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WO2025015066A1 - Composés contenant du nitro qui tuent des mycobactéries - Google Patents

Composés contenant du nitro qui tuent des mycobactéries Download PDF

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WO2025015066A1
WO2025015066A1 PCT/US2024/037413 US2024037413W WO2025015066A1 WO 2025015066 A1 WO2025015066 A1 WO 2025015066A1 US 2024037413 W US2024037413 W US 2024037413W WO 2025015066 A1 WO2025015066 A1 WO 2025015066A1
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compound
pharmaceutically acceptable
acceptable salt
formula
disclosure relates
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Robert B. Abramovitch
Ifeanyichukwu E. EKE
John T. Williams
Edmund Ellsworth
Matthew GILETTO
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Michigan State University MSU
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Michigan State University MSU
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/65—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/68—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/69—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/70—Nitro radicals
    • C07D307/71—Nitro radicals attached in position 5
    • C07D307/72—Nitro radicals attached in position 5 with hydrocarbon radicals, substituted by nitrogen-containing radicals, attached in position 2
    • C07D307/73—Nitro radicals attached in position 5 with hydrocarbon radicals, substituted by nitrogen-containing radicals, attached in position 2 by amino or imino, or substituted amino or imino radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D307/70—Nitro radicals
    • C07D307/71—Nitro radicals attached in position 5
    • C07D307/72—Nitro radicals attached in position 5 with hydrocarbon radicals, substituted by nitrogen-containing radicals, attached in position 2
    • C07D307/74—Nitro radicals attached in position 5 with hydrocarbon radicals, substituted by nitrogen-containing radicals, attached in position 2 by hydrazino or hydrazono or such substituted radicals
    • C07D307/75—Nitro radicals attached in position 5 with hydrocarbon radicals, substituted by nitrogen-containing radicals, attached in position 2 by hydrazino or hydrazono or such substituted radicals having carboxylic acyl radicals or their thio or nitrogen analogues directly attached to the hydrazino or hydrazono radical, e.g. hydrazides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • 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).
  • 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.
  • the disclosure relates to a compound described herein, or a pharmaceutically acceptable salt thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 ⁇ M. Hence, the line is not shown in the graph.
  • 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 10 8 CFU/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.
  • 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).
  • 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 standard deviations of three biological replicates. All experiments were independently conducted two times with similar results.
  • 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.
  • FIG. 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.
  • 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.
  • 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.
  • 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.
  • Figure 11 shows the activity of the nitrofurans against Mycobacterium abscessus. The dose responses were repeated twice with similar results.
  • Figure 12 shows resistance screening of Mycobacterium smegmatis mutants against different dinitrobenzamides.
  • Panel A shows confirmation of mutants that were generated in selection plates containing HC2217.
  • Panel B shows confirmation of mutants that were generated in selection plates containing HC2238.
  • 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.
  • 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 F 420 -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.
  • Mob Mycobacterium abscessus
  • nitro-containing compounds including dinitrobenzamides and a nitrofuran
  • DprE1 decaprenyl-phosphoryl- ribose 2'-epimerase 1
  • Msm Mycobacterium smegmatis
  • the inventors additionally demonstrate that a novel nitrofuran-piperazine-nitrophenol compound, HC2210, is effective, when delivered orally, in a chronic murine Mtb infection model.
  • HC2210 novel nitrofuran-piperazine-nitrophenol compound
  • the disclosure relates to a compound of formula (I): or a pharmaceutically
  • X is N or CH;
  • Y is N or CH;
  • L 1 is selected from bond, –O–, –NR’–, C 1 -C 3 alkylene, –C(O)–, –C(O)NR’–, –NR’C(O)–, –C(O)O–, –OC(O)–, and –S(O) 2 –;
  • A is selected from H, –NR’R’’, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, –(C 1 -C 3 alkylene)-(C 3 -C 10 cycloalkyl), –(C 1 -C 3 alkylene)-(C 6 -C 10 aryl), –(C 1 -C
  • 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.
  • the compounds of the disclosure comprise multiple variable groups (e.g., X, Y, A, B, L 1 , L 2 , L 3 , R a , R b , R 2a , R 2b , R 3a , R 3b , R 5a , R 5b , etc.).
  • 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.
  • 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.
  • halo means F, Cl, Br or I.
  • 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.
  • a “C 1 -C 6 alkyl” group is an alkyl group having between one and six carbon atoms.
  • 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.
  • a “C 2 -C 6 alkenyl” group is an alkenyl group having between two and six carbon atoms.
  • 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.
  • a “C 3 -C 8 cycloalkyl” group is a cycloalkyl group having between three and eight carbon atoms.
  • 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.
  • aryl may be used interchangeably with the term “aryl ring.”
  • alkoxy refers to a radical of the formula -OR where R is an alkyl group having the specified number of carbon atoms.
  • a “C 1 -C 6 alkoxy” group is a radical of the formula -OR where R is an alkyl group having the between one and six carbon atoms.
  • 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.
  • a “C 1 -C 6 haloalkyl” 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.
  • 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.
  • a “C 1 -C 6 haloalkenyl” 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.
  • 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.
  • 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.
  • a “C 1 -C 6 alkylene” group is an alkylene group having between one and six carbon atoms.
  • 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.
  • a “C 2 -C 6 alkenylene” is an alkenylene group having between one and six carbon atoms.
  • 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.
  • a “C 1 -C 6 haloalkylene” 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.
  • 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.
  • a “C 6 -C 10 arylene” group is an arylene having between six and ten carbon atoms.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • heteroaryl may be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”.
  • the compounds of the disclosure 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.
  • a non-bold, straight bond attached to a stereocenter of a compound denotes that the configuration may have any configuration, or a mixture of configurations, at the stereocenter.
  • 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.
  • 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.
  • 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.
  • 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).
  • H refers to hydrogen and includes any stable isotope of hydrogen, namely 1 H and D.
  • an atom is designated as “H”
  • 1 H 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.
  • 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.
  • 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).
  • stable isotopes which are commercially available and suitable for the disclosure include without limitation isotopes of hydrogen, carbon, nitrogen, oxygen, and phosphorus, for example 2 H, 13 C, 15 N, 18 O, 17 O, and 31 P, respectively.
  • the isotope-labeled compounds and salts can be used in a number of beneficial ways, including as medicaments.
  • the isotope-labeled compounds and salts are deuterium ( 2 H)-labeled.
  • Deuterium ( 2 H)-labeled compounds and salts are therapeutically useful with potential therapeutic advantages over the non- 2 H-labeled compounds.
  • deuterium ( 2 H)-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.
  • the deuterium ( 2 H)-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.
  • 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.
  • isotopic enrichment factor 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.
  • 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).
  • 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.
  • 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 L 1 is bond, –O–, C 1 -C 3 alkylene, –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 L 1 is bond.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 1 is –O–. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 1 is C 1 -C 3 alkylene. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 1 is –C(O)–. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 1 is –C(O)NR’–.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 1 is –C(O)O–. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 1 is –S(O) 2 –. In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 1 is bond, –O–, –CH 2 –, –C(O)–, –C(O)NH–, –C(O)O–, or –S(O) 2 –.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 1 is –CH 2 –. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 1 is –C(O)NH–.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is H, –NR’R’’, C 1 -C 6 alkyl, C 6 -C 10 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or –(C 1 -C 3 alkylene)-(C 6 -C 10 aryl), wherein said C 6 -C 10 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or –(C 1 -C 3 alkylene)- (C 6 -C 10 aryl) is optionally substituted with 1-3 R a .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is H, –NR’R’’, C 1 -C 6 alkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, or –(C 1 -C 3 alkylene)-(C 6 -C 10 aryl), wherein said C 6 -C 10 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or –(C 1 -C 3 alkylene)-(C 6 -C 10 aryl) is optionally substituted with 1-3 R a .
  • 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 C 1 -C 6 alkyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is C 6 -C 10 aryl optionally substituted with 1-3 R a .
  • 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 R a .
  • 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 R a .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is –(C 1 -C 3 alkylene)-(C 6 -C 10 aryl) optionally substituted with 1-3 R a .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R a is independently selected from halo, –CN, –NO 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, –C(O)R’’’, –C(O)NR’R’’, –C(O)OR’, –S(O) 2 (C 1 -C 3 alkyl), –Si(C 1 -C 3 alkyl) 3 , C 6 -C 10 aryl, and 3- to 10-membered heterocyclyl, wherein said aryl or heterocyclyl is optionally substituted with 1-4 substituents independently selected from halo, C 1 -C 3 alkyl, and C 1 -C 6 haloalkyl.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is halo. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –CN. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –NO 2 . In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is C 1 -C 6 alkyl.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is C 1 -C 6 haloalkyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is C 1 -C 6 alkoxy. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –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 R a is –C(O)NR’R’’.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(O)NH 2 .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(O)NH(C 1 -C 6 alkyl).
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(O)N(C 1 -C 6 alkyl) 2 .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –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 R a is –S(O) 2 (C 1 -C 3 alkyl). In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –Si(C 1 -C 3 alkyl) 3 .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is C 6 -C 10 aryl optionally substituted with 1-4 substituents independently selected from halo, C 1 -C 3 alkyl, and C 1 -C 6 haloalkyl.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is 3- to 10-membered heterocyclyl optionally substituted with 1-4 substituents independently selected from halo, C 1 -C 3 alkyl, and C 1 -C 6 haloalkyl.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R a is independently selected from F, Cl, Br, I, –CN, –NO 2 , –C(CH 3 ) 3 , –CF 3 , –OCH 3 , –C(O)H, –C(O)CH 3 , –C(O)-(phenyl), –C(O)N(CH 3 ) 2 , –C(O)OCH 2 CH 3 , –S(O) 2 CH 3 , –Si(CH 3 ) 3 , .
  • the disclosure relates to a compound of formula (I), salt thereof, wherein at least one R a is F. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is Cl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is Br. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is I.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(CH 3 ) 3 . In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –CF 3 . In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –OCH 3 . In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(O)H.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(O)CH 3 .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(O)-(phenyl).
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(O)NH 2 .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(O)N(CH 3 ) 2 .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(O)NHCH 3 .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein a at least one R is –C(O)OCH 2 CH 3 .
  • the disclosure to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –S(O) 2 CH 3 .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –Si(CH 3 ) 3 .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a is phenyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a . In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R a .
  • the disclosure relates to a compound of formula pharmaceutically acceptable salt thereof, wherein A is selected from: H, –N(CH 3 ) 2 , –CH 3 , –CH(CH 3 ) 2 , Br , O , , thereof, wherein A is H.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is –N(CH 3 ) 2 .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is –CH 3 .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is –CH(CH 3 ) 2 . In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A is –C(CH 3 ) 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 formula Br (I), or a pharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I), or a salt thereof, wherein A is .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I), or a acceptable salt thereof, wherein A is .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I), or a salt thereof, wherein A is .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I), or a acceptable salt thereof, wherein A .
  • 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 formula (I), or a acceptable salt thereof, wherein A . 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 formula (I), or a acceptable salt thereof, wherein A . 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 formula (I), or a pharmaceutically acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A .
  • 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 A 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 A is . In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, .
  • 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 a pharmaceutically 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 A 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 formula (I), or a acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I), or a acceptable salt thereof, wherein A other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I), or a acceptable salt thereof, wherein A is .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherei
  • the disclosure relates to a compound of formula (I), cceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I), or a salt thereof, wherein A is .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I), or a salt thereof, wherein A is .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I), or a salt thereof, wherein A is .
  • the disclosure 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 a acceptable salt thereof, wherein A is . 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 formula (I), or a pharmaceutically acceptable salt thereof, wherein A is . In other embodiments, the disclosure relates to a compound of formula (I), or a the A . In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 2 is bond.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 2 is –NR’–.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 2 is C 1 -C 3 alkylene.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 2 is –C(O)–. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 2 is –NR’C(O)–. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 2 is –S(O) 2 –.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 2 is bond, –NH–, –CH 2 , –C(O)–, –NHC(O)–, or –S(O) 2 –.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 2 is bond.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 2 is –NH–.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 2 is –CH 2 –.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 2 is –NHC(O)–.
  • 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.
  • the disclosure relates 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.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring B is furanyl.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein Ring B is imidazolyl.
  • 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.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R b is independently selected from halo, –CN, C 1 -C 3 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R b is independently selected from C 1 -C 3 alkyl.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R b is halo.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R b is –CN. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R b is C 1 -C 3 alkyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R b is C 1 -C 6 haloalkyl. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R b is C 1 -C 6 alkoxy.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one R b is –CH 3 .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 3 is bond or C 6 -C 10 arylene.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 3 is bond.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 3 is C 6 -C 10 arylene.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 3 is bond or phenylene. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein L 3 is phenylene. [0073] In some embodiments, the disclosure relates to a compound of formula (I), or a , O , or a pharmaceutically acceptable salt thereof, embodiments, the disclosure relates to a salt thereof, In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, is . In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, .
  • the disclosure relates to a acceptable salt thereof, .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, is .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, .
  • the disclosure relates to a acceptable salt .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, is .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, .
  • the disclosure relates to a acceptable salt thereof, wherein .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b are independently selected from H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, and C 1 -C 6 alkoxy, or R 2a and R 2b together form oxo.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b are independently selected from H and C 1 -C 6 alkyl.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of R 2a and R 2b is H.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b together form oxo.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2a is H or C 1 -C 6 alkyl.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2a is H.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2a is C 1 -C 6 alkyl.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2a is H or –CH 3 . In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2a is –CH 3 . [0076] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2b is H. [0077] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein each R 3a and R 3b are each H.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 6a and R 6b are each H. [0079] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 3a and R 6a join 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 R 5a and R 5b are independently selected from H and C 1 -C 6 alkyl.
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of R 5a or R 5b is H. In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of R 5a or R 5b is C 1 -C 6 alkyl. In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5a and R 5b are independently selected from H and –CH 3 . In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein at least one of R 5a or R 5b is –CH 3 .
  • the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5a is H or –CH 3 . In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5a is H. In other embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5a is –CH 3 . [0082] In some embodiments, the disclosure relates to a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 5b is H.
  • the disclosure relates to a compound of formula (I-A): or a pharmaceutically acceptable salt thereof, wherein: L 1 is selected from bond, –O–, –NR’–, C 1 -C 3 alkylene, –C(O)–, –C(O)NR’–, –NR’C(O)–, –C(O)O–, –OC(O)–, and –S(O) 2 –; A is selected from H, –NR’R’’, C 1 -C 6 alkyl, C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, –(C 1 -C 3 alkylene)-(C 3 -C 10 cycloalkyl), –(C 1 -C 3 alkylene)-(C 6 -C 10 aryl), –(C 1 -C 3 alkylene)-(C 6 -C 10
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L 1 is bond, C 1 -C 3 alkylene, –C(O)–, –C(O)NR’–, –C(O)O–, or –S(O) 2 –.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L 1 is bond.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L 1 is C 1 -C 3 alkylene.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L 1 is –C(O)–. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L 1 is –C(O)NR’–. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L 1 is –C(O)O–. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L 1 is –S(O) 2 –.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L 1 is bond, –CH 2 –, –C(O)–, –C(O)NH–, –C(O)O–, or –S(O) 2 –.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L 1 is –CH 2 –.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L 1 is –C(O)NH–.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A is H, –NR’R’’, C 1 -C 6 alkyl, C 6 -C 10 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or –(C 1 -C 3 alkylene)-(C 6 -C 10 aryl), wherein said C 6 -C 10 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or –(C 1 -C 3 alkylene)-(C 6 -C 10 aryl) is optionally substituted with 1-3 R a .
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A is H, –NR’R’’, C 1 -C 6 alkyl, C 6 -C 10 aryl, 5- to 10-membered heteroaryl, or –(C 1 -C 3 alkylene)-(C 6 -C 10 aryl), wherein said C 6 -C 10 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or –(C 1 -C 3 alkylene)-(C 6 -C 10 aryl) is optionally substituted with 1-3 R a .
  • 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 C 1 -C 6 alkyl. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A is C 6 -C 10 aryl optionally substituted with 1-3 R a .
  • 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 R a .
  • 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 R a .
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A is –(C 1 -C 3 alkylene)-(C 6 -C 10 aryl) optionally substituted with 1-3 R a .
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein each R a is independently selected from halo, –CN, –NO 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, –C(O)R’’’, –C(O)NR’R’’, –C(O)OR’, –S(O) 2 (C 1 -C 3 alkyl), –Si(C 1 -C 3 alkyl) 3 , C 6 -C 10 aryl, and 3- to 10-membered heterocyclyl, wherein said aryl or heterocyclyl is optionally substituted with 1-4 substituents independently selected from C 1 -C 3 alkyl and C 1 -C 6 haloalkyl.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is halo. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –CN. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –NO 2 . In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is C 1 -C 6 alkyl.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is C 1 -C 6 haloalkyl. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is C 1 -C 6 alkoxy. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(O)R’’’.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(O)NR’R’’.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(O)OR’.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –S(O) 2 (C 1 -C 3 alkyl).
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –Si(C 1 -C 3 alkyl) 3 .
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is C 6 -C 10 aryl optionally substituted with 1-4 substituents independently selected from C 1 -C 3 alkyl and C 1 -C 6 haloalkyl.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is and 3- to 10-membered heterocyclyl optionally substituted with 1-4 substituents independently selected from C 1 -C 3 alkyl and C 1 -C 6 haloalkyl.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein each R a is independently selected from F, Cl, Br, I, –CN, –NO 2 , –C(CH 3 ) 3 , –CF 3 , –OCH 3 , –C(O)H, –C(O)CH 3 , –C(O)-(phenyl), –C(O)N(CH 3 ) 2 , –C(O)OCH 2 CH 3 , –S(O) 2 CH 3 , –Si(CH 3 ) 3 , .
  • the disclosure relates to a compound of formula (I- salt thereof, wherein at least one R a is F. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is Cl. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is Br. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is I.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(CH 3 ) 3 .
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –CF 3 .
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –OCH 3 .
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(O)H.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(O)CH 3 . In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –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 R a is –C(O)N(CH 3 ) 2 .
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(O)OCH 2 CH 3 . In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –S(O) 2 CH 3 . In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –Si(CH 3 ) 3 .
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is phenyl. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a is . In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R a .
  • the disclosure relates to a compound of , or a pharmaceutically acceptable salt thereof, wherein A is selected from: H, –N(CH 3 ) 2 , –CH 3 , –CH(CH 3 ) 2 , Br , , , .
  • the disclosure salt thereof, wherein A is H.
  • a (I-A), or a pharmaceutically acceptable salt thereof, wherein A is –N(CH 3 ) 2 .
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A is –CH 3 .
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A is –CH(CH 3 ) 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 a acceptable salt thereof, 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 acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-A), or acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-A), or acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, embodiments, the disclosure relates to a compound of formula (I- salt thereof, wherein A .
  • the disclosure 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 salt thereof, wherein A .
  • 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- acceptable 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 formula (I- salt thereof, other embodiments, the disclosure relates to a compound of O formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A embodiments, the disclosure relates to a compound of formula (I-A), or salt thereof, .
  • 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-A), salt thereof, other embodiments, the disclosure relates to a compound of formula (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 of formula (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 .
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A is embodiments, the disclosure relates to a compound of formula (I-A), or a salt thereof, wherein A . 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- acceptable salt . In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-A), or acceptable salt thereof, 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 acceptable salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (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 salt thereof, wherein A . In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-A), or a acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-A), acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-A), acceptable salt thereof, wherein A is .
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-A), or acceptable salt thereof, wherein A is .
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-A), or a acceptable salt thereof, wherein L 2 is bond, –NR’–, C 1 -C 3 alkylene, –C(O)–, or –S(O) 2 –.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L 2 is bond.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L 2 is –NR’–.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L 2 is C 1 -C 3 alkylene.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L 2 is –C(O)–. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L 2 is –S(O) 2 –. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L 2 is bond, –NH–, –CH 2 –, –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 L 2 is –NH–.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein L 2 is –CH 2 –.
  • 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.
  • 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.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring B is phenyl.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein Ring B is furanyl.
  • 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.
  • 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.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein each R b is independently selected from C 1 -C 3 alkyl.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein at least one R b is –CH 3 .
  • the disclosure relates to a compound of formula (I-A), or a some embodiments, the disclosure relates to a compound of 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 salt thereof, In other embodiments, the disclosure relates to a compound of acceptable 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 salt thereof, .
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, is other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, embodiments, the disclosure relates to a acceptable salt thereof, . In other embodiments, the disclosure relates to a compound 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 a pharmaceutically acceptable salt thereof, . [0092] In some embodiments, the (I-A), or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b are independently selected from H and C 1 -C 6 alkyl.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 2a is H or –CH 3 and R 2b is H. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 2a is H and R 2b is H. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 2a is –CH 3 and R 2b is H. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b together form oxo.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 3a and R 6a are each H. In some embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 3a and R 6a join 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 R 5a is H or C 1 -C 6 alkyl. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 5a is H.
  • the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 5a is C 1 -C 6 alkyl. In other embodiments, the disclosure relates to a compound of formula (I-A), or a pharmaceutically acceptable salt thereof, wherein R 5a is –CH 3 [0096] In some embodiments, the disclosure relates to a compound of formula (I-B): or a L 1 is bond, C 1 -C 3 alkylene, –C(O)–, –C(O)NR’–, or –S(O) 2 –; A is C 6 -C 10 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or –(C 1 -C 3 alkylene)-(C 6 -C 10 aryl), wherein said C 6 -C 10 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or –(C 1 -C 10
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein A is C 6 -C 10 aryl, 5- to 10-membered heteroaryl, or –(C 1 -C 3 alkylene)-(C 6 -C 10 aryl), wherein said C 6 -C 10 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, or –(C 1 -C 3 alkylene)-(C 6 -C 10 aryl) is optionally substituted with 1-2 R a .
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein L 1 is bond, –CH 2 –, –C(O)–, –C(O)NH–, or –S(O) 2 –.
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein L 1 is bond.
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein L 1 is –CH 2 –.
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein L 1 is –C(O)–. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein L 1 is –C(O)NH–. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein L 1 is –S(O) 2 –.
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein each R a is independently selected from F, Cl, Br, I, –CN, –NO 2 , –C(CH 3 ) 3 , –CF 3 , –OCH 3 , –C(O)H, –C(O)CH 3 , –C(O)-(phenyl), –C(O)N(CH 3 ) 2 , –C(O)OCH 2 CH 3 , –S(O) 2 CH 3 , –Si(CH 3 ) 3 , .
  • the disclosure relates to a compound of formula (I- salt thereof, wherein at least one R a is F. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one R a is Cl. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one R a is Br. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one R a is I.
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –CN. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –NO 2 . In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(CH 3 ) 3 . In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –CF 3 .
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –OCH 3 . In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –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 R a is –C(O)CH 3 . In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(O)-(phenyl).
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(O)N(CH 3 ) 2 .
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(O)OCH 2 CH 3 .
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –S(O) 2 CH 3 .
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –Si(CH 3 ) 3 .
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one R a is phenyl.
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one R a is .
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein at least one .
  • the disclosure relates to a compound of formula Br , , , . Br , , , rein A .
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-B), or acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-B), acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-B), or a salt thereof, wherein A is .
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-B), acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein A i .
  • 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 a pharmaceutically acceptable salt thereof, wherein A . In some embodiments, the disclosure relates to a compound of formula (I-B), 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 A .
  • 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 a pharmaceutically 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, wherein O O A .
  • 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 a salt thereof, .
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein A embodiments, the disclosure relates to a compound of formula (I-B), or 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 embodiments, the disclosure relates to a compound of formula (I-B), or salt thereof, . In some embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein A embodiments, the disclosure relates to a compound of formula (I-B), or salt thereof, wherein A .
  • 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- acceptable 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 acceptable 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 a acceptable salt thereof, wherein A is .
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein A is .
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-B), acceptable salt thereof, wherein A is .
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein A .
  • the disclosure relates to a compound of formula (I-B), or 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 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 L 2 is bond, –CH 2 –, –C(O)–, or –S(O) 2 –.
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein L 2 is bond. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein L 2 is –CH 2 –. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein L 2 is –C(O)–. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein L 2 is –S(O) 2 –.
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 2a is H or –CH 3 , and R 2b is H. In some embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 2a is H and R 2b is H. In some embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 2a is –CH 3 and R 2b is H. In some embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b together form oxo.
  • the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 5a is H or –CH 3 . In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 5a is H. In other embodiments, the disclosure relates to a compound of formula (I-B), or a pharmaceutically acceptable salt thereof, wherein R 5a is –CH 3 .
  • the disclosure relates to a compound of formula (I-C): or a 1 L is bond, C 1 -C 3 alkylene, –C(O)–, –C(O)NR’–, or –S(O) 2 –; each R a is independently selected from halo, –CN, –NO 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, –C(O)R’’’, –C(O)NR’R’’, –C(O)OR’, –S(O) 2 (C 1 -C 3 alkyl), –Si(C 1 -C 3 alkyl) 3 , C 6 -C 10 aryl, and 3- to 10-membered heterocyclyl, wherein said aryl or heterocyclyl is optionally substituted with 1-4 substituents independently selected from C 1 -C 3 alkyl and C 1
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein L 1 is selected from bond, –CH 2 –, –C(O)–, –C(O)NH–, and –S(O) 2 –.
  • L 1 is selected from bond, –CH 2 –, –C(O)–, –C(O)NH–, and –S(O) 2 –.
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein L 1 is bond.
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein L 1 is –CH 2 –.
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein L 1 is –C(O)–. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein L 1 is –C(O)NH–. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein L 1 is –S(O) 2 –.
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein each R a is independently selected from F, Cl, Br, I, –CN, –NO 2 , –C(CH 3 ) 3 , –CF 3 , –OCH 3 , –C(O)H, –C(O)CH 3 , –C(O)-(phenyl), –C(O)N(CH 3 ) 2 , –C(O)OCH 2 CH 3 , –S(O) 2 CH 3 , –Si(CH 3 ) 3 , .
  • the disclosure relates to a compound of formula (I- salt thereof, wherein a at least one R is F. In other embodiments, the of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R a is Cl. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R a is Br. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R a is I. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –CN.
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –NO 2 . In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(CH 3 ) 3 . In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –CF 3 . In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –OCH 3 .
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –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 R a is –C(O)CH 3 . In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(O)-(phenyl).
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(O)N(CH 3 ) 2 .
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –C(O)OCH 2 CH 3 .
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –S(O) 2 CH 3 .
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R a is –Si(CH 3 ) 3 .
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R a is phenyl.
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one R a is .
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein at least one .
  • the disclosure relates to a compound of formula pharmaceutically 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 formula salt .
  • the disclosure relates to a compound 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 of formula (I-C), or a pharmaceutically acceptable salt thereof, In other embodiments, the disclosure relates to a compound of acceptable salt thereof, . In other embodiments, the disclosure relates to a compound of acceptable salt thereof, wherein . In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, .
  • the disclosure relates to a compound of acceptable salt thereof, . In other embodiments, the disclosure relates to a compound of 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 of acceptable salt thereof, . In other embodiments, the disclosure relates to a compound of salt thereof, wherein 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 acceptable salt thereof, In other embodiments, the disclosure relates to a acceptable salt thereof, wherein .
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, is O O . In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, embodiments, the disclosure relates to a salt . In other embodiments, the disclosure relates to a compound 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 In other acceptable salt other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, is .
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, .
  • the disclosure relates to a compound of formula salt thereof, .
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof,
  • the disclosure relates to a compound of acceptable salt thereof,
  • the disclosure relates to a compound of salt thereof, wherein .
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, .
  • the disclosure relates to a compound of acceptable salt thereof, .
  • the disclosure relates to a compound of salt thereof, wherein .
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, is .
  • the disclosure relates to a compound of formula (I-C), or a acceptable salt thereof, wherein L 2 is bond, –CH 2 –, –C(O)–, or –S(O) 2 –.
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein L 2 is bond.
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein L 2 is –CH 2 –.
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein L 2 is –C(O)–. In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein L 2 is –S(O) 2 –. [0110] In some embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R 2a is H or –CH 3 , and R 2b is H. In some embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R 2a is H and R 2b is H.
  • the disclosure relates to a compound of formula (I- C), or a pharmaceutically acceptable salt thereof, wherein R 2a is –CH 3 and R 2b is H. In some embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b together form oxo. [0111] In some embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R 5a is H or –CH 3 . In other embodiments, the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R 5a is H.
  • the disclosure relates to a compound of formula (I-C), or a pharmaceutically acceptable salt thereof, wherein R 5a is –CH 3 .
  • the disclosure relates to a compound selected from Table A, or a pharmaceutically acceptable salt thereof.
  • the disclosure relates to a compound selected from Table A, i.e., the compound in non-salt form.
  • Table A Compound Structures and Names.
  • 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.
  • compositions 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.
  • 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.
  • these compositions optionally further comprise one or more additional therapeutic agents.
  • the additional therapeutic agent is an anti-mycobacterial agent.
  • 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.
  • a mixture e.g., solution, suspension, or colloid
  • the term “inhibitorily active metabolite or residue thereof” means that a metabolite or residue thereof is also an inhibitor of mycobacterial growth.
  • 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.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid
  • 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.
  • 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,
  • Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 alkyl) 4 salts.
  • 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.
  • 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.
  • 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
  • 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.
  • 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 hydrogen phosphate, 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
  • the disclosure features a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • 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]
  • 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.
  • the Mycobacterium expresses Ddn and Fdg1.
  • 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.
  • the Mycobacterium is Mycobacterium tuberculosis.
  • the Mycobacterium is Mycobacterium abscessus.
  • 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.
  • the Mycobacterium expresses Ddn and Fdg1.
  • 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.
  • 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.
  • the Mycobacterium abscessus expresses Ddn and Fdg1.
  • 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.
  • the additional therapeutic agent is an anti-mycobacterial agent.
  • the disclosure features a compound of the disclosure, or a pharmaceutically acceptable salt or pharmaceutical composition thereof, for use as a medicament.
  • 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.
  • the Mycobacterium expresses Ddn and Fdg1.
  • 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.
  • 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.
  • 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.
  • the Mycobacterium tuberculosis expresses Ddn and Fdg1.
  • 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.
  • the Mycobacterium abscessus expresses Ddn and Fdg1.
  • 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.
  • the additional therapeutic agent is an anti-mycobacterial agent.
  • 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.
  • 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.
  • the Mycobacterium expresses Ddn and Fdg1.
  • 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.
  • the Mycobacterium is Mycobacterium tuberculosis.
  • the Mycobacterium is Mycobacterium abscessus.
  • 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.
  • the Mycobacterium expresses Ddn and Fdg1.
  • the Mycobacterium is Mycobacterium tuberculosis.
  • the Mycobacterium is Mycobacterium abscessus.
  • 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.
  • the Mycobacterium tuberculosis expresses Ddn and Fdg1.
  • 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.
  • the Mycobacterium abscessus expresses Ddn and Fdg1.
  • 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.
  • the additional therapeutic agent is an anti-mycobacterial agent.
  • Administration of Compounds, Pharmaceutically Acceptable Salts, and Compositions [0140]
  • 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.
  • 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.
  • dosage unit form 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.
  • subject or “patient,” as used herein, means an animal, preferably a mammal, and most preferably a human.
  • 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.
  • 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.
  • Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • 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.
  • inert diluents commonly used in the art such as, for example, water or other solvents,
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • 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.
  • the acceptable vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • 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.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • 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, cety
  • the dosage form may also comprise buffering agents.
  • 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.
  • embedding compositions examples 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.
  • the active compound or salt may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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 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.
  • 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 presently disclosed 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.
  • 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.
  • 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.
  • 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.
  • radiolabeled analogs of the compounds of the disclosure relate to radiolabeled analogs of the compounds of the disclosure.
  • 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.
  • the term “radioisotope” refers to an isotope of an element that is known to undergo spontaneous radioactive decay.
  • radioisotopes examples include 3 H, 14 C, 32 P, 35 S, 18 F, 36 Cl, and the 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).
  • the radiolabeled analogs can be used in a number of beneficial ways, including in various types of assays, such as substrate tissue distribution assays.
  • tritium ( 3 H)- and/or carbon-14 ( 14 C)-labeled compounds may be useful for various types of assays, such as substrate tissue distribution assays, due to relatively simple preparation and excellent detectability.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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).
  • Example 3 1-[(4-Methoxyphenyl)methyl]-4-[(5-nitrofuran-2-yl)methyl]piperazine [0172] To a 100 mL 2-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 for 18 hours at room temperature.
  • 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).
  • Example 4 1-[(5-Nitrofuran-2-yl)methyl]-4- ⁇ [4-(tert-butyl)phenyl] ⁇ piperazine [0175]
  • 2-carboxaldehyde 0.814 g, 5.70 mmol
  • dichloromethane (15.0 mL)
  • 1-(4-tert-butylbenzyl)piperazine (1.62 g, 7.00 mmol)
  • acetic acid (0.900 g, 15.0 mmol).
  • 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.
  • 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).
  • 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).
  • Example 6 1-[(5-Nitrothiophen-2-yl)methyl]-4-[4-(tert-butyl)phenyl]piperazine [0181] To a 100 mL round 2-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.
  • 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).
  • Example 7 1-([1,1'-Biphenyl]-4-yl)-4-[(5-nitrofuran-2-yl)methyl]piperazine [0184] To a 100 mL round 2-carboxaldehyde (0.315 g, 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.
  • sodium triacetoxyborohydride 0.847 g, 4.00 mmol
  • 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).
  • Example 8 [4-(4-tert-Butylphenyl)piperazin-1-yl](5-nitrofuran-2-yl)methanone O O [0187] To a 100 mL round added 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).
  • reaction vessel was sealed with a septum, flushed with argon, and stirred at room 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.
  • Example 9 4-(4-Chlorophenyl)-1-[(5-nitrofuran-2-yl)methyl]piperidine O 2N O N C l [0190] To a 100 mL round nitrofuran-2-carboxaldehyde (0.479 g, 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).
  • Example 10 1-(4-Chlorophenyl)-4-[(3-nitrophenyl)methyl]piperazine [0193] To a 100 mL round nitrobenzaldehyde (0.539 g, 3.56 mmol), 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 %).
  • Example 11 N 1 ,N 2 -Dimethyl-N 1 -[(5-nitrofuran-2-yl)methyl]-N 2 -phenylethane-1,2-diamine O 2N O N N [0196] To a 100 mL round methyl-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).
  • 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 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).
  • 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.
  • 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).
  • Example 14 1-[(4-Fluorophenyl)methyl]-4-(5-nitrofuran-2-sulfonyl)piperazine [0206] To a 100 mL round fluoro)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 0 o C 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.
  • 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 reaction vessel was sealed with a septum, flushed with argon, and cooled to 0 o C.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 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 (1.15 g, 78 % yield).
  • 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).
  • 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.
  • reaction mixture was stirred at 0 o C 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).
  • 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%).
  • 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).
  • 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 0 o C.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).
  • 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).
  • 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).
  • Example 21 Ethyl 4- ⁇ 4-[(5-nitrofuran-2-yl)methyl]piperazin-1-yl ⁇ benzoate [0242] To a 100 mL 4-(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.
  • 4-(piperazin-1-yl) benzoate 0.561 g, 2.39 mmol
  • dichloromethane (15.0 mL)
  • 5-nitrofuran-2-carboxaldehyde 0.423 g, 3.00 mmol
  • 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 (0.298 g, 36% yield).
  • 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.
  • sodium triacetoxyborohydride 0.846 g, 4.00 mmol
  • 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).
  • 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.
  • 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).
  • 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%).
  • 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%).
  • 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%).
  • Example 27 1-(3-Bromophenyl)-4-[(5-nitrofuran-2-yl)methyl]piperazine [0260] To a 100 mL round bromophenyl)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.
  • 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).
  • 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.
  • 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).
  • Example 29 (5-Nitro-1H-pyrazol-3-yl) ⁇ 4-[4-(trifluoromethyl)phenyl]piperazin-1-yl ⁇ methanone [0266] To a 100 mL round added 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).
  • reaction vessel was sealed with a septum, flushed with argon, 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.
  • Example 30 (5-Nitrofuran-2-yl) ⁇ 4-[4-(trifluoromethyl)phenyl]piperazin-1-yl ⁇ methanone O N N [0270] To a 100 mL round added 5-nitrofuran-2-carboxylic acid (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).
  • 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.
  • 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).
  • Example 32 1-[(5-Nitrofuran-2-yl)methyl]-4-[2-nitro-4-(trifluoromethyl)phenyl]piperazine [0278] To a 100 mL round nitro-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 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 (0.417 g, 53 % yield).
  • 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).
  • 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.
  • 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).
  • 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).
  • 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.
  • 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).
  • Example 37 1-[(5-Nitrofuran-2-yl)methyl]-4-(pyridin-3-yl)piperazine [0296] To a 100 piperazine (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.
  • 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).
  • reaction mixture was heated to 70 o C 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).
  • 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 vessel was sealed, flushed with argon, and stirred for 23 hours at room temperature.
  • sodium triacetoxyborohydride (1.69 g, 8.00 mmol
  • 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%).
  • 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.
  • reaction mixture was stirred at room temperature for 2 hours at which time it was cooled to 0 o C, 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.
  • 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.
  • 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 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 filtered through silica with 5 % methanol in dichloromethane.
  • 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-carboxylic acid (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).
  • 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 40 o C 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.
  • Example 45 (4- ⁇ 4-[(5-Nitrofuran-2-yl)methyl]piperazin-1-yl ⁇ phenyl)(phenyl)methanone [0330] To a 100 mL (4-piperazin-1-yl)phenyl methanone (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.
  • 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%).
  • Example 46 [4-(4-Benzoylphenyl)piperazin-1-yl](5-nitrofuran-2-yl)methanone [0333] To a 100 mL 5-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 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).
  • Example 47 4-(5-Nitrofuran-2-carbonyl)-1-(4-nitrophenyl)piperazin-2-one [0336] To a 100 mL round added 5-nitrofuran-2-carboxylic acid (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).
  • 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.
  • reaction mixture was heated to 70 o C 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.
  • 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-carboxylic acid (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).
  • 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.
  • 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).
  • reaction vessel was sealed with a septum, flushed with argon, 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.
  • Example 51 (1-Methyl-4-nitro-1H-pyrazol-3-yl) ⁇ 4-[4-(trifluoromethyl)phenyl]piperazin-1-yl ⁇ methanone [0350] To a 100 mL round added 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).
  • 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.
  • 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.
  • 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%).
  • 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).
  • 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.
  • 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.
  • reaction mixture was stirred at 50 o C 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).
  • 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).
  • 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; the product eluted in 1:9 methanol: ethyl acetate) to yield the product as the monohydrate (0.172 g, 18% yield).
  • 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.
  • 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 carboxylic acid (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).
  • 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 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 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 (0.333 g, 36% yield).
  • Example 63 1-[3,5-Bis(trifluoromethyl)phenyl]-4-[(5-nitrofuran-2-yl)methyl]piperazine [0391] To a 100 mL round 2-carboxaldehyde (0.423 g, 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).
  • 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).
  • Example 65 [5-(4-Nitrophenyl)furan-2-yl] ⁇ 4-[4-(trifluoromethyl)phenyl]piperazin-1-yl ⁇ methanone [0398] To a 100 mL 5-(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).
  • 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.
  • 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.
  • 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 carboxylic acid (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).
  • 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.
  • Example 68 (5-Nitrofuran-2-yl)[4-(4-nitrophenyl)piperazin-1-yl]methanone [0409] To a 100 mL round added 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).
  • 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).
  • Example 69 1-[4-Chloro-3-(trifluoromethyl)phenyl]-4-[(5-nitrofuran-2-yl)methyl]piperazine [0412] To a 100 mL round 2-carboxaldehyde (0.705 g, 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).
  • 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.
  • 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.
  • Example 72 1-[4-(Methanesulfonyl)phenyl]-4-[(5-nitrofuran-2-yl)methyl]piperazine [0423] To a 100 mL round added 1-(4-methylsulfonyl)phenyl piperazine, n-butanol (2.50 mL), and triethylamine (0.303 g, 3.00 mmol). The reaction mixture was heated to 50 o C 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 50 o C during which time a solid precipitated.
  • 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 carboxylic acid (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).
  • 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.
  • reaction mixture was stirred, heated to 50 o C, 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 50 o C for 1 hour during which time a precipitate formed.
  • the solid was filtered, washed with n-butanol and hexanes and purified 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).
  • 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 carboxylic acid (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).
  • 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.
  • 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 carboxylic acid (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).
  • 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.
  • 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.
  • 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 50 o C and 5-bromomethyl-2-nitrofuran (1.15 g, 6.00 mmol, dissolved in 4.00 mL n-butanol) was added via syringe.
  • reaction mixture was stirred for 22 minutes at 50 o C 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).
  • Example 79 4-[4-(5-Nitrofuran-2-carbonyl)piperazin-1-yl]benzaldehyde O O 2 N O N O [0447] To a 100 mL round added 5-nitrofuran-2 carboxylic acid (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).
  • 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).
  • Example 80 tert-Butyl 5-[(5-nitrofuran-2-yl)methyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate [0450] To a 100 mL round was 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 50 o C and 5-bromomethyl-2-nitrofuran (0.899 g, 4.36 mmol, dissolved in 5.00 mL n-butanol) was added via syringe.
  • reaction mixture was stirred for 19 hours at 50 o C 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).
  • 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 carboxylic acid (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).
  • 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).
  • 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 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 to yield the title product (0.367 g, 32% yield).
  • Example 84 4- ⁇ 4-[(5-Nitrofuran-2-yl)methyl]piperazin-1-yl ⁇ benzaldehyde [0462] To a 100 mL round 2-carboxaldehyde (0.499 g, 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).
  • Example 85 4- ⁇ 4-[(5-Nitrofuran-2-yl)methyl]piperazin-1-yl ⁇ -6-(trifluoromethyl)pyrimidine [0465] To a 100 mL round 2-carboxaldehyde (0.422 g, 2.99 mmol), dichloromethane (15.0 mL), 4-(1-piperazinyl)-6-trifluoromethyl pyrimidine (0.258 g, 1.11 mmol) and acetic acid (0.600 g, 10.0 mmol). The reaction mixture was stirred at room temperature and after 10 minutes sodium triacetoxyborohydride (1.26 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).
  • 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.
  • Example 88 4-[(5-nitrofuran-2-yl)methyl]-N-phenylpiperazine-1-carboxamide N O2 O N [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).
  • 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.
  • 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.
  • Example 92 Methyl 4-[(5-nitrofuran-2-yl)methyl]piperazine-1-carboxylate [0487] To a 20 mL screw-cap piperazine-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.
  • Example 93 Benzyl 4-[(5-nitrofuran-2-yl)methyl]piperazine-1-carboxylate [0490] To a 20 mL 1-carboxylate (0.33 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.
  • Example 94 N,N-Dimethyl-4-[(5-nitrofuran-2-yl)methyl]piperazine-1-carboxamide [0493] To a 20 mL screw-cap 1-carboxamide (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.
  • Example 95 [4-([1,1'-Biphenyl]-4-yl)piperazin-1-yl](5-nitrofuran-2-yl)methanone [0496] To a 250 mL round stir 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.
  • 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).
  • 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 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).
  • 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 mc 2 155 and M. abscessus ATTCC 19977 were grown shaking in 7H9/OADC media at 37°C.
  • OADC oleic acid-albumin-dextrose-catalase
  • 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.
  • ESI electrospray ionization
  • 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).
  • the test compounds HC2209, HC2210, HC2211, HC2217, HC2226, HC2233, HC2234, HC2238, HC2239, HC2250, pretomanid, isoniazid, and ethambutol.
  • HC2210, pretomanid, and isoniazid a 12-point (2-fold) dilution series starting from 40 ⁇ M were used.
  • the treated cultures were incubated for 6 days at 37°C and in 5% CO 2 .
  • 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 (EC 50 ) 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).
  • 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% CO 2 , 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).
  • 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.
  • test compounds 20 ⁇ M 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.
  • Isolation of resistant mutants The isolation and confirmation of resistant mutants were done as previously described (46). Briefly, 1 x 10 9 CFU streptomycin-resistant Erdman culture was plated onto 7H10/OADC agar plates containing 0.3 ⁇ M or 0.1 ⁇ M HC2210. The plates were incubated at 37°C until colonies appeared. Colonies were randomly picked from each plate and grown in 7H9/OADC broths.
  • mutant #300.1 ( ⁇ fdg1) from the above setup was used. Briefly, 1x10 9 of mutant #300.1 was plated onto 7H10/OADC agar plates supplemented with 5 ⁇ M or 20 ⁇ M 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.
  • 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 ⁇ M to 0.136 ⁇ M).
  • Rifampicin and DMSO were used as negative and positive controls, respectively.
  • bacterial survival was measured in a luciferase readout assay.
  • tuberculosis were determined by fitting the normalized data to a four-parameter logistic equation using GraphPad Prism software package.
  • 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 ⁇ M to 0.136 ⁇ M, 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.
  • 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.
  • 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.
  • nitrofurans 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 ).
  • 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).
  • DprE inhibitors 3, 4, 21.
  • DprE inhibitors 3, 4, 21.
  • An in vitro dose-response study against Mtb show all the compounds are relatively potent with half-maximal effective concentrations (EC 50 ) ranging from 0.05 ⁇ M to 6.86 ⁇ M (Fig.2, Table 2).
  • HC2210 a nitrofuran-piperazine- nitrophenol compound that has an EC 50 of 50 nM.
  • x v vo 50 ( ⁇ ) 50 o compoun s aga nst ntrace u ar t n one marrow-derived macrophages
  • CC 50 ( ⁇ M) macrophage cytotoxicity.
  • HC2233, HC2234, and HC2250 Three other nitrofurans in this study (HC2233, HC2234, and HC2250) were also bactericidal at the tested concentrations and time points, with 50 ⁇ M of HC2233 or HC2234 completely sterilizing the culture after 4 or 10 days of treatment, respectively (Fig.3B).
  • 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.
  • HC2210, HC2233, HC2234, and HC2250 are active against non-replicating Mtb.
  • Mtb can transition into a non-replicating persistent (NRP) state that is non-responsive to many antibiotics (24, 25).
  • 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 F 420 -dependent nitrofurans.
  • Spontaneous mutants resistant to HC2210 were isolated on media supplemented with either 0.1 ⁇ M or 0.3 ⁇ M HC2210 with a frequency of 1.6 x 10 -6 , similar to what was observed for pretomanid (1.8 x 10- 6 ).
  • 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 EC 50 of 5 ⁇ M, and 2) total resistance at all concentrations tested.
  • the partially resistant mutants were isolated from both the 0.1 ⁇ M and 0.3 ⁇ M HC2210 selection plates, while the fully resistant clones were only observed in the 0.3 ⁇ M selection plate. Without being bound to theory, the absence of fully resistant clones from the 0.1 ⁇ M 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).
  • HC2210 shares a related activation mechanism with pretomanid and delamanid.
  • 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).
  • 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.
  • HC2209, HC2210, and HC2211 are the only compounds in this study that depended on the F 420 bioreductive 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).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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).
  • 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).
  • 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.
  • nitrofurans such as HC2209, HC2210, and HC2211 depend on the fdg1 activation system for their antimicrobial activities.
  • Fdg1 provides the reduced form of cofactor F 420 that Ddn uses to activate the nitro- containing compounds into active metabolites.
  • 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.
  • the Fdg1-dependent nitrofurans did not fully lose their potency against the ddn mutants. They retained some levels of antimycobacterial activities at high concentrations (Fig.4; Fig.8).
  • Ddn the primary nitroreductase for these Fdg1- dependent nitrofurans and suggest a possible role for other secondary FDORs in the activation of the compounds.
  • CGI-17341 a parent nitroimidazole molecule for pretomanid and delamanid (11, 39, 40), depends on Fdg1 but not Ddn for activation (12, 16).
  • 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 Mab may be using an unknown FDOR to activate these compounds.
  • This FDOR may be found in both species but can only activate the nitrofurans described in this study. This hypothesis can be tested by the selection of spontaneous mutants or targeted disruption of candidate FDORs in Mab and testing for resistance. This study also identified two nitrofurans - HC2233 and HC2234 - which did not depend on either Fdg1 or Ddn for activation and do not elicit resistance in DprE1 mutants. It is possible that these compounds may not be prodrugs and do not require a nitroreductase for activation or they are prodrugs that require unknown activation systems.
  • DprE1 inhibitors The other five nitro-containing compounds in this study (HC2217, HC2226, HC2238, HC2239, and HC2250) are proposed to be DprE1 inhibitors. These inhibitors were potent against Mtb and Msm, probably owing to the high homology of DprE1 between both species (43, 44). Generally, DprE1 inhibitors can be classified as covalent or noncovalent inhibitors (31, 44). Resistance to covalent DprE1 inhibitors is usually characterized by the substitution of C387/384 to different residues (30, 31, 44). Due to the generation of C384S spontaneous mutants resistant to these compounds, it can be speculated that they may be covalent DprE1 inhibitors.
  • HC2250 seems to be different from other DprE1 inhibitors in terms of its bactericidal activity against NRP bacilli. During dormancy, cell wall biosynthesis, replication, or translation are minimized. Hence, drugs that target these physiologic activities in actively replicating cells are less effective against Mtb in the NRP state. As expected, NRP Mtb tolerated all the tested dinitrobenzamides (HC2217, HC2226, and HC2238) since these compounds likely target DprE1, an enzyme in the cell wall biosynthesis pathway. However, HC2250, a putative DprE1 inhibitor, continued to kill the bacilli even in the NRP phase.
  • HC2250 may also be targeting a cellular process that is needed by Mtb during dormancy.
  • partial resistance of F346C spontaneous mutants against the tested DprE1 inhibitors was observed.
  • the putative DprE1 inhibitors did not have any inhibitory activity against Mab, agreeing with a study done with PBTZ169, a covalent DprE1 inhibitor that have undergone clinical trials for TB treatment (32).
  • PBTZ169 a covalent DprE1 inhibitor that have undergone clinical trials for TB treatment (32).
  • HC2210 significantly reduced the burden of Mtb in both the lung and spleen of the infected mice when delivered orally. This finding shows the promise of HC2210 as a potential TB drug.
  • HC2210 is a nitrofuran with a piperazine backbone. HC2210 has two nitro groups, and an important question is whether one or both nitro groups are necessary for the full antimycobacterial activity of the compound.
  • A: EC 50 ⁇ 1 ⁇ M; B: 1 ⁇ M ⁇ EC 50 ⁇ 10 ⁇ M; C: 10 ⁇ M ⁇ EC 50 ⁇ 35 ⁇ M; D ⁇ 35 ⁇ M; ND Not Determined Example Mtb Mab Example Mtb Mab No. EC 50 EC 50 No. EC 50 EC 50 1 A A 50 D D Example Mtb Mab Example Mtb Mab No. EC 50 EC 50 No. EC 50 EC 50 45 ND A 94 C D R 1. Bagcchi S. WHO's Global Tuberculosis Report 2022. Lancet Microbe.2023;4(1):e20. 2.
  • Tuberculosis (Edinb).2018;108:186-94. 14.
  • Lee BM Harold LK, Almeida DV, Afriat-Jurnou L, Aung HL, Forde BM, et al. Predicting nitroimidazole antibiotic resistance mutations in Mycobacterium tuberculosis with protein engineering.
  • Rifat D Li SY, loerger T, Shah K, Lanoix JP, Lee J, et al. Mutations in fbiD (Rv2983) as a Novel Determinant of Resistance to Pretomanid and Delamanid in Mycobacterium tuberculosis.
  • Mutations in genes for the F420 biosynthetic pathway and a nitroreductase enzyme are the primary resistance determinants in spontaneous in vitro-selected PA-824-resistant mutants of Mycobacterium tuberculosis Antimicrob Agents Chemother.2015;59(9):5316-23. 18. Gupta R, Geiter LJ, Hafkin J, Wells CD. Delamanid and QT prolongation in the treatment of multidrug-resistant tuberculosis. Int J Tuberc Lung Dis.2015;19(10):1261-2. 19. Zheng H, Colvin CJ, Johnson BK, Kirchhoff PD, Wilson M, Jorgensen-Muga K, et al.
  • OPC- 67683 a nitro-dihydro-imidazooxazole derivative with promising action against tuberculosis in vitro and in mice.

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Abstract

L'invention concerne des composés, et des sels pharmaceutiquement acceptables de ceux-ci, utiles en tant qu'inhibiteurs de la croissance mycobactérienne. L'invention concerne également des compositions pharmaceutiques comprenant les composés ou des sels pharmaceutiquement acceptables et des procédés d'utilisation des composés, des sels pharmaceutiquement acceptables et des compositions pharmaceutiques dans le traitement de divers troubles, notamment l'infection par Mycobacterium tuberculosis et Mycobacterium abscessus.
PCT/US2024/037413 2023-07-10 2024-07-10 Composés contenant du nitro qui tuent des mycobactéries Pending WO2025015066A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020111492A1 (en) * 2000-11-15 2002-08-15 Eric Baque Heterocyclylalkylpiperidine derivatives, their preparation and compositions containing them
US20060100224A1 (en) * 2002-02-26 2006-05-11 Niels Svenstrup Piperidine ouracil used as a medicament for treating bacterial infections
US20210000799A1 (en) * 2017-12-22 2021-01-07 Board Of Trustees Of Michigan State University Chemical inhibitors of mycobacterium tuberculosis dosrst signaling and persistence

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020111492A1 (en) * 2000-11-15 2002-08-15 Eric Baque Heterocyclylalkylpiperidine derivatives, their preparation and compositions containing them
US20060100224A1 (en) * 2002-02-26 2006-05-11 Niels Svenstrup Piperidine ouracil used as a medicament for treating bacterial infections
US20210000799A1 (en) * 2017-12-22 2021-01-07 Board Of Trustees Of Michigan State University Chemical inhibitors of mycobacterium tuberculosis dosrst signaling and persistence

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE SUBSTANCE RECORD 31 May 2019 (2019-05-31), ANONYMOUS: "AKOS003976573", XP093267755, Database accession no. SID 108523777 *

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