mmol) was dissolved in N,N- dimethylformamide (2.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 20 hours, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) to yield the title product (0.341 g, 56% yield).

[0439] 1H NMR (500 MHz, dmso-d6) δ 8.13 (ddd, J = 4.9, 2.0, 0.9 Hz, 1H), 7.78 (dd, J = 3.9, 0.8 Hz, 1H), 7.61 – 7.51 (m, 1H), 7.31 (dd, J = 3.8, 0.8 Hz, 1H), 6.86 (dd, J = 8.7, 0.9 Hz, 1H), 6.72 – 6.64 (m, 1H), 3.77 (d, J = 41.9 Hz, 4H), 3.60 (dd, J = 6.7, 3.8 Hz, 4H).

[0440] HRMS ESI (+) calc’d for [M+H] = 303.1089, found = 303.1121. Example 77 (5-Nitrofuran-2-yl)[4-(pyridin-4-yl)piperazin-1-yl]methanone

[0441] To a 100 mL roundadded 5-nitrofuran-2 carboxylic acid (0.314 g, 2.00 mmol), N,N-dimethylformamide (1.50 mL), triethylamine (0.404 g, 4.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.798 g, 2.10 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature.1-(pyrid-2-yl) piperazine (0.359 g, 2.20 mmol) was dissolved in N,N- dimethylformamide (2.00 mL) and added to the first solution via syringe. The reaction mixture wasstirred at room temperature for 20 hours, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes to 1:9 methanol: ethyl acetate) to yield the title product (0.127 g, 21% yield).

[0442] 1H NMR (500 MHz, dmso-d6) δ 8.21 – 8.14 (m, 2H), 7.79 (d, J = 3.9 Hz, 1H), 7.33 (d, J = 3.9 Hz, 1H), 6.88 – 6.80 (m, 2H), 3.80 (d, J = 55.5 Hz, 4H), 3.46 (dd, J = 6.5, 4.1 Hz, 4H).

[0443] HRMS ESI (+) calc’d for [M+H] = 303.1089, found = 303.1125. Example 78 tert-Butyl 4-[(5-nitrofuran-2-yl)amino]piperazine-1-carboxylate

[0444] To a 100 mL round was added tert butyl 4-aminopipierazine-1-carboxylate g, , n- mL), and triethylamine (1.01 g, 10.0 mmol). The reaction mixture was heated to 50oC and 5-bromomethyl-2-nitrofuran (1.15 g, 6.00 mmol, dissolved in 4.00 mL n-butanol) was added via syringe. The reaction mixture was stirred for 22 minutes at 50oC after which it was cooled to room temperature and purified by reverse phase medium pressure liquid chromatography (0 – 100% methanol in 25 mM aqueous ammonium formate). Fractions containing product were combined, concentrated in vacuo, partitioned with ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to yield the product, which was additionally purified by silica gel chromatography 0 – 10% methanol in dichloromethane (0.212 g, 14% yield).

[0445] 1H NMR (500 MHz, cdcl3) δ 7.47 (d, J = 4.1 Hz, 1H), 5.39 (d, J = 4.2 Hz, 1H), 3.58 (t, J = 5.2 Hz, 4H), 3.45 (dd, J = 6.5, 4.0 Hz, 4H), 1.49 (s, 9H).

[0446] HRMS ESI (-) calc’d for [M-H] = 311.1360, found = 311.1375.Example 79 4-[4-(5-Nitrofuran-2-carbonyl)piperazin-1-yl]benzaldehyde O O2N O N O

[0447] To a 100 mL round added 5-nitrofuran-2 carboxylicacid (0.243 g, 1.55 mmol), N,N- , (0.404 g, 4.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.608 g, 1.60 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature.4-piperazin-1-yl benzaldehyde (0.325 g, 1.70 mmol) was dissolved in N,N- dimethylformamide (1.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 20 hours, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes). Fractions containing product were combined and concentrated in vacuo. This material was further purified by triturating the product from dichloromethane and hexanes and was isolated by filtration. The title product was obtained by purifying the triturated material with silica gel chromatography with 0 – 10 % methanol in dichloromethane (0.087 g, 18% yield).

[0448] 1H NMR (500 MHz, dmso-d6) δ 9.73 (s, 1H), 7.84 – 7.68 (m, 3H), 7.33 (d, J = 3.9 Hz, 1H), 7.10 – 6.97 (m, 2H), 3.83 (d, J = 61.3 Hz, 4H), 3.55 (dd, J = 6.5, 3.9 Hz, 4H).

[0449] ESI (+) calc’d for [M+H] = 330.1086, found = 330.1107. Example 80 tert-Butyl 5-[(5-nitrofuran-2-yl)methyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0450] To a 100 mL roundwas added 2-boc-2,5- diazabicyclo[2.2.1]heptane (0.934 g, 4.71 mmol), n-butanol (6.00 mL), and triethylamine (0.707 g, 7.00 mmol). The reaction mixture was heated to 50oC and 5-bromomethyl-2-nitrofuran (0.899 g, 4.36 mmol, dissolved in 5.00 mL n-butanol) was added via syringe. The reaction mixture was stirred for 19 hours at 50oC at which time it was purified by reverse phase medium pressure liquid chromatography (0 – 100% methanol in 25 mM aqueous ammonium formate). Fractions containing product were combined,concentrated in vacuo, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to yield the title product (0.630 g, 4% yield).

[0451] 1H NMR (500 MHz, cdcl3) δ 7.28 (d, J = 3.5 Hz, 1H), 6.54 – 6.38 (m, 1H), 4.35 (d, J = 63.7 Hz, 1H), 3.87 – 3.76 (m, 2H), 3.51 (dd, J = 37.7, 6.9 Hz, 2H), 3.23 (t, J = 10.7 Hz, 1H), 3.03 – 2.90 (m, 1H), 2.71 (dd, J = 69.1, 9.6 Hz, 1H), 1.84 (t, J = 10.1 Hz, 1H), 1.75 (dd, J = 20.7, 9.9 Hz, 1H), 1.47 (s, 9H).

[0452] ESI (+) calc’d for [M+H] = 324.1555, found = 324.1576. Example 81 tert-Butyl 5-(5-nitrofuran-2-carbonyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

[0453] To a 100 mL round was added 5-nitrofuran-2 carboxylicacid (0.314 [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.779 g, 2.05 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature. (1S, 4S)-2-Boc-2,5-diazabicyclo[2.2.1]heptane (0.416 g, 1.70 mmol) was dissolved in N,N-dimethylformamide (2.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 20 hours, diluted with ethyl acetate, washed with brine, saturated aqueous sodium bicarbonate, water and brine. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo and purified by silica gel chromatography (0 – 100% ethyl acetate in hexanes) then additionally with 0 – 10% methanol in dichloromethane (0.107 g, 15 % yield).

[0454] 1H NMR (500 MHz, cdcl3) δ 7.41 – 7.28 (m, 2H), 5.37 – 4.97 (m, 1H), 4.75 – 4.48 (m, 1H), 4.00 (s, 1H), 3.96 – 3.61 (m, 1H), 3.59 – 3.37 (m, 2H), 2.10 – 1.83 (m, 2H), 1.58 (s, 2H), 1.53 – 1.39 (m, 9H).

[0455] ESI (+) calc’d for [M + Na] = 360.1172, found = 360.1187.Example 82 (5-Nitrofuran-2-yl)[4-(6-nitropyridin-3-yl)piperazin-1-yl]methanone

[0456] To a 100 mL round added 5-nitrofuran-2 carboxylicacid (0.232 g, 1.80 mmol), N,N- , (0.202 g, 2.00 mmol) and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (0.703 g, 1.85 mmol). The reaction vessel was sealed with a septum, flushed with argon, and stirred at room temperature.1-(6-nitropyridin-3-yl) piperazine (0.416 g, 2.00 mmol) was dissolved in N,N- dimethylformamide (1.00 mL) and added to the first solution via syringe. The reaction mixture was stirred at room temperature for 23 hours during which time a solid precipitated. A 1:1 mixture of ethyl acetate: hexanes (20.0 mL) was added to the reaction mixture, the precipitate was filtered, washed with hexanes, and dried in vacuo to yield the title product (0.478 g, 76 % yield).

[0457] 1H NMR (500 MHz, dmso-d6) δ 8.26 (d, J = 3.0 Hz, 1H), 8.19 (d, J = 9.2 Hz, 1H), 7.80 (d, J = 3.9 Hz, 1H), 7.49 (dd, J = 9.3, 3.1 Hz, 1H), 7.34 (d, J = 3.8 Hz, 1H), 3.87 (d, J = 70.1 Hz, 4H), 3.67 (dd, J = 6.6, 4.0 Hz, 4H).

[0458] ESI (+) calc’d for [M+H] = 348.0940, found = 348.0964. Example 83 1-[(5-Nitrofuran-2-yl)methyl]-4-(6-nitropyridin-3-yl)piperazine

[0459] To a 100 mL round was a 5-nitrofuran-2-carboxaldehyde (0.842 g, 5.97 mmol), dichloromethane (20.0 mL), 1-(6-nitropyridin-3-yl) piperazine (0.581 g, 2.96 mmol) and acetic acid (0.900 g, 15.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (2.54 g, 12.0 mmol) was added as a solid. The reaction vessel was sealed with a septum, flushed with argon, stirred for 20 hours at room temperature, quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twicewith dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using 0 – 100% ethyl acetate in hexanes to yield the title product (0.367 g, 32% yield).

[0460] 1H NMR (500 MHz, cdcl3) δ 8.25 – 8.08 (m, 2H), 7.31 (d, J = 3.6 Hz, 1H), 7.21 (dd, J = 9.2, 3.0 Hz, 1H), 6.53 (d, J = 3.6 Hz, 1H), 3.73 (s, 2H), 3.52 – 3.46 (m, 4H), 2.77 – 2.69 (m, 4H).

[0461] ESI (+) calc’d for [M+H] = 334.1147, found = 334.1169. Example 84 4-{4-[(5-Nitrofuran-2-yl)methyl]piperazin-1-yl}benzaldehyde

[0462] To a 100 mL round 2-carboxaldehyde (0.499g, 3.53 mmol), dichloromethane (20.0 mL), 4-piperazin-1-yl benzaldehyde (0.241 g, 1.26 mmol) and acetic acid (0.600 g, 10.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (2.54 g, 12.0 mmol) was added as a solid. The reaction vessel was sealed with a septum, flushed with argon, stirred for 20 hours at room temperature, quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography using 0 – 100% ethyl acetate in hexanes to yield the title product (0.148 g, 37% yield).

[0463] 1H NMR (500 MHz, cdcl3) δ 9.79 (s, 1H), 7.85 – 7.60 (m, 2H), 7.27 (s, 1H), 7.04 – 6.86 (m, 2H), 6.53 (d, J = 3.6 Hz, 1H), 3.71 (s, 2H), 3.51 – 3.33 (m, 4H), 2.77 – 2.61 (m, 4H).

[0464] ESI (+) calc’d for [M+H] = 316.1293, found = 316.1317. Example 85 4-{4-[(5-Nitrofuran-2-yl)methyl]piperazin-1-yl}-6-(trifluoromethyl)pyrimidine

[0465] To a 100 mL round2-carboxaldehyde (0.422 g, 2.99 mmol), dichloromethane (15.0 mL), 4-(1-piperazinyl)-6-trifluoromethyl pyrimidine (0.258 g, 1.11mmol) and acetic acid (0.600 g, 10.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (1.26 g, 6.00 mmol) was added as a solid. The reaction vessel was sealed with a septum, flushed with argon, stirred for 20 hours at room temperature, quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography using 0 – 100% ethyl acetate in hexanes to yield the title product (0.347 g, 87% yield).

[0466] 1H NMR (500 MHz, cdcl3) δ 8.65 (s, 1H), 7.29 (t, J = 3.8 Hz, 1H), 6.80 (d, J = 5.3 Hz, 1H), 6.54 (dd, J = 18.8, 3.6 Hz, 1H), 4.72 (s, 1H), 3.74 (d, J = 29.3 Hz, 4H), 2.96 – 2.30 (m, 4H).

[0467] 19F NMR (470 MHz, cdcl3) δ -70.64.

[0468] ESI (+) calc’d for [M+H] = 358.1123, found = 358.1149. Example 86 tert-Butyl 4-[(5-nitrofuran-2-yl)methyl]piperazine-1-carboxylate

[0469] To a 250 mL round butyl piperazine-1-carboxylate(2.48 g, 13.3 mmol), 5-nitrofuran-2-carbaldehyde (1.97 g, 14.0 mmol), and 50 mL dichloromethane. The reaction mixture was purged with argon, stirred at room temperature for 15 minutes, then sodium triacetoxyborohydride (3.52 g, 16.6 mmol) was added in four equal portions and kept overnight. Thin layer chromatography on silica with ethyl acetate showed consumption of the piperazine. Reaction was quenched with saturated aqueous sodium bicarbonate and transferred to a separatory funnel. The aqueous layer was extracted once with dichloromethane, and the combined dichloromethane layers were washed successively with saturated sodium bicarbonate and brine then dried over sodium sulfate, decanted, and concentrated in vacuo. Crude material was purified with silica gel chromatography (20-30% isopropanol in hexanes), and fractions containing product were combined and concentrated in vacuo to yield the title product (1.23 g, 30% yield).

[0470] 1H NMR (500 MHz, CDCl3) δ 7.29 (d, J = 3.6, 1H), 6.49 (d, J = 3.6 Hz, 1H), 3.66 (s, 2H), 3.46 (t, J = 5.0 Hz, 4H), 2.48 (t, J = 5.0 Hz, 4H), 1.46 (d, J = 1.3 Hz, 9H).

[0471] HRMS ESI (+) calc’d for [M+H] = 312.1559, found 312.1561.Example 87 1-[(5-Nitrofuran-2-yl)methyl]piperazine

[0472] To a 20 mL screw-cap [(5-nitrofuran-2-yl)methyl]piperazine-1- carboxylate (404.6 mg, 1.300 mmol),mL 4 M hydrochloric acid in dioxane. The vial was sealed and stirred for four hours, concentrated in vacuo. 6 mL dichloromethane and 1 mL of triethylamine were added, stirred until homogeneous, and filtered through a silica plug. Elution with methanol in dichloromethane and concentration in vacuo gave 274.3 mg (100%) of the title compound.

[0473] 1H NMR (500 MHz, dmso-d6) δ 7.65 (d, J = 3.7 Hz, 1H), 6.75 (d, J = 3.8 Hz, 1H), 3.59 (s, 1H), 3.32 (m, 4H), 2.71 (s, 2H), 2.49 (p, J = 1.9 Hz, 13H), 2.42 – 2.28 (m, 4H), 1.31 – 1.05 (m, 1H).

[0474] HRMS calc’d for [M+H] = 212.1035, found 212.1044. Example 88 4-[(5-nitrofuran-2-yl)methyl]-N-phenylpiperazine-1-carboxamide NO2ON

[0475] To a 20 mL screw-yl)methyl]piperazine (206.1 mg, 0.9758 mmol), 6 mL dichloromethane, 4 mL triethylamine, and isocyanatobenzene (0.50 mL, 4.6 mmol). The reaction was monitored by TLC on silica with ethyl acetate eluent and complete withing 30 minutes, concentrated in vacuo, and purified by silica gel chromatography (0-10% methanol in dichloromethane) and fractions containing product were combined and concentrated in vacuo to yield the title product (148 mg, 46% yield).

[0476] 1H NMR (500 MHz, CDCl3) δ 7.38 – 7.25 (m, 5H), 7.05 (t, J = 3.8 Hz, 1H), 6.51 (t, J = 2.8 Hz, 1H), 6.35 (s, 1H), 3.69 (s, 2H), 3.57 – 3.51 (m, 4H), 2.62 – 2.56 (m, 4H).

[0477] HRMS calc’d for [M+Na] = 353.1226, found 353.1219.Example 89 N-Benzyl-4-[(5-nitrofuran-2-yl)methyl]piperazine-1-carboxamide

[0478] To a 20 mL screw- methyl]piperazine (30A, 216.7 mg, 0.9758 mmol), 6 mLbenzene (0.50 mL, 3.5 mmol). The reaction was monitored by TLC on silica with ethyl acetate eluent, complete withing 30 minutes, and purified by silica gel chromatography (0-10% methanol in dichloromethane) and fractions containing product were combined and concentrated in vacuo to yield the title product (162 mg, 46% yield).

[0479] 1H NMR (500 MHz, CDCl3) δ 7.38 – 7.25 (m, 5H), 7.05 (t, J = 3.8 Hz, 1H), 6.51 (t, J = 2.8 Hz, 1H), 6.35 (s, 1H), 3.69 (s, 2H), 3.57 – 3.51 (m, 4H), 2.62 – 2.56 (m, 4H).

[0480] HRMS calc’d for [M+Na] = 353.1226, found 353.1219. Example 90 2-methyl-1-{4-[(5-nitrofuran-2-yl)methyl]piperazin-1-yl}propan-1-one

[0481] To a 20 mL screw-cap1-(piperazin-1-yl)propan-1-one (0.23 g, 1.0 mmol), 5-nitrofuran-2-carbaldehyde (0.246 g, 1.74 mmol), and 2 mL ethyl acetate. The reaction mixture was purged with argon, stirred at room temperature for 30 minutes, then sodium triacetoxyborohydride (0.750 g, 3.54 mmol) was added in one portion and kept overnight. Thin layer chromatography on silica with ethyl acetate showed consumption of the piperazine. Reaction was quenched with saturated aqueous sodium carbonate and transferred to a separatory funnel. The organic layer was washed with deionized water then brine, dried over sodium sulfate, decanted, and concentrated in vacuo. Crude material was purified with silica gel chromatography (10-100% ethyl acetate in hexanes), and fractions containing product were combined and concentrated in vacuo to yield the title product (0.3881 g, 92% yield).

[0482] 1H NMR (500 MHz, CDCl3) δ 7.28 (d, J = 3.6 Hz, 1H), 6.49 (d, J = 3.6 Hz, 1H), 3.66 (s, 2H), 3.67-3.64 (m, 2H), 3.57 – 3.51 (m, 2H), 2.77 (hept, J = 6.8 Hz, 1H), 2.52 (dt, J = 20.0, 5.0 Hz, 4H), 1.12 (d, J = 6.8 Hz, 6H).

[0483] HRMS calc’d for [M+H] = 282.1454, found 282.1457. Example 91 {4-[(5-nitrofuran-2-yl)methyl]piperazin-1-yl}(phenyl)methanone

[0484] To a 20 mL screw-cap (0.28 g, 1.0 mmol), 5-nitrofuran-2-carbaldehyde (0.246 g, , acetate. The reaction mixture was purged with argon, stirred at room temperature for 30 minutes, then sodium triacetoxyborohydride (0.750 g, 3.54 mmol) was added in one portion and kept overnight. Thin layer chromatography on silica with ethyl acetate showed consumption of the piperazine. Reaction was quenched with saturated aqueous sodium carbonate and transferred to a separatory funnel. The organic layer was washed with deionized water then brine, dried over sodium sulfate, decanted, and concentrated in vacuo. Crude material was purified with silica gel chromatography (10-100% ethyl acetate in hexanes), and fractions containing product were combined and concentrated in vacuo to yield the title product (0.276 g, 86% yield).

[0485] 1H NMR (500 MHz, CDCl3) δ 7.45-7.38 (m, 5H), 7.29 (d, J = 3.6 Hz, 1H), 6.50 (d, J = 3.6 Hz, 1H), 3.83 (br s, 2H), 3.68 (s, 2H), 3.48 (br s, 2H), 2.62 (br s, 2H), 2.49 (br s, 2H).

[0486] HRMS calc’d for [M+H] = 316.1297, found 316.1298. Example 92 Methyl 4-[(5-nitrofuran-2-yl)methyl]piperazine-1-carboxylate

[0487] To a 20 mL screw-cappiperazine-1-carboxylate (0.21 g, 1.0 mmol), 5-nitrofuran-2-carbaldehyde (0.246 g, 1.74 mmol), and 2 mL ethyl acetate. The reaction mixture was purged with argon, stirred at room temperature for 30 minutes, then sodium triacetoxyborohydride (0.750 g, 3.54 mmol) was added in one portion and kept overnight. Thin layer chromatography on silica with ethyl acetate showed consumption of the piperazine. Reaction was quenched with saturated aqueoussodium carbonate and transferred to a separatory funnel. The organic layer was washed with deionized water then brine, dried over sodium sulfate, decanted, and concentrated in vacuo. Crude material was purified with silica gel chromatography (10-100% ethyl acetate in hexanes), and fractions containing product were combined and concentrated in vacuo to yield the title product (0.245 g, 91% yield).

[0488] 1H NMR (500 MHz, CDCl3) δ 7.28 (d, J = 3.6 Hz, 1H), 6.48 (d, J = 3.6 Hz, 1H), 3.69 (s, 3H), 3.65 (s, 2H), 3.51 (br s, 4H), 2.49 (t, J = 5.0 Hz, 4H).

[0489] HRMS calc’d for [M+Na] = 292.0909, found 292.0911. Example 93 Benzyl 4-[(5-nitrofuran-2-yl)methyl]piperazine-1-carboxylate

[0490] To a 20 mL 1-carboxylate (0.33 g, 1.0mmol), 5-nitrofuran-2-carbaldehyde (0.246 g, 1.74 mmol), and 2 mL ethyl acetate. The reaction mixture was purged with argon, stirred at room temperature for 30 minutes, then sodium triacetoxyborohydride (0.750 g, 3.54 mmol) was added in one portion and kept overnight. Thin layer chromatography on silica with ethyl acetate showed consumption of the piperazine. Reaction was quenched with saturated aqueous sodium carbonate and transferred to a separatory funnel. The organic layer was washed with deionized water then brine, dried over sodium sulfate, decanted, and concentrated in vacuo. Crude material was purified with silica gel chromatography (10-100% ethyl acetate in hexanes), and fractions containing product were combined and concentrated in vacuo to yield the title product (0.339 g, 95% yield).

[0491] 1H NMR (500 MHz, CDCl3) δ 7.40 – 7.29 (m, 5H), 7.28 (d, J = 3.6 Hz, 1H), 6.48 (d, J = 3.6 Hz, 1H), 5.12 (s, 2H), 3.65 (s, 2H), 3.54 (t, J = 5.1 Hz, 4H), 2.50 (br s, 4H).

[0492] HRMS calc’d for [M+Na] = 368.1221, found 368.1221. Example 94 N,N-Dimethyl-4-[(5-nitrofuran-2-yl)methyl]piperazine-1-carboxamide

[0493] To a 20 mL screw-cap1-carboxamide (0.23 g, 1.0 mmol), 5-nitrofuran-2-carbaldehyde (0.246 g, 1.74 mmol), and 2 mL ethyl acetate. Thereaction mixture was purged with argon, stirred at room temperature for 30 minutes, then sodium triacetoxyborohydride (0.750 g, 3.54 mmol) was added in one portion and kept overnight. Thin layer chromatography on silica with ethyl acetate showed consumption of the piperazine. Reaction was quenched with saturated aqueous sodium carbonate and transferred to a separatory funnel. The organic layer was washed with deionized water then brine, dried over sodium sulfate, decanted, and concentrated in vacuo. Crude material was purified with silica gel chromatography (10-100% ethyl acetate in hexanes), and fractions containing product were combined and concentrated in vacuo to yield the title product (0.223 g, 77% yield).

[0494] 1H NMR (500 MHz, cdcl3) δ 7.28 (d, J = 3.6 Hz, 1H), 6.48 (d, J = 3.5 Hz, 1H), 3.66 (s, 2H), 3.30 – 3.24 (m, 4H), 2.82 (s, 6H), 2.56 – 2.50 (m, 4H).

[0495] HRMS calc’d for [M+H] = 283.1406, found 283.1409. Example 95 [4-([1,1'-Biphenyl]-4-yl)piperazin-1-yl](5-nitrofuran-2-yl)methanone

[0496] To a 250 mL roundstir bar, added 5-nitrofuran-2- carboxylic acid (0.3140 g, 2.00 mmol) and 20 mL argon-sparged dichloromethane. Hexafluorophosphate azabenzotriazole tetramethyl uronium (0.780 g, 2.05 mmol) and diisopropylethylamine (0.260 g, 2.01 mmol) were added and the reaction mixture stirred until homogeneous, 15 minutes. Half of the solution was withdrawn via syringe and added to 1-([1,1'-biphenyl]-4-yl)piperazine (0.241 g, 1.01 mmol) in 10 mL dichloromethane under argon in a 50 mL round bottom flask equipped with a magnetic stir bar. The reaction was stirred overnight. A scant precipitate was removed by filtration, the filtrate evaporated, and the solids were washed with 10 mL ethyl acetate then deionized water until the wash water remained colorless (300 mL). The solid was dried in a vacuum oven at 50 °C overnight (0.1849 g, 49% yield).

[0497] 1H NMR (500 MHz, dmso-d6) δ 7.79 (d, J = 3.9 Hz, 1H), 7.63 – 7.53 (m, 4H), 7.44 – 7.37 (m, 2H), 7.33 (d, J = 3.9 Hz, 1H), 7.30 – 7.23 (m, 1H), 7.09 – 7.02 (m, 2H), 3.87-3.79 (br d, J = 3.9 Hz, 4H), 3.30 – 3.28 (m, 4H).

[0498] HRMS ESI (+) calc’d for [M+H] = 378.1448, found = 378.1441.Example 96 (5-nitrofuran-2-yl)(4-(4-(trifluoromethyl)phenyl)-1,4-diazepan-1-yl)methanone Step 1: 1-[4-

[0499] 1- carboxylate (0.312 g, 1.56 mmol) were combined in a 4 mL screw-cap vial with 2 mL anhydrous dimethyl sulfoxide, potassium carbonate (0.305 g, 2.21 mmol), and a magnetic stir bar, sealed, and stirred in a 100 °C aluminum block overnight. The reaction was allowed to cool, poured into a separatory funnel containing water and dichloromethane, and shaken. The organic layer was washed thrice with saturated aqueous lithium chloride and dried over sodium sulfate, then concentrated in vacuo. The material was purified with silica gel chromatography (dichloromethane in hexanes 0-100%), and fractions containing product were combined and concentrated in vacuo to yield the intermediate product (0.5027 g, 94% yield).

[0500] 1H NMR (500 MHz, CDCl3) δ 7.44 (d, J = 8.6 Hz, 2H), 6.71 (d, J = 8.6 Hz, 2H), 3.59 (td, J = 9.2, 6.3 Hz, 6H), 3.33 (t, J = 5.9 Hz, 1H), 3.22 (t, J = 6.2 Hz, 1H), 1.97 (p, J = 6.1 Hz, 2H), 1.43 (s, 5H), 1.35 (s, 4H).

[0501] This was treated with 2 mL 4M hydrochloric acid in dioxane in a 20 mL screw-cap vial with occasional swirling for one hour, solids washed down the sides with 4 mL dichloromethane and allowed to stand another hour before being concentrated in vacuo, then potassium carbonate (0.2045 g, 1.480 mmol) was added along with 5 mL methanol, briefly heated to reflux with a heat gun, allowed to cool, filtered through a plug of basic alumina, concentrated in vacuo, the solids extracted with dichloromethane. The filtrate was concentrated in vacuo giving the title product (0.347 g, 91%).

[0502] 1H NMR (500 MHz, CDCl3) δ 7.46 – 7.40 (m, 2H), 6.71 (d, J = 8.8 Hz, 2H), 3.60 (dt, J = 21.3, 5.8 Hz, 4H), 3.07 – 3.01 (m, 2H), 2.86 – 2.80 (m, 2H), 1.91 (tt, J = 7.2, 5.1 Hz, 2H), 1.46 (s, 1H).19F NMR (470 MHz, CDCl3) δ -60.88. HRMS ESI (+) calc’d for [M+H] = 245.1260, found = 245.1258.Step 2: (5-nitrofuran-2-yl)(4-(4 n-1-yl)methanone

[0503] To a 100 mL round bottom as was added 5-n tro uran- -carboxylic acid (0.14 g, 0.89 mmol) and hexafluorophosphate azabenzotriazole tetramethyl uronium (0.34 g, 0.89 mmol). The flask was purged with argon, then 5 mL dichloromethane and diisopropylethylamine (0.16 mL, 0.89 mmol) were added, and the reaction mixture stirred until homogeneous.1-[4-(trifluoromethyl)phenyl]-1,4- diazepane (0.22 g, 0.89 mmol) was dissolved in 5 mL dichloromethane and added via syringe. The reaction was followed by TLC and complete in 6 hours, when the reaction mixture was injected directly to a silica gel column and eluted with dichloromethane. Fractions containing the product were combined and concentrated in vacuo (0.150 g, 54 % yield).

[0504] 1H NMR (500 MHz, CDCl3) δ 7.46 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 3.8 Hz, 1H), 7.29 – 7.24 (m, 1H), 6.58 (d, J = 8.6 Hz, 2H), 3.59 (dt, J = 9.7, 7.3 Hz, 2H), 3.46 (ddd, J = 9.6, 8.3, 5.3 Hz, 2H), 3.39 (dd, J = 10.2, 4.1 Hz, 2H), 2.46 (ddt, J = 12.9, 8.2, 6.5 Hz, 2H), 2.19 (ddt, J = 13.0, 7.8, 5.3 Hz, 2H).

[0505] 19F NMR (470 MHz, CDCl3) δ -60.84.

[0506] HRMS ESI (+) calc’d for [M+H] = 384.1166, found = 384.1170. Example 97 1-[(5-Nitrofuran-2-yl)methyl]-4-[4-(trifluoromethyl)phenyl]-1,4-diazepane

[0507] To a 20 mL screw-phenyl]-1,4-diazepane (0.0375 g, 0.154 mmol), 5-nitrofuran-2-carbaldehyde (0.023 g, 0.164 mmol), and 3 mL ethyl acetate. The reaction mixture was stirred at room temperature for 15 minutes, then sodium triacetoxyborohydride (0.068 g, 0.322 mmol) was added in one portion.30 uL of ethanoic acid was added, the mixture briefly sparged with argon, the vial sealed, and stirred one hour when complete by thin layer chromatography on silica with dichloroethane. Reaction was quenched with saturated aqueous sodium bicarbonate, the lower aqueous layer removed with a pipet, organics washed with brine then dried over sodium sulfate, decanted, and concentrated in vacuo. Crude material was purified with silica gel chromatography (SiO2, dichloromethane), and fractions containing product were combined and concentrated in vacuo to yield the title product (0.035 g, 62 % yield).

[0508] 1H NMR (500 MHz, CDCl3) δ 7.43 (dq, J = 8.4, 0.7 Hz, 2H), 7.27 (m, 1H), 6.69 (d, J = 8.8 Hz, 2H), 6.43 (dt, J = 3.6, 0.7 Hz, 1H), 3.78 (d, J = 0.7 Hz, 2H), 3.64 – 3.58 (m, 2H), 3.54 (t, J = 6.3 Hz, 2H), 2.87 – 2.82 (m, 2H), 2.72 – 2.66 (m, 2H), 2.00 (dt, J = 11.8, 6.0 Hz, 2H.

[0509] 19F NMR (470 MHz, CDCl3) δ -60.88.

[0510] HRMS ESI (+) calc’d for [M+H] = 370.1373, found = 370.1399. Example 98 2-{4-[(5-nitrofuran-2-yl)methyl]piperazine-1-sulfonyl}-2-azabicyclo[2.1.1]hexane HN bar, 2-azabicyclo[2.2.1]hexane-2-sulfuryl. The reaction vessel was sealed with a septum, flushed with argon, and cooled to 0oC in an ice bath. In a separate vial, piperazine (4.30 g, 50.0 mmol) was dissolved in dichloromethane (10.0 mL) and added to the sulfuryl chloride solution. The reaction mixture was stirred for 2 hours while warming to room temperature, at which time it was transferred to a separatory funnel, washed with water and brine, dried over sodium sulfate, filtered, and concentrated in vacuo to yield the final product (0.950 g, 72 % yield).

[0512] 1H NMR (500 MHz, cdcl3) δ 4.12 (dt, J = 6.9, 1.7 Hz, 1H), 3.31 (s, 2H), 3.27 – 3.22 (m, 4H), 2.92 (dd, J = 6.0, 3.9 Hz, 4H), 2.87 – 2.80 (m, 1H), 1.88 (dq, J = 5.0, 2.1 Hz, 2H), 1.57 (dt, J = 4.9, 1.4 Hz, 2H). O -2-g, , , 2- carboxaldehyde (0.564 g, 4.00 mmol) and acetic acid (0.720 g, 12.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (1.69 g, 8.00 mmol) was added as a solid and the reaction vessel was sealed, flushed with argon, and stirred for 23 hours at room temperature. The reaction mixture was quenched by adding saturated aqueous sodium carbonate, transferred to a separatory funnel, partitioned, and extracted twice with dichloromethane. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo.The crude material was purified by silica gel chromatography (0 – 100 % ethyl acetate in hexanes) to yield the final product (0.342 g, 39 % yield).

[0514] 1H NMR (500 MHz, cdcl3) δ 7.28 (d, J = 3.6 Hz, 1H), 6.49 (d, J = 3.6 Hz, 1H), 4.11 (dt, J = 6.8, 1.7 Hz, 1H), 3.67 (s, 2H), 3.38 – 3.27 (m, 6H), 2.85 (dtd, J = 6.7, 3.1, 1.6 Hz, 1H), 2.60 (t, J = 5.0 Hz, 4H), 1.92 – 1.85 (m, 2H), 1.56 (dd, J = 5.0, 2.0 Hz, 2H).

[0515] HRMS calc’d for [M+H] = 357.1228, found = 357.1265. Example 99 MATERIALS AND METHODS

[0516] Culture conditions, strains and compounds. Unless otherwise specified, streptomycin- resistant or wild type Erdman and CDC1551 Mtb strains were used. The strains were maintained in 7H9 Middlebrook medium supplemented with 10% oleic acid-albumin-dextrose-catalase (OADC), 0.05% Tween 80, and with or without 0.2% cycloheximide and were incubated at 37°C and 5% CO2 in standing vented flasks. M. smegmatis mc2155 and M. abscessus ATTCC 19977 were grown shaking in 7H9 / OADC media at 37°C. Other cultures used in this study include Staphylococcus aureus Wichita (29213) or Seattle (25923), Escherichia coli (Migula), Pseudomonas aeruginosa (Schroeter), Proteus vulgaris (Hauser emend. Judicial Commission), and Enterococcus faecalis (Andrewes and Harder). Except for E. faecalis which was grown in either brain heart infusion medium or Luria-Bertani (LB), all the non- mycobacterial cultures were grown exclusively in LB broth at 37°C.

[0517] Antimycobacterial compounds were purchased from commercial vendors that supply compounds with >90% purity. HC2209, HC2210, and HC2211 were supplied by Chembridge; HC2217 by Enamine; HC2226 from Chemdiv; HC2233 and HC2234 from Specs; and, HC2238, HC2239 and HC2250 from Vitas-M. To authenticate the supplied compounds, the mass of the compounds was examined by electrospray ionization (ESI) mass spectrometry in the positive mode. All of the tested compounds had observed masses matching the predicted masses (Table 1). For HC2210 the oxalic acid cannot be detected using the ESI method.

[0518] Table 1. Authentication of commercially supplied compounds by mass spectrometry.* ESI was run in the positive mode [M+H]+ resulting the observed masses having an additional H. **HC2210 is composed of two distinct molecules - HC2210 (332.319 / mol) and oxalic acid (90.039 / mol). Oxalic acid cannot be detected using the ESI MS method employed.

[0519] In vitro dose response study in M. tuberculosis and spectrum of activity in other mycobacteria and non-mycobacterial species. Mtb cultures were aliquoted (0.2 ml) into 96-well assay plates to an initial optical density (OD) of 0.1. Starting at 80 μM, the cultures were treated with an 8-point (2.5-fold) dilution series of the test compounds (HC2209, HC2210, HC2211, HC2217, HC2226, HC2233, HC2234, HC2238, HC2239, HC2250, pretomanid, isoniazid, and ethambutol). For comparative study of the most potent compounds (HC2210, pretomanid, and isoniazid), a 12-point (2-fold) dilution series starting from 40 μM were used. The treated cultures were incubated for 6 days at 37°C and in 5% CO2. After incubation, the OD of the cultures was measured in a plate reader (PerkinElmer Enspire) at 595nm, and the growth of the cultures was normalized based on the OD relative to a rifampicin-positive control (100% growth inhibition) and a DMSO-negative control (0% growth inhibition). The half-maximal effective concentrations (EC50) of each compound were determined by fitting the normalized data to a four-parameter logistic equation using GraphPad Prism software package. For Msm and Mab, the cultures were diluted to an initial OD of 0.1 and aliquoted into 96-well plates (0.2 ml) or 384-well plates (0.05 ml). This is followed by the treatment of the cultures with 2.5-fold serial dilutions of the compounds starting from either 200 µM or 80 µM. The cultures were incubated for 3 days before measuring the OD. Growth was normalized based on a positive control (kanamycin for Msm or amikacin for Mab) and aDMSO negative control. The EC50values of the compounds were determined by fitting the normalized data to a four-parameter logistic equation using GraphPad Prism software package.

[0520] For the non-mycobacterial cultures, an initial OD of 0.05 was prepared and aliquoted into 96- well plates (0.2 ml) or 384-well plates (0.05 ml). The cultures were treated with 2.5-fold serial dilutions of the compounds starting from either 200 μM or 80 μM and were incubated for 5-8 hours before measuring the OD. Except for P. aeruginosa which was normalized with tobramycin-positive control (100% inhibition), other cultures were normalized with kanamycin (100% inhibition). DMSO was used as the negative control (0% inhibition). The normalized data was fitted to a four-parameter logistic equationto calculate the EC505of the compounds using GraphPad Prism software package.

[0521] Kinetic killing assays. For Mtb, an initial OD of 0.1 OD was prepared and dispensed in 0.2 ml aliquots into 96-well assay plates. The cultures were treated with two different doses of the compounds, with an equivalent volume of DMSO used as a negative control. After 4- and 10-days incubation at 37°C and in 5% CO2, the cultures were diluted serially in phosphate-buffered saline-Tween- 80 solution and plated for colony forming units (CFU) in 7H10 / OADC agar quadrant plates. The bactericidal activity was determined by comparing the CFU of the initial inoculum to the bacterial CFU after treatment.

[0522] Hypoxic shift-down assay to test activity against NRP Mtb. The hypoxic shift-down assay (27) was used to generate NRP bacilli and was performed as previously described with slight modifications (19). Briefly, 0.2 ml aliquots of CDC1551 (hspX'::GFP) culture in 7H9 / OADC medium was dispensed into 96-well assay plates to an initial OD of 0.25. The cultures were incubated at 37°C in an anaerobic chamber (BO GasPak). At 4 days of incubation, cultures have become completely anaerobic as indicated by the methylene blue indicator turning to colorless. This was considered to be the first day of anaerobiosis. Aliquots of cultures from day 1 were collected and plated onto 7H10 / OADC to quantify the initial CFU. Subsequently, 20 µM of the test compounds were added to the cultures and incubated for 10 days in the anaerobic chamber. DMSO was used as the negative control. The surviving bacterial CFU at different treatments was enumerated at day 10 by plating onto 7H10 / OADC agar.

[0523] Isolation of resistant mutants. The isolation and confirmation of resistant mutants were done as previously described (46). Briefly, 1 x 109CFU streptomycin-resistant Erdman culture was plated onto 7H10 / OADC agar plates containing 0.3 µM or 0.1 µM HC2210. The plates were incubated at 37°C until colonies appeared. Colonies were randomly picked from each plate and grown in 7H9 / OADC broths. The broth cultures were subjected to a dose-response study using HC2210 as previously described above. Resistance was confirmed by an increase in the EC50of the mutants when compared to that of the Erdman streptomycin-resistant culture.

[0524] To generate mutants resistant to HC2238, mutant #300.1 (Δfdg1) from the above setup was used. Briefly, 1x109of mutant #300.1 was plated onto 7H10 / OADC agar plates supplemented with 5 µM or 20 µM of HC2238 and incubated at 37°C until colonies appeared. Colonies were grown in broth cultures and subjected to a dose-response study with HC2238 as the test compound. Resistance was confirmed by an increase in the EC50values of the spontaneous mutants with respect to that of mutant #300.2. The same protocol was used in generating HC2238- and HC2217-resistant mutants in M. smegmatis background except that the agar plates were amended with 10 µM or 20 µM of the compounds.

[0525] Whole-genome sequencing and analysis. The genomic DNAs of the confirmed resistant mutants and an Erdman streptomycin-resistant control (or Msm wild-type control) were extracted and submitted for lllumina-based whole-genome sequencing. The breseq computational pipeline was used to analyze the sequence reads and identify single-nucleotide variations (47, 48). Erdman reference genome (for Mtb) or mc2155 (for Msm) was used in the analysis. After subtracting the mutations shared by the resistant mutants with the Erdman streptomycin-resistant control (for HC2210- resistant mutants), mutant #300.2 control (for HC2238-resistant mutants), or mc2155 WT (for Msm), all the unique mutations in the resistant mutant strains were determined using techniques commonly known in the field.

[0526] Inhibitory activity against intracellular M. tuberculosis. A previously described protocol was adapted in testing the efficacy of the compounds against intracellular M. tuberculosis (46). Briefly, primary bone marrow-derived macrophages were harvested from C57BL / 6 mice and distributed into 96- well assay plates in preparation for mycobacterial infection. The macrophages were infected for 1 h with CDC1551 luciferase reporter strain, followed by treatment with different concentrations of the nitro- containing compounds (80 µM to 0.136 µM). Rifampicin and DMSO were used as negative and positive controls, respectively. After incubating the samples for 6 days at 37°C and 5% CO2, bacterial survival was measured in a luciferase readout assay. The EC50values of the compounds against intracellular M. tuberculosis were determined by fitting the normalized data to a four-parameter logistic equation using GraphPad Prism software package.

[0527] Eukaryotic cytotoxicity assay. Murine primary bone marrow-derived macrophages were distributed into 96-well assay plates as described above. Different concentrations of the indicated inhibitors, ranging from 80 µM to 0.136 µM, were used in treating the macrophages. Cells were treated with DMSO as a positive control, while 4% Triton X-100 served as the negative control. Following a 3- day incubation of the macrophages at 37°C and in 5% CO2, the viability of the cells was assessed with the CellTiter-Glo (Promega) luciferase assay kit. The half-maximal cell cytotoxicity concentration (CC50) values were calculated by fitting the normalized data into a non-linear four-parameter least squares regression model in the GraphPad prism package.

[0528] Evaluation of the efficacy of HC2210 is a chronic murine TB infection model. All animal studies were approved by the Michigan State University Institutional Animal Care and Use Committee. Female, ~8-week-old C57BL / 6 mice purchased from Jackson Laboratories were used in this study. Low dose infection was initiated by aerosol exposure to 100 CFU of M. tuberculosis Erdman strain using a Glas-Col aerosol inhalation exposure device. One day after infection, 5 mice were euthanized, and the lungs were aseptically collected to assess the initial infection dose. The remaining mice were randomly distributed into three groups of eight mice and allowed for 38 days to develop a chronic infection. Treatment was then initiated by administering the mice with oral doses of the vehicle (corn oil / 5% DMSO), 75mg / kg of HC2210, or 10mg / kg rifampicin through oral gavage. HC2210 was administered once daily, while rifampicin and vehicle doses were given twice daily. The mice were treated five days a week, with a two-day resting period. The treatment lasted four weeks after which the mice were euthanized. The lungs and spleens were aseptically removed and homogenized, and the mycobacterial burdens were assessed by enumerating CFUs. For statistical analysis, one-way ANOVA was used to determine the effects of the treatments on the mycobacterial load of the tissues. The mean differences between the groups were compared in an unpaired Student's t-test and were considered statistically significant at a 95% confidence interval. RESULTS New nitro-containing compounds have potent antitubercular activities.

[0529] As part of their efforts towards developing a mechanistic understanding for the antimycobacterial activity of the small molecules discovered from the previous high-throughput screen of the MLSMR, the inventors selected 10 nitro-containing compounds (Fig.1) and characterized their mechanisms of action. Six of these compounds are nitrofurans and they include HC2209 (1-(4- fluorophenyl)-4-[(5-nitro-2-furyl)methyl]piperazine), HC2210 (1-[(5-nitro-2-furyl)methyl]-4-(4- nitrophenyl)piperazine oxalate), HC2211 (1-[(5- nitro-2-furyl)methyl]-4-phenylpiperazine), HC2233 (N- {4-[4-(2- methylpropanoyl)piperazin-1-yl]phenyl}-5-nitrofuran-2-carboxamide ), HC2234 (N-{4-[4-(2,2- dimethylpropanoyl)piperazin-1-yl]phenyl}-5-nitrofuran-2-carboxamide ), and HC2250 (N'-[(E)-(5- nitrofuran-2-yl)methylidene]-2-phenoxyacetohydrazide ). Previously, nitrofuran piperazine and nitrofuran triazine compounds have been reported as Mtb growth inhibitors (2, 20). The other four compounds, with their nitro groups attached to a parent benzene ring, are dinitrobenzamides and they include HC2217 (N- (2-morpholin-4-yl-2- thiophen-2-ylethyl)-3,5-dinitrobenzamide), HC2226 (N-(cyclopropylmethyl)-3,5- dinitrobenzamide), HC2238 (N-[(4-fluorophenyl)methyl]-4-methyl-3,5-dinitrobenzamide), and HC2239 (N-[2-(3-methoxyphenoxy)ethyl]-3,5-dinitrobenzamide). Notably, related dinitrobenzamide compounds have previously been described as DprE inhibitors (3, 4, 21).

[0530] An in vitro dose-response study against Mtb show all the compounds are relatively potent with half-maximal effective concentrations (EC50) ranging from 0.05 µM to 6.86 µM (Fig.2, Table 2). Of particular interest is HC2210, a nitrofuran-piperazine- nitrophenol compound that has an EC50of 50 nM. By comparison, in this assay, HC2210 is >2X more potent than isoniazid (EC50= 140 nM), and 12X more potent than pretomanid (EC50= 620 nM). During infection, Mtb can replicate inside macrophages, therefore the inventors tested compound activity against intracellular Mtb and for cytotoxicity against murine bone marrow-derived macrophages. In a dose-response study, all the nitro- containing compounds exhibited high potency against intracellular Mtb and had limited eukaryotic cytotoxicity (Table 2). These data demonstrate that the compounds can selectively inhibit intracellular Mtb with no or limited cytotoxicity on macrophages.

[0531] Table 2. Potency of nitro-containing compounds against Mycobacterial and non- mycobacterial species. Myco acterium a scessus; x v vo50(µ ) =50o compoun s aga nst ntrace u ar t n one marrow-derived macrophages; and CC50(µM) = macrophage cytotoxicity.

[0532] Next, the inventors sought to determine whether the compounds were bactericidal or bacteriostatic against Mtb. For most antibiotics, it is important to note that this classification system depends on the dose and time allowed for treatment (22, 23). Treatment of Mtb with HC2210, pretomanid and isoniazid showed the compounds are bactericidal at the tested concentrations (Fig.3A). Three other nitrofurans in this study (HC2233, HC2234, and HC2250) were also bactericidal at the tested concentrations and time points, with 50 µM of HC2233 or HC2234 completely sterilizing the culture after4 or 10 days of treatment, respectively (Fig.3B). For the dinitrobenzamides, the inventors tested HC2217, HC2226, and HC2238. At 4 days of incubation, all the compounds exhibited bactericidal activity even at the lowest test concentrations (Fig.3C). The inventors noticed interesting differences at 10 days of incubation. While HC2238 continued to kill the pathogen at 10 days of incubation, HC2217 and HC2226 start to lose their bactericidal activity at this time point. In fact, the two test concentrations of HC2217 completely lose their bactericidal profile at this time point Without being bound to theory, this lost activity may be due to instability of the compounds. HC2210, HC2233, HC2234, and HC2250 are active against non-replicating Mtb.

[0533] In response to different environmental signals such as hypoxia during infection, Mtb can transition into a non-replicating persistent (NRP) state that is non-responsive to many antibiotics (24, 25). One of the goals of modern TB chemotherapy is to develop drugs that can kill Mtb in this dormant state (19, 26). Using a hypoxic shiftdown assay (27), the inventors investigated the effect of the nitro- containing compounds on the survival of NRP Mtb. All the tested dinitrobenzamides (HC2217, HC2226, HC2238) had no impact on viability of the pathogen relative to the DMSO-vehicle control (Fig.3D). lsoniazid, a cell wall inhibitor, was used as a control in this assay and was inactive against NRP bacteria. In contrast, all the tested nitrofuran compounds (HC2210, HC2233, HC2234, HC2250) significantly reduced the viability of the NRP bacteria relative to the control, with HC2233 and HC2234 again showing sterilizing activity, suggesting that these compounds may be inhibiting essential cellular activities during Mtb dormancy. HC2209, HC2210, and HC2211 are cofactor F420-dependent nitrofurans.

[0534] Due to the presence of one or more nitro groups in these compounds and without being bound to theory, the inventors reasoned that, like other nitro containing compounds, they might be prodrugs that need mycobacterial proteins for activation. Isolation of resistant mutants has previously been used to identify activating enzymes (2, 12, 21, 28). Spontaneous mutants resistant to HC2210 were isolated on media supplemented with either 0.1 µM or 0.3 µM HC2210 with a frequency of 1.6 x 10-6, similar to what was observed for pretomanid (1.8 x 10-6).

[0535] Ten resistant colonies from each plate were isolated and confirmed for resistance against HC2210 (Fig.4 and Fig.7). Notably, two resistance patterns were observed from the dose-response curves, 1) partial resistance with an EC50of 5 µM, and 2) total resistance at all concentrations tested. The partially resistant mutants were isolated from both the 0.1 µM and 0.3 µM HC2210 selection plates, while the fully resistant clones were only observed in the 0.3 µM selection plate. Without being bound to theory, the absence of fully resistant clones from the 0.1 µM HC2210 plate may be due to a lower selective pressure to evolve full resistance to the compound.

[0536] To ascertain mutations that cause these resistance patterns, the inventors sequenced the genomes of the isolated resistant mutants. For the fully resistant clones, the inventors identified nonsense, insertion, and deletion mutations of fdg1, while the partially resistant clones harbored missense mutations or deletion in ddn (Table 3). Since the inventors selected mutants in these genes, it was hypothesized that HC2210 shares a related activation mechanism with pretomanid and delamanid. Notably, partial resistance of the ddn mutants for HC2210 suggests that a second nitroreductase may be required for its activation, as was previously observed for nitro-containing triazines (2). As expected, cross-resistance screening of two fdg1 spontaneous mutants against pretomanid showed a full loss of activity of the drug (Figure 4). The ddn spontaneous mutants also showed full resistance to high concentrations of pretomanid, further highlighting the role of the nitroreductase in the activation of the compound. Cross- resistance profiling of the spontaneous mutants also showed HC2209 and HC2211 to be dependent on Fdg1 and Ddn for activation (Fig.8), with fdg1 mutants providing full resistance and the ddn mutants providing partial resistance.

[0537] Table 3. Mutations of ddn and fdg1 in resistant clones.

[0538] d their full potency against the fdg1 and ddn spontaneous mutants (Fig.4 and 8). This suggests that they do not depend on the F420machinery for their activity. The same can be said for all the dinitrobenzamides since they did not show any change in their potency against the spontaneous mutants (Fig.9), consistent with their presumed target of DprE. Overall, HC2209, HC2210, and HC2211 are the only compounds in this study that depended on the F420bioreductive activation system. Mutations in dprE confer resistance to the nitrofuran HC2250 and dinitrobenzamides

[0539] Dinitrobenzamides are known DprE1 inhibitors (3, 4, 21, 29). To determine if the compounds are potential DprE1 inhibitors, resistant mutants to HC2238 were isolated and their resistance confirmed in a dose-response study (Fig.5 and 10). Whole genome sequencing identified the mutants harbored single nucleotide variants leading to a C384S substitution in DprE1. DprE1 is a conserved protein that catalyzes an essential epimerization step during the synthesis of mycobacterial arabinogalactan (21, 30-32). Cross-resistance profiling of the mutants against other dinitrobenzamides in this study further confirmed that they share the same likely target (Fig.5; Fig.10). As expected, the mutants did not show any cross-resistance against a common cell wall inhibitor such as ethambutol (Fig.10), indicating that they target different proteins in the cell wall biogenesis pathway.

[0540] Since HC2233, HC2234, and HC2250 remained the only compounds in this study whose mechanism of action remained unknown, the inventors attempted to select resistant mutants on agar plates amended with the respective compounds at various concentrations. However, these efforts were unsuccessful. The inventors also examined their inhibitory activity against the dprE1 mutants. HC2233 and HC2234 retained their full potency against the mutants, indicating that they likely do not target DprE1 or that other mutations are required for resistance (Fig.5; Fig.10). HC2250 had reduced potency in these mutants, indicating that it might be a DprE1 inhibitor (Fig.5). Recently, Batt et al. showed that nitrofurans can also target DprE (33). Together, these findings support potential for developing nitrofuran scaffolds as DprE1 inhibitors. All the nitro-containing compounds have a narrow spectrum of activity

[0541] Several of the nitro compounds need a mycobacterial-specific target or system for activation, therefore, it was hypothesized they would have a narrow spectrum of activity. To test this hypothesis, the inventors carried out a dose-response study of the compounds against Escherichia coli, Pseudomonas aeruginosa, Proteus vufgaris, Enterobacter faecalis, and Staphylococcus aureus. Pretomanid was also used as a control. As expected, pretomanid did not affect any of the test organisms, indicating a narrow spectrum of activity (Table 2). Similarly, the nitro-containing compounds had a narrow spectrum of activity displaying little or no effect on the tested pathogens not belonging to the genus Mycobacterium (Table 2). HC2209, HC2210, and HC2211 are active against M. abscessus

[0542] The inhibitory activity of the prioritized compounds was next tested against the mycobacterial species, M. smegmatis (Msm) and M. abscessus (Mab). Without being bound to theory, these organisms retain some degree of genome homology with Mtb, suggesting that the compounds may also inhibit these mycobacterial species. Interestingly, different inhibitory profiles for the nitro-containing scaffolds with respect to the test species were observed.

[0543] Pretomanid and the F420-dependent nitrofurans had no inhibitory effects on Msm (Table 2). This agrees with previous reports on the loss of activity of pretomanid against Msm (14, 34, 35). However, when tested against Mab, the F420-dependent nitrofurans diverged from pretomanid (Table 2, Fig.11). While pretomanid did not inhibit the pathogen even at high concentrations, the F420-dependent nitrofurans showed potency against the pathogen (EC50= 0.81 - 5 µM) that is better or comparable toamikacin (EC50= 5.4 µM). Studies are currently underway to decipher the mechanisms of action of these nitrofurans against Mab.

[0544] While the putative DprE1 inhibitors (HC2217, HC2226, HC2238, HC2239, and HC225O) retain their activity against Msm, they lose their activity against Mab (Table 2). Indeed, the isolation and whole-genome sequencing of Msm-resistant mutants further confirmed the compounds are likely DprE1 inhibitors in Msm (Fig.12 and 13). From the genome sequence analysis, it was also observed that mutations in the regulator, MSMEG_6503, caused resistance against the tested putative DprE inhibitors. This corroborates previous studies that show mutations in MSMEG_6503 lead to the overexpression of a nearby nitroreductase, NfnB, in Msm (21, 36). NfnB can subsequently inactivate the exposed nitro groups of the compounds, reducing their potency. The Msm-resistant mutants retained their susceptibility to other cell wall inhibitors such as isoniazid and ethambutol (Fig.13), further confirming the different cellular targets of the compounds. HC2210 is orally bioavailable and efficacious in a chronic murine Mtb infection model

[0545] Based on the promising drug-like potency of HC2210, the inventors examined its efficacy in a murine model of chronic tuberculosis. C57BI / 6 mice were aerosol infected with Mtb Erdman and the infection was allowed to progress for 39 days before initiating treatment. For treatment, one group was treated by oral gavage with HC2210 at 75mg / kg, dosed once daily, five days a week. The other groups were either treated twice daily with rifampicin (10mg / kg) as a positive control or sham control (corn oil / DMSO). After 4 weeks of treatment, compared to the vehicle control group, HC2210 reduced the bacterial burden by 1.1-log and 1.2-log CFU in the lungs and spleens of infected mice, respectively (Fig. 6). Overall, these data show HC2210 is orally bioavailable and efficacious in a mouse model of Mtb infection and support its further development. DISCUSSION

[0546] The nitro-containing compounds in this study have potent antimycobacterial activities against both Mtb and Mab. Other nitrofurans or dinitrobenzamides have been previously described (2, 4, 5, 21), however, several of the tested compounds are chemically distinct, and based on their potency warranted further characterization. Using a genetic selection method, it was found that nitrofurans such as HC2209, HC2210, and HC2211 depend on the fdg1 activation system for their antimicrobial activities. This system of activation is also used by pretomanid and delamanid, two clinically approved TB drugs. Fdg1 provides the reduced form of cofactor F420that Ddn uses to activate the nitro- containing compounds into active metabolites. To date, Ddn is the only nitroreductase that has been described in the activation of pretomanid and delamanid (7, 9-14, 16, 17). This was further confirmed with the full loss of activity of pretomanid when tested against the ddn mutants in this study. Interestingly, the Fdg1-dependentnitrofurans did not fully lose their potency against the ddn mutants. They retained some levels of antimycobacterial activities at high concentrations (Fig.4; Fig.8). This suggests the presence of other Fdg1-dependent reductases (FDORs) that may be playing a role in the activation of the compounds. A similar observation was made by Wang et al. (2) for JSF-2019, another nitrofuran. Deletion of fdg1 led to a large loss in the activity of JSF-2019, while perturbation of ddn only led to a slight potency loss. This led the authors to suggest that Ddn is not the primary reductase for JSF-2019. In this case, the inventors observed a large potency loss when they tested the ddn spontaneous mutants against the nitrofurans. Without being bound to theory, the inventors propose Ddn as the primary nitroreductase for these Fdg1- dependent nitrofurans and suggest a possible role for other secondary FDORs in the activation of the compounds. Many computationally and functionally annotated FDORs exist in the literature (34, 37, 38), but only Ddn is involved in the activation of different antimycobacterial nitro compounds. Interestingly, CGI-17341, a parent nitroimidazole molecule for pretomanid and delamanid (11, 39, 40), depends on Fdg1 but not Ddn for activation (12, 16). This same conclusion was made in another study that associated a full loss of antitubercular activity of some nitrofurans with spontaneous mutations in fdg1 or the F420 biosynthesis pathway (41). These compounds, however, retained their efficacy against a ddn mutant. Taken together, these studies suggest the possibility of uncovering other clinically relevant FDORs.

[0547] The Fdg1-dependent nitrofurans were also different from pretomanid in their activity against growth of Mab. While pretomanid did not have any inhibitory effect on Mab, HC2209, HC2210, and HC2211 retained their activity against the pathogen. Mab is a challenging to treat pathogen that is non- responsive to many antibiotics. The intrinsic resistance of Mab limits the chemotherapeutic strategies for treating the infection (42). Among other factors, the intrinsic resistance of Mab may be attributed to its highly efficient efflux system. Genetic polymorphic differences may also explain the lack of activity of pretomanid against the pathogen. Indeed, phylogenetic analysis and multiple sequence alignment showed a low homology or relatedness between the Ddn in Mtb and Mab (35). However, these reasons do not fully explain why we see differences in the susceptibility of Mab to pretomanid and the Fdg1-dependent nitrofurans described here. We suggest two hypotheses to further explain the susceptibility of Mab to these nitrofurans. Ddn of Mtb and its Mab homolog may share residues that interact with these nitrofurans but not pretomanid. This can be tested through detailed biochemical studies and co-crystallization of the compounds with the Ddn of both species. Unfortunately, researchers have been unable to isolate co- crystals of pretomanid with Ddn (7). Only the crystal structure of Mtb Ddn has been solved, and molecular docking has been used to identify residues that interact with pretomanid (7, 14, 16, 34). A second hypothesis, reinforced by the partial resistance of the Mtb ddn mutants to the tested nitrofurans, is that ...

Claims

CLAIMS What is claimed is:

1. A compound of formula (I): or a pharmaceuticallyX is N or CH; Y is N or CH; L1is selected from bond, –O–, –NR’–, C1-C3alkylene, –C(O)–, –C(O)NR’–, –NR’C(O)–, –C(O)O–, –OC(O)–, and –S(O)2–; A is selected from H, –NR’R’’, C1-C6alkyl, C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, –(C1-C3alkylene)-(C3-C10cycloalkyl), –(C1-C3alkylene)-(C6-C10aryl), –(C1-C3alkylene)-(5- to 10-membered heterocyclyl), and –(C1-C3alkylene)-(5- to 10-membered heteroaryl), wherein said C3-C10cycloalkyl, C6-C10aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, –(C1-C3alkylene)-(C3-C10cycloalkyl), –(C1-C3alkylene)-(C6-C10aryl), –(C1-C3alkylene)-(5- to 10-membered heterocyclyl), or –(C1-C3alkylene)-(5- to 10-membered heteroaryl) is optionally substituted with 1-3 Ra; each Rais independently selected from halo, –CN, –NO2, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, –C(O)R’’’, –C(O)NR’R’’, –C(O)OR’, –S(O)2(C1-C3alkyl), –Si(C1-C3alkyl)3, C6-C10aryl, and 3- to 10-membered heterocyclyl, wherein said aryl or heterocyclyl is optionally substituted with 1-4 substituents independently selected from halo, C1-C3alkyl, and C1-C6haloalkyl; L2is selected from bond, –O–, –NR’–, C1-C3alkylene, –C(O)–, –C(O)NR’–, –NR’C(O)–, –C(O)O–, –OC(O)–, and –S(O)2–; Ring B is C6-C10aryl or 5- to 10-membered heteroaryl, wherein said aryl or heteroaryl is optionally substituted with 1-3 Rb; each Rbis independently selected from halo, –CN, C1-C3alkyl, C1-C6haloalkyl, and C1-C6alkoxy;L3is bond or C6-C10arylene; R2aand R2bare independently selected from H, C1-C6alkyl, C1-C6haloalkyl, and C1-C6alkoxy, or R2aand R2btogether form oxo; each R3aand R3bare independently selected from H, C1-C6alkyl, C1-C6haloalkyl, and C1-C6alkoxy, or R3aand R3btogether form oxo; R5aand R5bare independently selected from H, C1-C6alkyl, C1-C6haloalkyl, and C1-C6alkoxy, or R4aand R4btogether form oxo; R6aand R6bare independently selected from H, C1-C6alkyl, C1-C6haloalkyl, and C1-C6alkoxy, or R2aand R2btogether form oxo; or R3aand R6ajoin to form a bicyclic heterocyclyl; each R’ and R’’ is independently selected from H and C1-C6alkyl; each R’’’ is independently selected from H, C1-C6alkyl, C6-C10aryl, and 5- to 10-membered heteroaryl, wherein said aryl or heteroaryl is optionally substituted with 1-4 substituents independently selected from halo, C1-C3alkyl, C1-C6haloalkyl, and C1-C6alkoxy; and n is 0, 1, or 2, provided that at least one of X and Y is N.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is N.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is CH.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is N.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is CH.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein n is 0.

7. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein n is 1.

8. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein n is 2.

9. The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein L1is bond, –O–, C1-C3alkylene, –C(O)–, –C(O)NR’–, –C(O)O–, or –S(O)2–.

10. The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein L1is bond, –O–, –CH2–, –C(O)–, –C(O)NH–, –C(O)O–, or –S(O)2–.

11. The compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein A is H, –NR’R’’, C1-C6alkyl, C6-C10aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or –(C1-C3alkylene)-(C6-C10aryl), wherein said C6-C10aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or –(C1-C3alkylene)-(C6-C10aryl) is optionally substituted with 1-3 Ra.

12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, wherein each Rais independently selected from F, Cl, Br, I, –CN, –NO2, –C(CH3)3, –CF3, –OCH3, –C(O)H, –C(O)CH3,Br ,,, . , wherein L2is bond, –NR’–, C1-C3alkylene, –C(O)–, –NR’C(O)–, or –S(O)2–.

15. The compound of claim 14, or a pharmaceutically acceptable salt thereof, wherein L2is bond, –NH–, –CH2–, –C(O)–, –NHC(O)–, or –S(O)2–.

16. The compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from phenyl, furanyl, pyrazolyl, pyrrolyl, thiophenyl, and pyrazolo[1,5-a]pyrimidinyl.

17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein each Rbis independently selected from C1-C3alkyl.

18. The compound of claim 17, or a pharmaceutically acceptable salt thereof, wherein at least one Rbis –CH3.

19. The compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein L3is bond or phenylene.

20. The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, ,, , wherein R2aand R2bare independently selected from H and C1-C6alkyl.

22. The compound of any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R2ais H or –CH3.

23. The compound of any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein R2bis H.

24. The compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R2aand R2btogether form oxo.

25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein each R3aand R3bare each H.

26. The compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R6aand R6bare each H.

27. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein R3aand R6ajoin to form a bicyclic heterocyclyl.

28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R5aand R5bare independently selected from H and C1-C6alkyl.

29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R5ais H or –CH3.

30. The compound of any one of claims 1 to 29, or a pharmaceutically acceptable salt thereof, wherein R5bis H.

31. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-A): .

32. The compound of claim 31, or a pharmaceutically acceptable salt thereof, wherein L1is bond, C1-C3alkylene, –C(O)–, –C(O)NR’–, –C(O)O–, or –S(O)2–.

33. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein L1is bond, –CH2–, –C(O)–, –C(O)NH–, –C(O)O–, or –S(O)2–.

34. The compound of any one of claims 31 to 33, or a pharmaceutically acceptable salt thereof, wherein A is H, –NR’R’’, C1-C6alkyl, C6-C10aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or –(C1-C3alkylene)-(C6-C10aryl), wherein said C6-C10aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or –(C1-C3alkylene)-(C6-C10aryl) is optionally substituted with 1-3 Ra.

35. The compound of any one of claims 31 to 34, or a pharmaceutically acceptable salt thereof, wherein each Rais independently selected from halo, –CN, –NO2, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, –C(O)R’’’, –C(O)NR’R’’, –C(O)OR’, –S(O)2(C1-C3alkyl), –Si(C1-C3alkyl)3, C6-C10aryl, and 3- to 10-membered heterocyclyl, wherein said aryl or heterocyclyl is optionally substituted with 1-4 substituents independently selected from C1-C3alkyl and C1-C6haloalkyl.

36. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein each Rais independently selected from F, Cl, Br, I, –CN, –NO2, –C(CH3)3, –CF3, –OCH3, –C(O)H, –C(O)CH3,37. The compound of any one of claims 31 to 36, or a pharmaceutically acceptable salt thereof, Br ,38. The compound of any one of claims 31 to 37, or a pharmaceutically acceptable salt thereof, wherein L2is bond, –NR’–, C1-C3alkylene, –C(O)–, or –S(O)2–.

39. The compound of claim 38, or a pharmaceutically acceptable salt thereof, wherein L2is bond, –NH–, –CH2–, –C(O)–, or –S(O)2–.

40. The compound of any one of claims 31 to 39, or a pharmaceutically acceptable salt thereof, wherein Ring B is selected from phenyl, furanyl, imidazolyl, pyrazolyl, pyrrolyl, thiophenyl, and pyrazolo[1,5-a]pyrimidinyl.

41. The compound of any one of claims 31 to 40, or a pharmaceutically acceptable salt thereof, wherein each Rbis independently selected from C1-C3alkyl.

42. The compound of claim 41, or a pharmaceutically acceptable salt thereof, wherein at least one Rbis –CH3.

43. The compound of any one of claims 31 to 42, or a pharmaceutically acceptable salt thereof,any one to or a thereof, wherein R2aand R2bare independently selected from H and C1-C6alkyl.

45. The compound of claim 44, or a pharmaceutically acceptable salt thereof, wherein R2ais H or –CH3and R2bis H.

46. The compound of any one of claims 31 to 43, or a pharmaceutically acceptable salt thereof, wherein R2aand R2btogether form oxo.

47. The compound of any one of claims 31 to 46, or a pharmaceutically acceptable salt thereof, wherein R3aand R6aare each H.

48. The compound of any one of claims 31 to 46, or a pharmaceutically acceptable salt thereof, wherein R3aand R6ajoin to form a bicyclic heterocyclyl.

49. The compound of any one of claims 31 to 48, or a pharmaceutically acceptable salt thereof, wherein R5ais H or C1-C6alkyl.

50. The compound of claim 49, or a pharmaceutically acceptable salt thereof, wherein R5ais H or –CH3.

51. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-B):wherein: L1is bond, C1-C3alkylene, –C(O)–, –C(O)NR’–, or –S(O)2–; A is C6-C10aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or –(C1-C3alkylene)-(C6-C10aryl), wherein said C6-C10aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or –(C1-C3alkylene)-(C6-C10aryl) is optionally substituted with 1-2 Ra; each Rais independently selected from halo, –CN, –NO2, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, –C(O)R’’’, –C(O)NR’R’’, –C(O)OR’, –S(O)2(C1-C3alkyl), –Si(C1-C3alkyl)3, C6-C10aryl, and 3- to 10-membered heterocyclyl, wherein said aryl or heterocyclyl is optionally substituted with 1-4 substituents independently selected from C1-C3alkyl and C1-C6haloalkyl; L2is bond, C1-C3alkylene, –C(O)–, or –S(O)2–; R2aand R2bare independently selected from H and C1-C6alkyl, or R2aand R2btogether form oxo; R5ais H or C1-C6alkyl; each R’ and R’’ is independently selected from H and C1-C6alkyl; and each R’’’ is independently selected from H, C1-C6alkyl, and C6-C10aryl.

52. The compound of claim 51, or a pharmaceutically acceptable salt thereof, wherein L1is bond, –CH2–, –C(O)–, –C(O)NH–, or –S(O)2–.

53. The compound of claim 51 or 52, or a pharmaceutically acceptable salt thereof, wherein each Rais independently selected from F, Cl, Br, I, –CN, –NO2, –C(CH3)3, –CF3, –OCH3, –C(O)H, –C(O)CH3,and . , reof, Br wherein A is selected ,, , ,55. The compound of any one of claims 51 to 54, or a pharmaceutically acceptable salt thereof, wherein L2is bond, –CH2–, –C(O)–, or –S(O)2–.

56. The compound of any one of claims 51 to 55, or a pharmaceutically acceptable salt thereof, wherein R2ais H or –CH3, and R2bis H.

57. The compound of any one of claims 51 to 55, or a pharmaceutically acceptable salt thereof, wherein R2aand R2btogether form oxo.

58. The compound of any one of claims 51 to 57, or a pharmaceutically acceptable salt thereof, wherein R5ais H or –CH3.

59. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula (I-C):L1is bond, C1-C3alkylene, –C(O)–, –C(O)NR’–, or –S(O)2–; each Rais independently selected from halo, –CN, –NO2, C1-C6alkyl, C1-C6haloalkyl, C1-C6alkoxy, –C(O)R’’’, –C(O)NR’R’’, –C(O)OR’, –S(O)2(C1-C3alkyl), –Si(C1-C3alkyl)3, C6-C10aryl, and 3- to 10-membered heterocyclyl, wherein said aryl or heterocyclyl is optionally substituted with 1-4 substituents independently selected from C1-C3alkyl and C1-C6haloalkyl; L2is bond, C1-C3alkylene, –C(O)–, or –S(O)2–; R2aand R2bare independently selected from H and C1-C6alkyl, or R2aand R2btogether form oxo; R5ais H or C1-C6alkyl; each R’ and R’’ is independently selected from H and C1-C6alkyl; each R’’’ is independently selected from H, C1-C6alkyl, and C6-C10aryl; and p is 0, 1, or 2.

60. The compound of claim 59, or a pharmaceutically acceptable salt thereof, wherein L1is selected from bond, –CH2–, –C(O)–, –C(O)NH–, and –S(O)2–.

61. The compound of claim 59 or 60, or a pharmaceutically acceptable salt thereof, wherein each Rais independently selected from F, Cl, Br, I, –CN, –NO2, –C(CH3)3, –CF3, –OCH3, –C(O)H, –C(O)CH3,wherein p is 0.

63. The compound of any one of claims 59 to 61, or a pharmaceutically acceptable salt thereof, wherein p is 1.

64. The compound of any one of claims 59 to 61, or a pharmaceutically acceptable salt thereof, wherein p is 2.

65. The compound of any one of claims 59 to 64, or a pharmaceutically acceptable salt thereof, Br ,and . , , wherein L2is bond, –CH2–, –C(O)–, or –S(O)2–.

67. The compound of any one of claims 59 to 66, or a pharmaceutically acceptable salt thereof, wherein R2ais H or –CH3, and R2bis H.

68. The compound of any one of claims 59 to 67, or a pharmaceutically acceptable salt thereof, wherein R2aand R2btogether form oxo.

69. The compound of any one of claims 59 to 68, or a pharmaceutically acceptable salt thereof, wherein R5ais H or –CH3.

70. A compound selected from Table A, or a pharmaceutically acceptable salt thereof.

71. The compound of any one of claims 1 to 70, wherein the compound is in a non-salt form.

72. A pharmaceutical composition comprising the compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof, or the compound of claim 71, and one or more pharmaceutically acceptable carriers or vehicles.

73. A method of inhibiting the growth of a Mycobacterium comprising contacting the mycobacterium with: (i) a compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof; (ii) a compound selected from Table B, or a pharmaceutically acceptable salt thereof; (iii) the compound of claim 71; or (iv) the pharmaceutical composition of claim 72.

74. The method of claim 73, wherein the Mycobacterium expresses Ddn and Fdg1.

75. The method of claim 73 or 74, wherein the Mycobacterium is Mycobacterium tuberculosis.

76. The method of claim 73 or 74, wherein the Mycobacterium is Mycobacterium abscessus.

77. A method of treating a Mycobacterium infection in a subject comprising administering to the subject: (i) a compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof; (ii) a compound selected from Table B, or a pharmaceutically acceptable salt thereof; (iii) the compound of claim 71; or (iv) the pharmaceutical composition of claim 72.

78. The method of claim 77, wherein the Mycobacterium expresses Ddn and Fdg1.

79. A method of treating Mycobacterium tuberculosis infection in a subject comprising administering to the subject: (i) a compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof; (ii) a compound selected from Table B, or a pharmaceutically acceptable salt thereof; (iii) the compound of claim 71; or (iv) the pharmaceutical composition of claim 72.

80. A method of treating Mycobacterium abscessus infection in a subject comprising administering to the subject: (i) a compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof; (ii) a compound selected from Table B, or a pharmaceutically acceptable salt thereof; (iii) the compound of claim 71; or (iv) the pharmaceutical composition of claim 72.

81. The method of any one of claims 77 to 80, wherein said subject is treated with one or more additional therapeutic agents administered concurrently with, prior to, or subsequent to treatment with the compound, pharmaceutically acceptable salt, or pharmaceutical composition.

82. Use of the compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof, a compound selected from Table B, or a pharmaceutically acceptable salt thereof, the compound of claim 71, or the pharmaceutical composition of claim 72, as a medicament.

83. Use of the compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof, a compound selected from Table B, or a pharmaceutically acceptable salt thereof, the compound of claim 71, or the pharmaceutical composition of claim 72 in the manufacture of a medicament for the treatment of a Mycobacterium infection in a subject.

84. The compound of any one of claims 1 to 70, or a pharmaceutically acceptable salt thereof, a compound selected from Table B, or a pharmaceutically acceptable salt thereof, the compound of claim 71, or the pharmaceutical composition of claim 72 for use in treating a Mycobacterium infection in a subject.

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