Pyrazinamide-mimicking small molecules as treatment for tuberculosis

Abstract

The present disclosure provides small molecule anti-tuberculosis agents and pharmaceutical compositions comprising the anti-tuberculosis agents. The disclosure further provides a method of treating tuberculosis, including drug-resistant tuberculosis, in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the anti-tuberculosis agent.

Description

PYRAZINAMIDE-MIMICKING SMALL MOLECULES AS TREATMENT FOR TUBERCULOSIS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to U.S. Provisional Application No.63 / 606,434, filed December 5, 2023, the entirety of which is incorporated herein by reference. FIELD

[0002] The disclosure relates generally to small molecules which are active against Mycobacterium tuberculosis and methods of using the same for treating tuberculosis in a subject in need thereof. BACKGROUND

[0003] Drug-resistant tuberculosis (TB) continues to be a devastating threat to public health. Current anti-TB therapy commonly involves a long treatment (6-12 months) of a complex combination therapy containing at least four different drugs. Among the available anti-TB drugs, pyrazinamide (PZA) represents a cornerstone of modern anti-TB medicine by killing non- growing bacteria (known as persisters) that are not sensitive to other anti-TB agents in vivo. The global market of PZA reached $143.9 million in 2020 and is expected to have a 4.6% CAGR from 2020 to 2027. Despite its success in the clinic, PZA only shows weak anti-TB potency (MIC >1 mM). There is a need for small molecules which are active against Mycobacterium tuberculosis.

[0004] The present disclosure fulfills this need and provides additional advantages set forth herein. SUMMARY

[0005] In one aspect, the present disclosure provides a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof:Formula (I) wherein in Formula (Iis selected from phenyl and C6-C12heteroaryl, R10is selected from optionally substituted alkyl and -(CH2)m-O-C(O)-R10a, each R11is independently selected from hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, alkoxy, acyl, -NR12aR12b, -NR13-C(O)-OR14, -O-C(O)-NR15aR15b, -NR16-C(O)-R17, -NR18-C(O)-N- R19aR19b, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, and optionally substituted heterocyclyl, wherein two or more R11can bond or fuse to form optionally substituted heterocyclyl, R12a,R13, R15a, R15b, R16, R17, R18, R19a, and R19bare each independently selected from H and optionally substituted alkyl, R10ais optionally substituted alkyl, and R12bis optionally substituted alkyl; m is 1, 2, 3, or 4; and n is 0, 1, 2, 3, 4, or 5. O

[0006] In some embodiments, R10 is n-butyl, n-pentyl, n-hexyl, or. n some embodiments,is phenyl. In some embodiments, n is 1 and R11is selected from -NR12aR12b, -NR13-C(O)-OR14, -NR16-C(O)-R17, -NR18-C(O)-N- R19aR19b, and optionally substituted heterocyclyl. In some embodiments, R11is selected from -N(CH3)2,, nd - NH-C(O)-O-(CH2)p-CH3, wherein p is 1, 2, or 3. In some embodiments, two or more R11bond or fuse to form optionally substituted heterocyclyl. In some embodiments, two or more R11,

[0007] In some embodiments, the compound of Formula (I) is a compound of Formula (II), or a stereoisomer or a pharmaceutically acceptable salt thereof: (RFormula (II)wherein in Formula (II) R20is selected from optionally substituted alkyl and -(CH2)m-O-C(O)- R20a, each R21is independently selected from hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, alkoxy, acyl, -NR22aR22b, -NR23-C(O)-OR24, -O-C(O)- NR25aR25b, -NR26-C(O)-R27, -NR28-C(O)-N-R29aaR29ba, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, and optionally substituted heterocyclyl, wherein two or more R21can bond or fuse to form optionally substituted heterocyclyl, R22a,R23, R25a, R25b, R26, R27, R28, R29a, and R29baare each independently selected from H and optionally substituted alkyl, R22b is optionally substituted alkyl, R20ais optionally substituted alkyl, m is 1, 2, 3, or 4, n is 1, 2, 3, 4, or 5. In some embodiments, R20is unsubstituted C1-C6alkyl. In some embodiments, R20is n- O butyl, n-pentyl, n-hexyl, or. In some embodiments, n is 1. In some embodiments, R21is selected from -NR22aR22b, -NR23-C(O)-OR24, -N R26-C(O)- R27, -NR28-C(O)-N- R29aR29ba, and optionally substituted heterocyclyl. In some embodiments, R21is selected from -N(CH3)2,, and -NH-C(O)-O-(CH2)p-CH3, wherein p is 1, 2, or 3. In some embodiments, two or more R21bond or fuse to form optionally substituted heterocyclyl.

[0008] In some embodiments, two or more R11bond or fuse to form a compound of Formula (IIa) or a stereoisomer or a pharmaceutically acceptable salt thereof:Formula (IIa).

[0009] In some embodiments, the compound of Formula (I) or Formula (II) is selected from a compound having any one of formula 1001-1006, 1013-1020 or a stereoisomer or a pharmaceutically acceptable salt thereof:.

[0010] In some embodiments,s C6-C12heteroaryl. In some embodiments,

[0011] In some embodiments, the compound of Formula (I) is a compound of Formula (III), or a stereoisomer or a pharmaceutically acceptable salt thereof: EFormula (III) wherein in Formula (III) R30is optionally substituted alkyl and -(CH2)m-O-C(O)-R30a; R30ais optionally substituted alkyl, andn some embodiments, R30is unsubstituted C1-C6alkyl. In some embodiments, R30is n-butyl, n-pentyl, n- hexyl,

[0012] In some embodiments, the compound of Formula (III) is selected from a compound having any one of formula 1007-1012, or a stereoisomer or a pharmaceutically acceptable salt thereof:.

[0013] In some embodiments, the compound has a minimum inhibitory concentration of less than about 10 µM against tuberculosis.

[0014] In one aspect, the disclosure provides a pharmaceutical composition comprising one or more compounds of the disclosure, or a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition is for treating tuberculosis. In some embodiments, the pharmaceutical composition is formulated for oral administration.

[0015] In some embodiments the disclosure provides a method of treating tuberculosis in a subject in need thereof, the method includes administering to the subject a therapeutically effective amount of the compounds of the disclosure. In some embodiments, the tuberculosis is drug-resistant tuberculosis. BRIEF DESCRIPTION OF THE FIGURES

[0016] FIG.1 is a scheme depicting the in vivo activation of the bio-precursor PZA by the enzyme amidase to yield the active metabolite pyrazinoic acid.

[0017] FIG.2 depicts a non-limiting example of the design of new anti-TB agents based on the mechanism of action of PZA.

[0018] FIG.3 depicts select compounds of the disclosure.

[0019] FIG.4 depicts an image illustrating the determination of the Minimum Inhibitory Concentration (MIC) of FX6018 (left) and PZA (right) in PZA-S1 media using the Broth Microdilution Method. MICs were determined against three M. tuberculosis strains: PZA susceptible strain H37Ra (A); PZAR #6 strain (PncA mutation L159P) (B); and PZAR #136 strain (PanD mutation E126*) (C).DETAILED DESCRIPTION

[0020] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this disclosure belongs. All patents and publications referred to herein are incorporated by reference in their entireties. Definitions

[0021] As used herein, the terms “administer,” “administration” or “administering” refer to (1) providing, giving, dosing, and / or prescribing by either a health practitioner or his authorized agent or under his or her direction according to the disclosure; and / or (2) putting into, taking or consuming by the mammal, according to the disclosure.

[0022] The terms “co-administration,” “co-administering,” “administered in combination with,” “administering in combination with,” “simultaneous,” and “concurrent,” as used herein, encompass administration of two or more active pharmaceutical ingredients to a subject so that both active pharmaceutical ingredients and / or their metabolites are present in the subject at the same time. Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which two or more active pharmaceutical ingredients are present. Simultaneous administration in separate compositions and administration in a composition in which both agents are present are preferred.

[0023] The terms “active pharmaceutical ingredient” and “drug” include, but are not limited to, the compounds described herein and, more specifically, compounds of any of Formula (I Formula (II), or Formula (III), and their features and limitations as described herein.

[0024] The term “in vivo” refers to an event that takes place in a subject’s body.

[0025] The term “in vitro” refers to an event that takes places outside of a subject’s body. In vitro assays encompass cell-based assays in which cells alive or dead are employed and may also encompass a cell-free assay in which no intact cells are employed.

[0026] The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or combination of compounds as described herein that is sufficient to effect the intended application including, but not limited to, disease treatment. A therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject anddisease condition being treated (e.g., the weight, age and gender of the subject), the severity of the disease condition, the manner of administration, etc. which can readily be determined by one of ordinary skill in the art. The term also applies to a dose that will induce a particular response in target cells (e.g., increased sensitivity to apoptosis). The specific dose will vary depending on the particular compounds chosen, the dosing regimen to be followed, whether the compound is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which the compound is carried.

[0027] A “therapeutic effect” as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0028] The terms “QD,” “qd,” or “q.d.” mean quaque die, once a day, or once daily. The terms “BID,” “bid,” or “b.i.d.” mean bis in die, twice a day, or twice daily. The terms “TID,” “tid,” or “t.i.d.” mean ter in die, three times a day, or three times daily. The terms “QID,” “qid,” or “q.i.d.” mean quater in die, four times a day, or four times daily.

[0029] The term “pharmaceutically acceptable salt” refers to salts derived from a variety of organic and inorganic counter ions known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Preferred inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid and phosphoric acid. Preferred organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins. Specific examples include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In someembodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. The term “cocrystal” refers to a molecular complex derived from a number of cocrystal formers known in the art. Unlike a salt, a cocrystal typically does not involve hydrogen transfer between the cocrystal and the drug, and instead involves intermolecular interactions, such as hydrogen bonding, aromatic ring stacking, or dispersive forces, between the cocrystal former and the drug in the crystal structure.

[0030] “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and inert ingredients. The use of such pharmaceutically acceptable carriers or pharmaceutically acceptable excipients for active pharmaceutical ingredients is well known in the art. Except insofar as any conventional pharmaceutically acceptable carrier or pharmaceutically acceptable excipient is incompatible with the active pharmaceutical ingredient, its use in the therapeutic compositions of the disclosure is contemplated. Additional active pharmaceutical ingredients, such as other drugs disclosed herein, can also be incorporated into the described compositions and methods.

[0031] As used herein, the terms “treat,” “treatment,” and / or “treating” may refer to the management of a disease, disorder, or pathological condition, or symptom thereof with the intent to cure, ameliorate, stabilize, and / or control the disease, disorder, pathological condition or symptom thereof. Regarding control of the disease, disorder, or pathological condition more specifically, “control” may include the absence of condition progression, as assessed by the response to the methods recited herein, where such response may be complete (e.g., placing the disease in remission) or partial (e.g., lessening or ameliorating any symptoms associated with the condition).

[0032] As used herein, the terms “modulate” and “modulation” refer to a change in biological activity for a biological molecule (e.g., a protein, gene, peptide, antibody, and the like), where such change may relate to an increase in biological activity (e.g., increased activity, agonism, activation, expression, upregulation, and / or increased expression) or decrease in biological activity (e.g., decreased activity, antagonism, suppression, deactivation, downregulation, and / or decreased expression) for the biological molecule.

[0033] Unless otherwise stated, the chemical structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. Forexample, compounds where one or more hydrogen atoms is replaced by deuterium or tritium, or wherein one or more carbon atoms is replaced by13C- or14C-enriched carbons, are within the scope of this disclosure.

[0034] When ranges are used herein to describe, for example, physical or chemical properties such as molecular weight or chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. Use of the term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range may vary. The variation is typically from 0% to 15%, preferably from 0% to 10%, more preferably from 0% to 5% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) includes those embodiments such as, for example, an embodiment of any composition of matter, method or process that “consist of” or “consist essentially of” the described features.

[0035] “Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., (C1-10)alkyl or C1-10alkyl). Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range - e.g., “1 to 10 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the definition is also intended to cover the occurrence of the term “alkyl” where no numerical range is specifically designated. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl and decyl. The alkyl moiety may be attached to the rest of the molecule by a single bond, such as for example, methyl (Me), ethyl (Et), n-propyl (Pr), 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t- butyl) and 3-methylhexyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of substituents which are independently heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, - ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa(where tis 1 or 2), -S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tN(Ra)2(where t is 1 or 2), or PO3(Ra)2where each Rais independently hydrogen, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0036] “Alkylaryl” refers to an -(alkyl)aryl radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.

[0037] “Alkylhetaryl” refers to an -(alkyl)hetaryl radical where hetaryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.

[0038] “Alkylheterocycloalkyl” refers to an -(alkyl) heterocyclyl radical where alkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heterocycloalkyl and alkyl respectively.

[0039] An “alkene” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond, and an “alkyne” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon triple bond. The alkyl moiety, whether saturated or unsaturated, may be branched, straight chain, or cyclic.

[0040] “Alkenyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one double bond, and having from two to ten carbon atoms (i.e., (C2-10)alkenyl or C2-10alkenyl). Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range - e.g., “2 to 10 carbon atoms” means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. The alkenyl moiety may be attached to the rest of the molecule by a single bond, such as for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl and penta-1,4-dienyl. Unless stated otherwise specifically in the specification, an alkenyl group is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, - ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tN(Ra)2(where t is 1 or2), or PO3(Ra)2, where each Rais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0041] “Alkenyl-cycloalkyl” refers to an -(alkenyl)cycloalkyl radical where alkenyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for alkenyl and cycloalkyl respectively.

[0042] “Alkynyl” refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one triple bond, having from two to ten carbon atoms (i.e., (C2-10)alkynyl or C2-10alkynyl). Whenever it appears herein, a numerical range such as “2 to 10” refers to each integer in the given range - e.g., “2 to 10 carbon atoms” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms. The alkynyl may be attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl and hexynyl. Unless stated otherwise specifically in the specification, an alkynyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, - N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa(where t is 1 or 2), - S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tN(Ra)2(where t is 1 or 2), or PO3(Ra)2, where each Rais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0043] “Alkynyl-cycloalkyl” refers to an -(alkynyl)cycloalkyl radical where alkynyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for alkynyl and cycloalkyl respectively.

[0044] “Carboxaldehyde” refers to a -(C=O)H radical.

[0045] “Carboxyl” refers to a -(C=O)OH radical.

[0046] “Cyano” refers to a -CN radical.

[0047] “Cycloalkyl” refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated, or partially unsaturated. Cycloalkyl groups include groupshaving from 3 to 10 ring atoms (i.e. (C3-10)cycloalkyl or C3-10cycloalkyl). Whenever it appears herein, a numerical range such as “3 to 10” refers to each integer in the given range - e.g., “3 to 10 carbon atoms” means that the cycloalkyl group may consist of 3 carbon atoms, etc., up to and including 10 carbon atoms. Illustrative examples of cycloalkyl groups include, but are not limited to the following moieties: cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like. Unless stated otherwise specifically in the specification, a cycloalkyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, - N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa(where t is 1 or 2), - S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tN(Ra)2(where t is 1 or 2), or PO3(Ra)2, where each Rais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0048] “Cycloalkyl-alkenyl” refers to a -(cycloalkyl)alkenyl radical where cycloalkyl and alkenyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and alkenyl, respectively.

[0049] “Cycloalkyl-heterocycloalkyl” refers to a -(cycloalkyl)heterocycloalkyl radical where cycloalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heterocycloalkyl, respectively.

[0050] “Cycloalkyl-heteroaryl” refers to a -(cycloalkyl)heteroaryl radical where cycloalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for cycloalkyl and heteroaryl, respectively.

[0051] The term “alkoxy” refers to the group -O-alkyl, including from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy and cyclohexyloxy. “Lower alkoxy” refers to alkoxy groups containing one to six carbons.

[0052] The term “substituted alkoxy” refers to alkoxy wherein the alkyl constituent is substituted (i.e., -O-(substituted alkyl)). Unless stated otherwise specifically in the specification, the alkyl moiety of an alkoxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, - N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tN(Ra)2(where t is 1 or 2), or PO3(Ra)2, where each Rais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0053] The term “alkoxycarbonyl” refers to a group of the formula (alkoxy)(C=O)- attached through the carbonyl carbon wherein the alkoxy group has the indicated number of carbon atoms. Thus a (C1-6)alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker. “Lower alkoxycarbonyl” refers to an alkoxycarbonyl group wherein the alkoxy group is a lower alkoxy group.

[0054] The term “substituted alkoxycarbonyl” refers to the group (substituted alkyl)-O-C(O)- wherein the group is attached to the parent structure through the carbonyl functionality. Unless stated otherwise specifically in the specification, the alkyl moiety of an alkoxycarbonyl group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, - OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa(where t is 1 or 2), - S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tN(Ra)2(where t is 1 or 2), or PO3(Ra)2, where each Rais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0055] “Acyl” refers to the groups (alkyl)-C(O)-, (aryl)-C(O)-, (heteroaryl)-C(O)-, (heteroalkyl)- C(O)- and (heterocycloalkyl)-C(O)-, wherein the group is attached to the parent structure through the carbonyl functionality. If the R radical is heteroaryl or heterocycloalkyl, the heteroring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise specifically in the specification, the alkyl, aryl or heteroaryl moiety of the acyl group is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, - OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa(where t is 1 or 2), - S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tN(Ra)2(where t is 1 or 2), or PO3(Ra)2, where each Rais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0056] “Acyloxy” refers to a R(C=O)O- radical wherein R is alkyl, aryl, heteroaryl, heteroalkyl or heterocycloalkyl, which are as described herein. If the R radical is heteroaryl or heterocycloalkyl, the hetero ring or chain atoms contribute to the total number of chain or ring atoms. Unless stated otherwise specifically in the specification, the R of an acyloxy group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, - OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa(where t is 1 or 2), - S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tN(Ra)2(where t is 1 or 2), or PO3(Ra)2, where each Rais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0057] “Acylsulfonamide” refers a -S(O)2-N(Ra)-C(=O)- radical, where Rais hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl. Unless stated otherwise specifically in the specification, an acylsulfonamide group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, - ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tN(Ra)2(where t is 1 or 2), or PO3(Ra)2, where each Rais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl

[0058] “Amino” or “amine” refers to a -N(Ra)2radical group, where each Rais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl, unless stated otherwise specifically in the specification. When a -N(Ra)2group has two Rasubstituents other than hydrogen, they can be combined with the nitrogen atom to form a 4-, 5-, 6- or 7-membered ring. For example, -N(Ra)2is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl. Unless stated otherwise specifically in the specification, an amino group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, - N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa(where t is 1 or 2), - S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tN(Ra)2(where t is 1 or 2), or PO3(Ra)2, where each Rais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0059] The term “substituted amino” also refers to N-oxides of the groups -NHRa, and NRaRaeach as described above. N-oxides can be prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid.

[0060] “Amide” or “amido” refers to a chemical moiety with formula -C(O)N(R)2or -NHC(O)R, where R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon), each of which moiety may itself be optionally substituted. The R2 of -N(R)2of the amide may optionally be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6- or 7- membered ring. Unless stated otherwise specifically in the specification, an amido group is optionally substituted independently by one or more of the substituents as described herein foralkyl, cycloalkyl, aryl, heteroaryl, or heterocycloalkyl. An amide may be an amino acid or a peptide molecule attached to a compound disclosed herein, thereby forming a prodrug. The procedures and specific groups to make such amides are known to those of skill in the art and can readily be found in seminal sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rdEd., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety.

[0061] “Aromatic” or “aryl” or “Ar” refers to an aromatic radical with six to ten ring atoms (e.g., C6-C10aromatic or C6-C10aryl) which has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl). Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in “-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene. Whenever it appears herein, a numerical range such as “6 to 10” refers to each integer in the given range; e.g., “6 to 10 ring atoms” means that the aryl group may consist of 6 ring atoms, 7 ring atoms, etc., up to and including 10 ring atoms. The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Unless stated otherwise specifically in the specification, an aryl moiety is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, - OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tN(Ra)2(where t is 1 or 2), or PO3(Ra)2, where each Rais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0062] The term “aryloxy” refers to the group -O-aryl.

[0063] The term “substituted aryloxy” refers to aryloxy wherein the aryl substituent is substituted (i.e., -O-(substituted aryl)). Unless stated otherwise specifically in the specification, the aryl moiety of an aryloxy group is optionally substituted by one or more substituents whichindependently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, - N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tN(Ra)2(where t is 1 or 2), or PO3(Ra)2, where each Rais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0064] “Aralkyl” or “arylalkyl” refers to an (aryl)alkyl-radical where aryl and alkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for aryl and alkyl respectively.

[0065] “Ester” refers to a chemical radical of formula -COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). The procedures and specific groups to make esters are known to those of skill in the art and can readily be found in seminal sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rdEd., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety. Unless stated otherwise specifically in the specification, an ester group is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -ORa, -SRa, -OC(O)- Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa(where t is 1 or 2), - S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tN(Ra)2(where t is 1 or 2), or PO3(Ra)2, where each Rais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0066] “Fluoroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, as defined above, for example, trifluoromethyl, difluoromethyl, 2,2,2- trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. The alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group.

[0067] “Halo,” “halide,” or, alternatively, “halogen” is intended to mean fluoro, chloro, bromo or iodo. The terms “haloalkyl,” “haloalkenyl,” “haloalkynyl,” and “haloalkoxy” include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof. For example, the terms “fluoroalkyl” and “fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.

[0068] “Heteroalkyl,” “heteroalkenyl,” and “heteroalkynyl” refer to optionally substituted alkyl, alkenyl and alkynyl radicals and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. A numerical range may be given - e.g., C1-C4heteroalkyl which refers to the chain length in total, which in this example is 4 atoms long. A heteroalkyl group may be substituted with one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -ORa, -SRa, -OC(O)-Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, - C(O)N(Ra)2, -N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, - N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tN(Ra)2(where t is 1 or 2), or PO3(Ra)2, where each Rais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0069] “Heteroalkylaryl” refers to an -(heteroalkyl)aryl radical where heteroalkyl and aryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and aryl, respectively.

[0070] “Heteroalkylheteroaryl” refers to an -(heteroalkyl)heteroaryl radical where heteroalkyl and heteroaryl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heteroaryl, respectively.

[0071] “Heteroalkylheterocycloalkyl” refers to an -(heteroalkyl)heterocycloalkyl radical where heteroalkyl and heterocycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and heterocycloalkyl, respectively.

[0072] “Heteroalkylcycloalkyl” refers to an -(heteroalkyl)cycloalkyl radical where heteroalkyl and cycloalkyl are as disclosed herein and which are optionally substituted by one or more of the substituents described as suitable substituents for heteroalkyl and cycloalkyl, respectively.

[0073] “Heteroaryl” or “heteroaromatic” or “HetAr” or “Het” refers to a 5- to 18-membered aromatic radical (e.g., C5-C13heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system. Whenever it appears herein, a numerical range such as “5 to 18” refers to each integer in the given range - e.g., “5 to 18 ring atoms” means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, etc., up to and including 18 ring atoms. Bivalent radicals derived from univalent heteroaryl radicals whose names end in “-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical - e.g., a pyridyl group with two points of attachment is a pyridylidene. A N-containing “heteroaromatic” or “heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. The polycyclic heteroaryl group may be fused or non-fused. The heteroatom(s) in the heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, benzo[b][1,4]oxazinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2-c]pyridinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9,10- hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9,10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6,7,8-tetrahydroquinazolinyl, naphthyridinyl, 1,6- naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6a,7,8,9,10,10a- octahydrobenzo[h]quinazolinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4- d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl,pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8-tetrahydroquinazolinyl, 5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3- d]pyrimidinyl, 6,7,8,9-tetrahydro-5H-cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8- tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -ORa, -SRa, -OC(O)- Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, -N(Ra)C(O)ORa, - N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa(where t is 1 or 2), - S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tN(Ra)2(where t is 1 or 2), or PO3(Ra)2, where each Rais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0074] Substituted heteroaryl also includes ring systems substituted with one or more oxide (-O-) substituents, such as, for example, pyridinyl N-oxides.

[0075] “Heteroarylalkyl” refers to a moiety having an aryl moiety, as described herein, connected to an alkylene moiety, as described herein, wherein the connection to the remainder of the molecule is through the alkylene group.

[0076] “Heterocycloalkyl” refers to a stable 3- to 18-membered non-aromatic ring radical that comprises two to twelve carbon atoms and from one to six heteroatoms selected from nitrogen, oxygen and sulfur. Whenever it appears herein, a numerical range such as “3 to 18” refers to each integer in the given range - e.g., “3 to 18 ring atoms” means that the heterocycloalkyl group may consist of 3 ring atoms, 4 ring atoms, etc., up to and including 18 ring atoms. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical is a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which may include fused or bridged ring systems. The heteroatoms in the heterocycloalkyl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heterocycloalkyl radical is partially or fully saturated. The heterocycloalkyl may be attached to the rest of the molecule through any atom of the ring(s). Examples of such heterocycloalkyl radicals include, but are not limited to,dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2- oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4- piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo- thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl moiety is optionally substituted by one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -ORa, -SRa, -OC(O)- Ra, -N(Ra)2, -C(O)Ra, -C(O)ORa, -OC(O)N(Ra)2, -C(O)N(Ra)2, - N(Ra)C(O)ORa, -N(Ra)C(O)Ra, -N(Ra)C(O)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(O)tRa(where t is 1 or 2), -S(O)tRa(where t is 1 or 2), -S(O)tORa(where t is 1 or 2), -S(O)tN(Ra)2(where t is 1 or 2), or PO3(Ra)2, where each Rais independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

[0077] “Heterocycloalkyl” also includes bicyclic ring systems wherein one non-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms; and the other ring, usually with 3 to 7 ring atoms, optionally contains 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen and is not aromatic.

[0078] “Nitro” refers to the -NO2radical.

[0079] “Oxa” refers to the -O- radical.

[0080] “Oxo” refers to the =O radical.

[0081] “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space - i.e., having a different stereochemical configuration. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer the stereochemistry at each chiral carbon can be specified by either (R) or (S). Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) which they rotate plane polarized light at the wavelength of the sodium D line. Certain of the compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R) or (S). The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0082] “Enantiomeric purity” as used herein refers to the relative amounts, expressed as a percentage, of the presence of a specific enantiomer relative to the other enantiomer. For example, if a compound, which may potentially have an (R)- or an (S)-isomeric configuration, is present as a racemic mixture, the enantiomeric purity is about 50% with respect to either the (R)- or (S)-isomer. If that compound has one isomeric form predominant over the other, for example, 80% (S)-isomer and 20% (R)-isomer, the enantiomeric purity of the compound with respect to the (S)-isomeric form is 80%. The enantiomeric purity of a compound can be determined in a number of ways known in the art, including but not limited to chromatography using a chiral support, polarimetric measurement of the rotation of polarized light, nuclear magnetic resonance spectroscopy using chiral shift reagents which include but are not limited to lanthanide containing chiral complexes or Pirkle’s reagents, or derivatization of a compounds using a chiral compound such as Mosher’s acid followed by chromatography or nuclear magnetic resonance spectroscopy.

[0083] In some embodiments, the enantiomerically enriched composition has a higher potency with respect to therapeutic utility per unit mass than does the racemic mixture of that composition. Enantiomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred enantiomers can be prepared by asymmetric syntheses.See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions, Wiley Interscience, New York (1981); E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw-Hill, New York (1962); and E. L. Eliel and S. H. Wilen, Stereochemistry of Organic Compounds, Wiley- Interscience, New York (1994).

[0084] The terms “enantiomerically enriched” and “non-racemic,” as used herein, refer to compositions in which the percent by weight of one enantiomer is greater than the amount of that one enantiomer in a control mixture of the racemic composition (e.g., greater than 1:1 by weight). For example, an enantiomerically enriched preparation of the (S)-enantiomer, means a preparation of the compound having greater than 50% by weight of the (S)-enantiomer relative to the (R)-enantiomer, such as at least 75% by weight, or such as at least 80% by weight. In some embodiments, the enrichment can be significantly greater than 80% by weight, providing a “substantially enantiomerically enriched” or a “substantially non-racemic” preparation, which refers to preparations of compositions which have at least 85% by weight of one enantiomer relative to other enantiomer, such as at least 90% by weight, or such as at least 95% by weight. The terms “enantiomerically pure” or “substantially enantiomerically pure” refers to a composition that comprises at least 98% of a single enantiomer and less than 2% of the opposite enantiomer.

[0085] “Moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0086] “Tautomers” are structurally distinct isomers that interconvert by tautomerization. “Tautomerization” is a form of isomerization and includes prototropic or proton-shift tautomerization, which is considered a subset of acid-base chemistry. “Prototropic tautomerization” or “proton-shift tautomerization” involves the migration of a proton accompanied by changes in bond order, often the interchange of a single bond with an adjacent double bond. Where tautomerization is possible (e.g., in solution), a chemical equilibrium of tautomers can be reached. An example of tautomerization is keto-enol tautomerization. A specific example of keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4- hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. A specific example of phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.

[0087] A “leaving group or atom” is any group or atom that will, under selected reaction conditions, cleave from the starting material, thus promoting reaction at a specified site. Examples of such groups, unless otherwise specified, include halogen atoms and mesyloxy, p- nitrobenzensulphonyloxy and tosyloxy groups.

[0088] “Protecting group” is intended to mean a group that selectively blocks one or more reactive sites in a multifunctional compound such that a chemical reaction can be carried out selectively on another unprotected reactive site and the group can then be readily removed or deprotected after the selective reaction is complete. A variety of protecting groups are disclosed, for example, in T. H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, Third Edition, John Wiley & Sons, New York (1999).

[0089] “Solvate” refers to a compound in physical association with one or more molecules of a pharmaceutically acceptable solvent.

[0090] “Substituted” means that the referenced group may have attached one or more additional groups, radicals or moieties individually and independently selected from, for example, acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, carbonate, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, oxo, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. The substituents themselves may be substituted, for example, a cycloalkyl substituent may itself have a halide substituent at one or more of its ring carbons. The term “optionally substituted” means optional substitution with the specified groups, radicals or moieties.

[0091] “Sulfanyl” refers to groups that include -S-(optionally substituted alkyl), -S-(optionally substituted aryl), -S-(optionally substituted heteroaryl) and -S-(optionally substituted heterocycloalkyl).

[0092] “Sulfinyl” refers to groups that include -S(O)-H, -S(O)-(optionally substituted alkyl), -S(O)-(optionally substituted amino), -S(O)-(optionally substituted aryl), -S(O)- (optionally substituted heteroaryl) and -S(O)-(optionally substituted heterocycloalkyl).

[0093] “Sulfonyl” refers to groups that include -S(O2)-H, -S(O2)-(optionally substituted alkyl), -S(O2)-(optionally substituted amino), -S(O2)-(optionally substituted aryl), -S(O2)- (optionally substituted heteroaryl), and -S(O2)-(optionally substituted heterocycloalkyl).

[0094] “Sulfonamidyl” or “sulfonamido” refers to a -S(=O)2-NRR radical, where each R is selected independently from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). The R groups in -NRR of the -S(=O)2-NRR radical may be taken together with the nitrogen to which it is attached to form a 4-, 5-, 6- or 7-membered ring. A sulfonamido group is optionally substituted by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.

[0095] “Sulfoxyl” refers to a -S(=O)2OH radical.

[0096] “Sulfonate” refers to a -S(=O)2-OR radical, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon) and heteroalicyclic (bonded through a ring carbon). A sulfonate group is optionally substituted on R by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.

[0097] Compounds of the disclosure also include crystalline and amorphous forms of those compounds, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof. “Crystalline form” and “polymorph” are intended to include all crystalline and amorphous forms of the compound, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, as well as mixtures thereof, unless a particular crystalline or amorphous form is referred to.

[0098] For the avoidance of doubt, it is intended herein that particular features (for example integers, characteristics, values, uses, diseases, formulae, compounds or groups) described in conjunction with a particular aspect, embodiment or example of the disclosure are to be understood as applicable to any other aspect, embodiment or example described herein unless incompatible therewith. Thus such features may be used where appropriate in conjunction with any of the definition, claims or embodiments defined herein. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of the features and / or steps are mutually exclusive. The disclosure is not restricted to any details of any disclosed embodiments. The disclosure extends to any novel one, or novel combination, of the features disclosed in this specification (includingany accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0099] Moreover, as used herein, the term “about” means that dimensions, sizes, formulations, parameters, shapes and other quantities and characteristics are not and need not be exact, but may be approximate and / or larger or smaller, as desired, reflecting tolerances, conversion factors, rounding off, measurement error and the like, and other factors known to those of skill in the art. In general, a dimension, size, formulation, parameter, shape or other quantity or characteristic is “about” or “approximate” whether or not expressly stated to be such. It is noted that embodiments of very different sizes, shapes and dimensions may employ the described arrangements.

[0100] Furthermore, the transitional terms “comprising”, “consisting essentially of” and “consisting of”, when used in the appended claims, in original and amended form, define the claim scope with respect to what unrecited additional claim elements or steps, if any, are excluded from the scope of the claim(s). The term “comprising” is intended to be inclusive or open-ended and does not exclude any additional, unrecited element, method, step or material. The term “consisting of” excludes any element, step or material other than those specified in the claim and, in the latter instance, impurities ordinary associated with the specified material(s). The term “consisting essentially of” limits the scope of a claim to the specified elements, steps or material(s) and those that do not materially affect the basic and novel characteristic(s) of the disclosure. All embodiments of the disclosure can, in the alternative, be more specifically defined by any of the transitional terms “comprising,” “consisting essentially of,” and “consisting of.” Small molecule anti-TB agents

[0101] In one aspect, the present disclosure provides small molecule anti-TB agents. In one embodiment, the small molecule anti-TB agent is a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof: (R11Formula (I)wherein in Formula (I):is selected from phenyl and C6-C12heteroaryl; R10is selected from optionally substituted alkyl and -(CH2)m-O-C(O)-R10a; each R11is independently selected from hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, alkoxy, acyl, -NR12aR12b, -NR13-C(O)-OR14, -O-C(O)- NR15aR15b, -NR16-C(O)-R17, -NR18-C(O)-N-R19aR19b, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, and optionally substituted heterocyclyl, wherein one or more R11can bond or fuse toto form one or more optionally substituted heterocyclyls; R12a, R13, R14, NR15aR15b, R16, R17, R18, R19a, and R19bare each independently selected from H and optionally substituted alkyl; R12bis optionally substituted alkyl, wherein R12aand R12bcan bond or fuse to form an optionally substituted heterocyclyl; R10ais optionally substituted alkyl; m is 1, 2, 3, or 4; and n is 0, 1, 2, 3, 4, or 5.

[0102] In one embodiment, R10is unsubstituted C1-C6alkyl. In one embodiment, R10is methyl. In one embodiment, R10is ethyl. In one embodiment, R10is n-propyl. In one embodiment, R10is i-propyl. In one embodiment, R10is n-butyl. In one embodiment, R10is i- butyl. In one embodiment, R10is t-butyl. In one embodiment, R10is n-pentyl. In one embodiment, R10is i-pentanyl. In one embodiment, R10is neopentyl. In one embodiment, R10is n-hexyl. In one embodiment, R10is 2-methylpentyl. In one embodiment, R10is 3-methylpentyl. In one embodiment, R10is 2,3-dimethylbutyl. In one embodiment, R10is 2,2-dimethylbutyl. In one embodiment, R10is -(CH2)m-O-C(O)-R10a. In one embodiment, R10ais unsubstituted C1-C6alkyl. In one embodiment, R10ais methyl. In one embodiment, R10ais ethyl. In one embodiment, R10ais n-propyl. In one embodiment, R10ais i-propyl. In one embodiment, R10ais n-butyl. In one embodiment, R10ais i-butyl. In one embodiment, R10ais t-butyl. In one embodiment, R10ais n-pentyl. In one embodiment, R10ais i-pentanyl. In one embodiment, R10ais neopentyl. In one embodiment, R10ais n-hexyl. In one embodiment, R10ais 2-methylpentyl.In one embodiment, R10ais 3-methylpentyl. In one embodiment, R10ais 2,3-dimethylbutyl. In one embodiment, R10ais 2,2-dimethylbutyl.

[0103] In one embodiment, R10is substituted C1-C6alkyl. In some embodiments, R10is a C1-C6alkyl substituted with an ester. In one embodiment, the ester is a methyl ester. In one embodiment, the ester is an ethyl ester. In one embodiment, the ester is an n-propyl ester. In one embodiment, the ester is an i-propyl ester. In one embodiment, the ester is an n-butyl ester. In one embodiment, the ester is an i-butyl ester. In one embodiment, the ester is a t-butyl ester. In one embodiment, the ester is an n-pentyl ester. In one embodiment, the ester is an i-pentanyl ester. In one embodiment, the ester is a neopentyl ester. In one embodiment, the ester is an n- hexyl ester. In one embodiment, the ester is a 2-methylpentyl ester. In one embodiment, the ester is a 3-methylpentyl ester. In one embodiment, the ester is a 2,3-dimethylbutyl ester. In one embodiment, the ester is a 2,2-dimethylbutyl ester.

[0104] In one embodiment,s phenyl.

[0105] In one embodiment, n is 1. In one embodiment, n is 1 and R11is selected from -NR12aR12b, -NR13-C(O)-OR14, and optionally substituted heterocyclyl. In one embodiment, n is 1 and R11is selected from -N(CH3)2,, nd -NH-C(O)-O-(CH2)p-CH3, wherein p is 1, 2, or 3. In another embodiment, one or more R11bond or fuse to form optionally substituted heterocyclyl. In one embodiment, one or more R11, together withorm-NR12aR12b, wherein R12a and R12bbond or fuse toIn another non-limiting example, n isA 1 and R11is -NR12aR12b, wherein R12a and R12bbond or fuse to to form,

[0106] In one embodiment, the compound of Formula (I) is a compound of Formula (II), or a stereoisomer or a pharmaceutically acceptable salt thereof: (Formula (II) wherein in Formula (II): R20is selected from optionally substituted alkyl and -(CH2)m-O-C(O)-R20a; each R21is independently selected from hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, alkoxy, acyl, -NR22aR22b, -NR23-C(O)-OR24, -O-C(O)- NR25aR25b, -NR26-C(O)-R27, -NR28-C(O)-N-R29aR29b, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, and optionally substituted heterocyclyl, wherein one or more R21can bond or fuse to the phenyl ring to form one or more optionally substituted heterocyclyls; R22a,R23, R24, R25a, R25b, R26, R27, R28, R29a, and R29bare each independently selected from H and optionally substituted alkyl; R22b is optionally substituted alkyl, wherein R22a and R22b can bond or fuse to form an optionally substituted heterocyclyl; R20ais optionally substituted alkyl, m is 1, 2, 3, or 4; and n is 1, 2, 3, 4, or 5.

[0107] In one embodiment, R20is unsubstituted C1-C6alkyl. In one embodiment, R20is unsubstituted C1-C6alkyl. In one embodiment, R20is methyl. In one embodiment, R20is ethyl. In one embodiment, R20is n-propyl. In one embodiment, R20is i-propyl. In one embodiment, R20is n-butyl. In one embodiment, R20is i-butyl. In one embodiment, R20is t-butyl. In oneembodiment, R20is n-pentyl. In one embodiment, R20is i-pentanyl. In one embodiment, R20is neopentyl. In one embodiment, R20is n-hexyl. In one embodiment, R20is 2-methylpentyl. In one embodiment, R20is 3-methylpentyl. In one embodiment, R20is 2,3-dimethylbutyl. In one embodiment, R20is 2,2-dimethylbutyl. In one embodiment, R20is -(CH2)m-O-C(O)-R20a. In one embodiment, R20ais unsubstituted C1-C6alkyl. In one embodiment, R20ais methyl. In one embodiment, R20ais ethyl. In one embodiment, R20ais n-propyl. In one embodiment, R20ais i- propyl. In one embodiment, R20ais n-butyl. In one embodiment, R20ais i-butyl. In one embodiment, R20ais t-butyl. In one embodiment, R20ais n-pentyl. In one embodiment, R20ais i- pentanyl. In one embodiment, R20ais neopentyl. In one embodiment, R20ais n-hexyl. In one embodiment, R20ais 2-methylpentyl. In one embodiment, R20ais 3-methylpentyl. In one embodiment, R20ais 2,3-dimethylbutyl. In one embodiment, R20ais 2,2-dimethylbutyl.

[0108] In one embodiment, R20is substituted C1-C6alkyl. In some embodiments, R20is a C1-C6alkyl substituted with an ester. In one embodiment, the ester is a methyl ester. In one embodiment, the ester is an ethyl ester. In one embodiment, the ester is an n-propyl ester. In one embodiment, the ester is an i-propyl ester. In one embodiment, the ester is an n-butyl ester. In one embodiment, the ester is an i-butyl ester. In one embodiment, the ester is a t-butyl ester. In one embodiment, the ester is an n-pentyl ester. In one embodiment, the ester is an i-pentanyl ester. In one embodiment, the ester is a neopentyl ester. In one embodiment, the ester is an n- hexyl ester. In one embodiment, the ester is a 2-methylpentyl ester. In one embodiment, the ester is a 3-methylpentyl ester. In one embodiment, the ester is a 2,3-dimethylbutyl ester. In one embodiment, the ester is a 2,2-dimethylbutyl ester.

[0109] In one embodiment, the compound of Formula (I) is a compound of Formula (II) wherein n is 1. In one embodiment, n is 1 and R21is selected from -NR22aR22b, -NR23-C(O)- OR24, and optionally substituted heterocyclyl. In one embodiment, n is 1 and R21is selected from -N(CH3)2,and -NH-C(O)-O-(CH2)p-CH3, wherein p is 1, 2, or 3.

[0110] In another embodiment, one or more R21bond or fuse to the phenyl ring to form one or more optionally substituted heterocyclyls. In one embodiment, one or more R21bond or fuse to form a compound of Formula (IIa) or a stereoisomer or a pharmaceutically acceptable salt thereof:Formula (IIa).

[0111] In one embodiment, one or more R21bond or fuse to form a compound of Formula (IIb) or a stereoisomer or a pharmaceutically acceptable salt thereof:Formula (IIb).

[0112] In one embodiment, the compound of Formula (I) or Formula (II) is selected from a compound having any one of formula 1001-1006, or 1013-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof:

[0113] In another embodiment,s C6-C12heteroaryl. In one embodiment, the C6- C12heteroaryl comprises a phenyl ring fused to a ring comprising one or more heteroatoms. In one embodiment, the C6-C12heteroaryl comprises a phenyl ring fused to a ring comprising one or more nitrogen atoms, wherein the ring optionally comprises one or more oxygen atoms. In one embodiment, the C6-C12heteroaryl comprises a phenyl ring fused to a ring comprising two or three nitrogen atoms. In one embodiment, the C6-C12heteroaryl comprises a phenyl ring fused to a ring comprising one nitrogen atom and one oxygen atom. In one embodiment,isO In one embodiment,s C6-C12heteroaryl and n of Formula (I) is 0.

[0114] In one embodiment, the compound of Formula (I) is a compound of Formula (III) or Formula (IIIa), or a stereoisomer or a pharmaceutically acceptable salt thereof: EFormula (III) Formula (IIIa). wherein in Formula (III) or Formula (IIIa): R30is selected from optionally substituted alkyl and -(CH2)m-O-C(O)-R30a; R30ais optionally substituted alkyl, and

[0115] In one embodiment, R30is unsubstituted C1-C6alkyl. In one embodiment, R30is unsubstituted C1-C6alkyl. In one embodiment, R30is methyl. In one embodiment, R30is ethyl. In one embodiment, R30is n-propyl. In one embodiment, R30is i-propyl. In one embodiment, R30is n-butyl. In one embodiment, R30is i-butyl. In one embodiment, R30is t-butyl. In one embodiment, R30is n-pentyl. In one embodiment, R30is i-pentanyl. In one embodiment, R30is neopentyl. In one embodiment, R30is n-hexyl. In one embodiment, R30is 2-methylpentyl. In one embodiment, R30is 3-methylpentyl. In one embodiment, R30is 2,3-dimethylbutyl. In one embodiment, R30is 2,2-dimethylbutyl. In one embodiment, R30is -(CH2)m-O-C(O)-R30a. In one embodiment, R30ais unsubstituted C1-C6alkyl. In one embodiment, R30ais methyl. In one embodiment, R30ais ethyl. In one embodiment, R30ais n-propyl. In one embodiment, R30ais i- propyl. In one embodiment, R30ais n-butyl. In one embodiment, R30ais i-butyl. In one embodiment, R30ais t-butyl. In one embodiment, R30ais n-pentyl. In one embodiment, R30ais i- pentanyl. In one embodiment, R30ais neopentyl. In one embodiment, R30ais n-hexyl. In one embodiment, R30ais 2-methylpentyl. In one embodiment, R30ais 3-methylpentyl. In one embodiment, R30ais 2,3-dimethylbutyl. In one embodiment, R30ais 2,2-dimethylbutyl.

[0116] In one embodiment, R30is substituted C1-C6alkyl. In some embodiments, R30is a C1-C6alkyl substituted with an ester. In one embodiment, the ester is a methyl ester. In one embodiment, the ester is an ethyl ester. In one embodiment, the ester is an n-propyl ester. In one embodiment, the ester is an i-propyl ester. In one embodiment, the ester is an n-butyl ester. In one embodiment, the ester is an i-butyl ester. In one embodiment, the ester is a t-butyl ester. In one embodiment, the ester is an n-pentyl ester. In one embodiment, the ester is an i-pentanyl ester. In one embodiment, the ester is a neopentyl ester. In one embodiment, the ester is an n- hexyl ester. In one embodiment, the ester is a 2-methylpentyl ester. In one embodiment, the ester is a 3-methylpentyl ester. In one embodiment, the ester is a 2,3-dimethylbutyl ester. In one embodiment, the ester is a 2,2-dimethylbutyl ester.

[0117] In one embodiment, the compound of Formula (III) is selected from a compound having any one of formula 1007-1012, or a stereoisomer or a pharmaceutically acceptable salt thereof:

[0118] In one embodiment, the compound of Formula (I), the compound of Formula (II), the compound of Formula (III), or a stereoisomer or a pharmaceutically acceptable salt thereof, has a minimum inhibitory concentration (MIC) of less than about 150 µM, less than about 140 µM, less than about 130 µM, less than about 120 µM, less than about 110 µM, less than about 100 µM, less than about 90 µM, less than about 80 µM, less than about 70 µM, less than about 60 µM, less than about 50 µM, less than about 40 µM, less than about 30 µM, less than about 20 µM, less than about 10 µM, less than about 5 µM, or less than about 1 µM against Mycobacterium tuberculosis. In one embodiment, the compound of Formula (I), the compound of Formula (II), the compound of Formula (III), or a stereoisomer or a pharmaceutically acceptable salt thereof, has a minimum inhibitory concentration (MIC) of less than about 10 µM, less than about 5 µM, or less than about 1 µM against Mycobacterium tuberculosis.Methods of Treatment

[0119] In another aspect, the present disclosure relates to a method of treating tuberculosis in a subject in need thereof. In one embodiment, the method comprises administering to the administering to the subject a therapeutically effective amount of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof. Exemplary compounds of Formula (I), Formula (II), and Formula (III) are provided elsewhere herein. In one embodiment, the tuberculosis is drug-resistant tuberculosis.

[0120] In one embodiment, the method comprises administering to the subject in need thereof a pharmaceutical composition comprising a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof. In one embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. Exemplary pharmaceutically acceptable carriers are described elsewhere herein.

[0121] In some embodiments, the method further comprises administering to the subject a therapeutically effective amount of one or more additional anti-TB agents. In one embodiment, the one or more additional anti-TB agents comprise the current standard of care for tuberculosis. In one embodiment, the one or more additional anti-TB agents are selected from isoniazid, rifampin (rifadin, rimactane), ethambutol (myambutol), and pyrazinamide.

[0122] In one embodiment, the compound of Formula (I), the compound of Formula (II), the compound of Formula (III), or a stereoisomer or a pharmaceutically acceptable salt thereof, is administered orally to the subject. In one embodiment, the one or more additional anti-TB agents is administered orally to the subject. In one embodiment, the compound of Formula (I), the compound of Formula (II), the compound of Formula (III), or a stereoisomer or a pharmaceutically acceptable salt thereof, and the one or more additional anti-TB agents are administered concurrently to the subject. In one embodiment, the compound of Formula (I), the compound of Formula (II), the compound of Formula (III), or a stereoisomer or a pharmaceutically acceptable salt thereof, and the one or more additional anti-TB agents are co- formulated into a pharmaceutical composition which is administered to the subject. In another embodiment, the compound of Formula (I), the compound of Formula (II), the compound ofFormula (III), or a stereoisomer or a pharmaceutically acceptable salt thereof, and the one or more additional anti-TB agents are administered sequentially to the subject.

[0123] In some embodiments, the methods of treatment include providing certain dosage amounts of a compound of Formula (I), Formula (II), Formula (III), or a stereoisomer or a pharmaceutically acceptable salt thereof to a subject. In some embodiments, the dosage levels of each active agent of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of tuberculosis in the subject (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single unit dosage form will vary depending upon the subject treated and the particular mode of administration.

[0124] In some embodiments a therapeutically effect amount is an amount that provide a plasma Cmax of a compound of a compound of any of Formula (I), Formula (II), Formula (III), or a stereoisomer or a pharmaceutically acceptable salt thereof of about of 0.25 mcg / mL to about 125 mcg / mL, or about 1 mcg / mL to about 50 mcg / mL in the subject. Pharmaceutical Compositions

[0125] In an embodiment, the disclosure provides a pharmaceutical composition for use in the treatment of tuberculosis. In one embodiment, the tuberculosis is drug resistant tuberculosis.

[0126] The pharmaceutical compositions are typically formulated to provide a therapeutically effective amount of a compound of any of Formula (I), Formula (II), Formula (III), or a stereoisomer or a pharmaceutically acceptable salt thereof, as described herein, as the active ingredient. Typically, the pharmaceutical compositions also comprise one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. In one embodiment, the pharmaceutical composition is formulated for oral administration.

[0127] In one aspect, the present disclosure relates to a pharmaceutical composition comprising one or more small molecule anti-TB agents described elsewhere herein. In one embodiment, the small molecule anti-TB agent is a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or astereoisomer or a pharmaceutically acceptable salt thereof. In another aspect, the present disclosure relates to pharmaceutical composition for treating tuberculosis, the pharmaceutical composition comprising one or more small molecule anti-TB agents described elsewhere herein. In one embodiment, the small molecule anti-TB agent is a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof.

[0128] In some embodiments, the concentration of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, provided in the pharmaceutical compositions of the disclosure is less than, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w / w, w / v or v / v of the pharmaceutical composition.

[0129] In some embodiments, the concentration of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, provided in the pharmaceutical compositions of the disclosure is independently greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18.25%, 18%, 17.75%, 17.50%, 17.25%, 17%, 16.75%, 16.50%, 16.25% 16%, 15.75%, 15.50%, 15.25%, 15%, 14.75%, 14.50%, 14.25%, 14%, 13.75%, 13.50%, 13.25% 13%, 12.75%, 12.50%, 12.25%, 12%, 11.75%, 11.50%, 11.25% 11%, 10.75%, 10.50%, 10.25%, 10%, 9.75%, 9.50%, 9.25%, 9%, 8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25% 6%, 5.75%, 5.50%, 5.25% 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001% w / w, w / v, or v / v of the pharmaceutical composition.

[0130] In some embodiments, the concentration of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, provided in the pharmaceutical compositions of the disclosure is in the range from about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12% or about 1% to about 10% w / w, w / v or v / v of the pharmaceutical composition.

[0131] In some embodiments, the concentration of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, provided in the pharmaceutical compositions of the disclosure is in the range from about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9% w / w, w / v or v / v of the pharmaceutical composition.

[0132] In some embodiments, the amount of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, provided in the pharmaceutical compositions of the disclosure is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g.

[0133] In some embodiments, the amount of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, provided in the pharmaceutical compositions of the disclosure is more than 0.0001 g, 0.0002 g, 0.0003 g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g, 0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g,0.004 g, 0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g, 0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g, 0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g, 0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g, 0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g, 0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g, 1.5 g, 2 g, 2.5 g, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g, 7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.

[0134] Each of the compounds provided according to the disclosure is effective over a wide dosage range. For example, in the treatment of adult humans, dosages independently ranging from 0.01 to 1000 mg, from 0.5 to 100 mg, from 1 to 50 mg per day, and from 5 to 40 mg per day are examples of dosages that may be used. The exact dosage will depend upon the route of administration, the form in which the compound is administered, the gender and age of the subject to be treated, the body weight of the subject to be treated, and the preference and experience of the attending physician.

[0135] Described below are non-limiting pharmaceutical compositions and methods for preparing the same. Pharmaceutical Compositions for Oral Administration

[0136] In preferred embodiments, the disclosure provides a pharmaceutical composition for oral administration containing: a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein, and a pharmaceutical excipient suitable for administration.

[0137] In preferred embodiments, the disclosure provides a solid pharmaceutical composition for oral administration containing: (i) an effective amount of: a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, and (ii) a pharmaceutical excipient suitable for administration. In some embodiments, the composition further contains (iii) an effective amount of an additional active pharmaceutical ingredient. For example, additional active pharmaceutical ingredients, as used herein, may include one or more compounds that are useful in the treatment or prevention of tuberculosis.

[0138] In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption.

[0139] Pharmaceutical compositions of the disclosure suitable for oral administration can be presented as discrete dosage forms, such as capsules, sachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil-in-water emulsion, a water-in-oil liquid emulsion, powders for reconstitution, powders for oral consumptions, bottles (including powders or liquids in a bottle), orally dissolving films, lozenges, pastes, tubes, gums, and packs. Such dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient(s) into association with the carrier, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient(s) with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granules, optionally mixed with an excipient such as, but not limited to, a binder, a lubricant, an inert diluent, and / or a surface active or dispersing agent. Molded tablets can be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.

[0140] The disclosure further encompasses anhydrous pharmaceutical compositions and dosage forms since water can facilitate the degradation of some compounds. For example, water may be added (e.g., 5%) in the pharmaceutical arts as a means of simulating long-term storage in order to determine characteristics such as shelf-life or the stability of formulations over time. Anhydrous pharmaceutical compositions and dosage forms of the disclosure can be prepared using anhydrous or low moisture containing ingredients and low moisture or low humidity conditions. Pharmaceutical compositions and dosage forms of the disclosure which contain lactose can be made anhydrous if substantial contact with moisture and / or humidity during manufacturing, packaging, and / or storage is expected. An anhydrous pharmaceutical composition may be prepared and stored such that its anhydrous nature is maintained. Accordingly, anhydrous compositions may be packaged using materials known to preventexposure to water such that they can be included in suitable formulary kits. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.

[0141] Active pharmaceutical ingredients can be combined in an intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier can take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for an oral dosage form, any of the usual pharmaceutical media can be employed as carriers, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols; or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose. For example, suitable carriers include powders, capsules, and tablets, with the solid oral preparations. If desired, tablets can be coated by standard aqueous or nonaqueous techniques.

[0142] Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.

[0143] Examples of suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch, and mixtures thereof.

[0144] Disintegrants may be used in the compositions of the disclosure to provide tablets that disintegrate when exposed to an aqueous environment. Too much of a disintegrant may produce tablets which disintegrate in the bottle. Too little may be insufficient for disintegration to occur, thus altering the rate and extent of release of the active ingredients from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much todetrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein. The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art. About 0.5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, other starches, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums or mixtures thereof.

[0145] Lubricants which can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, calcium stearate, magnesium stearate, sodium stearyl fumarate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethylaureate, agar, or mixtures thereof. Additional lubricants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, silicified microcrystalline cellulose, or mixtures thereof. A lubricant can optionally be added in an amount of less than about 0.5% or less than about 1% (by weight) of the pharmaceutical composition.

[0146] When aqueous suspensions and / or elixirs are desired for oral administration, the active pharmaceutical ingredient(s) may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and / or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.

[0147] The tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be employed. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil.

[0148] Surfactants which can be used to form pharmaceutical compositions and dosage forms of the disclosure include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed.

[0149] A suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-lipophilic balance (“HLB” value). Surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions. Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10. However, HLB value of a surfactant is merely a rough guide generally used to enable formulation of industrial, pharmaceutical and cosmetic emulsions.

[0150] Hydrophilic surfactants may be either ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkylammonium salts; fusidic acid salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithins and hydrogenated lecithins; lysolecithins and hydrogenated lysolecithins; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyllactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di-glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[0151] Within the aforementioned group, ionic surfactants include, by way of example: lecithins, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; salts of alkylsulfates; fatty acid salts; sodium docusate; acyllactylates; mono- and di-acetylated tartaric acid esters of mono- and di-glycerides; succinylated mono- and di- glycerides; citric acid esters of mono- and di-glycerides; and mixtures thereof.

[0152] Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG- phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglycerides, mono / diacetylated tartaric acid esters of mono / diglycerides, citric acid esters of mono / diglycerides, cholylsarcosine, caproate, caprylate, caprate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, linolenate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines, palmitoyl carnitines, myristoyl carnitines, and salts and mixtures thereof.

[0153] Hydrophilic non-ionic surfactants may include, but not limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides; lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters; polyethylene glycol glycerol fatty acid esters; polyglycerol fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols, derivatives, and analogues thereof; polyoxyethylated vitamins and derivatives thereof; polyoxyethylene-polyoxypropylene block copolymers; and mixtures thereof; polyethylene glycol sorbitan fatty acid esters and hydrophilic transesterification products of a polyol with at least one member of the group consisting of triglycerides, vegetable oils, and hydrogenated vegetable oils. The polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.

[0154] Other hydrophilic-non-ionic surfactants include, without limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30glyceryl laurate, PEG-40 glyceryl laurate, PEG-40 palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil, PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6 caprate / caprylate glycerides, PEG-8 caprate / caprylate glycerides, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol, PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate, PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and poloxamers.

[0155] Suitable lipophilic surfactants include, by way of example only: fatty alcohols; glycerol fatty acid esters; acetylated glycerol fatty acid esters; lower alcohol fatty acids esters; propylene glycol fatty acid esters; sorbitan fatty acid esters; polyethylene glycol sorbitan fatty acid esters; sterols and sterol derivatives; polyoxyethylated sterols and sterol derivatives; polyethylene glycol alkyl ethers; sugar esters; sugar ethers; lactic acid derivatives of mono- and di-glycerides; hydrophobic transesterification products of a polyol with at least one member of the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols; oil-soluble vitamins / vitamin derivatives; and mixtures thereof. Within this group, preferred lipophilic surfactants include glycerol fatty acid esters, propylene glycol fatty acid esters, and mixtures thereof, or are hydrophobic transesterification products of a polyol with at least one member of the group consisting of vegetable oils, hydrogenated vegetable oils, and triglycerides.

[0156] In an embodiment, the composition may include a solubilizer to ensure good solubilization and / or dissolution of the compound of the present disclosure and to minimize precipitation of the compound of the present disclosure. This can be especially important for compositions for non-oral use - e.g., compositions for injection. A solubilizer may also be added to increase the solubility of the hydrophilic drug and / or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion.

[0157] Examples of suitable solubilizers include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol,transcutol, dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodextrins and cyclodextrin derivatives; ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG; amides and other nitrogen-containing compounds such as 2-pyrrolidone, 2-piperidone, Ɛ-caprolactam, N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters such as ethyl propionate, tributylcitrate, acetyl triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, .epsilon.- caprolactone and isomers thereof, δ-valerolactone and isomers thereof, β-butyrolactone and isomers thereof; and other solubilizers known in the art, such as dimethyl acetamide, dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin, diethylene glycol monoethyl ether, and water.

[0158] Mixtures of solubilizers may also be used. Examples include, but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene glycol 200-100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.

[0159] The amount of solubilizer that can be included is not particularly limited. The amount of a given solubilizer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art. In some circumstances, it may be advantageous to include amounts of solubilizers far in excess of bioacceptable amounts, for example to maximize the concentration of the drug, with excess solubilizer removed prior to providing the composition to a patient using conventional techniques, such as distillation or evaporation. Thus, if present, the solubilizer can be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug, and other excipients. If desired, very small amounts of solubilizer may also be used, such as 5%, 2%, 1% or even less. Typically, the solubilizer may be present in an amount of about 1% to about 100%, more typically about 5% to about 25% by weight.

[0160] The composition can further include one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, without limitation, detackifiers,anti-foaming agents, buffering agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

[0161] In addition, an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane (TRIS) and the like. Also suitable are bases that are salts of a pharmaceutically acceptable acid, such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid, uric acid, and the like. Salts of polyprotic acids, such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used. When the base is a salt, the cation can be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals and alkaline earth metals. Example may include, but not limited to, sodium, potassium, lithium, magnesium, calcium and ammonium.

[0162] Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid, nitric acid, boric acid, phosphoric acid, and the like. Examples of suitable organic acids include acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic acid, propionic acid, p-toluenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, thioglycolic acid, toluenesulfonic acid and uric acid.Pharmaceutical Compositions for Injection

[0163] In another embodiment, the disclosure provides a pharmaceutical composition for injection comprising: a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein, and a pharmaceutical excipient suitable for injection. Components and amounts of compounds in the compositions are as described herein.

[0164] The forms in which the compositions of the disclosure may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0165] Aqueous solutions in saline are also conventionally used for injection. Ethanol, glycerol, propylene glycol and liquid polyethylene glycol (and suitable mixtures thereof), cyclodextrin derivatives, and vegetable oils may also be employed. The proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, for the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and thimerosal.

[0166] Sterile injectable solutions are prepared by incorporating a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein, in the required amounts in the appropriate solvent with various other ingredients as enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, certain desirable methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof. Pharmaceutical Compositions for Topical Delivery

[0167] In another embodiment, the disclosure provides a pharmaceutical composition for transdermal delivery containing: a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein, and a pharmaceutical excipient suitable for transdermal delivery.

[0168] Compositions of the present disclosure can be formulated into preparations in solid, semi-solid, or liquid forms suitable for local or topical administration, such as gels, water soluble jellies, creams, lotions, suspensions, foams, powders, slurries, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, dimethylsulfoxide (DMSO)-based solutions. In general, carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients. In contrast, a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.

[0169] The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients, which are compounds that allow increased penetration of, or assist in the delivery of, therapeutic molecules across the stratum corneum permeability barrier of the skin. There are many of these penetration-enhancing molecules known to those trained in the art of topical formulation. Examples of such carriers and excipients include, but are not limited to, humectants (e.g., urea), glycols (e.g., propylene glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid), surfactants (e.g., isopropyl myristate and sodium lauryl sulfate), pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g., menthol), amines, amides, alkanes, alkanols, water, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

[0170] Another exemplary formulation for use in the methods of the present disclosure employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of: a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein, in controlled amounts, either with or without another active pharmaceutical ingredient.

[0171] The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos.5,023,252; 4,992,445and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents. Pharmaceutical Compositions for Inhalation

[0172] Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. Preferably the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner. Dry powder inhalers may also be used to provide inhaled delivery of the compositions. Other Pharmaceutical Compositions

[0173] Pharmaceutical compositions may also be prepared from compositions described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. Preparations for such pharmaceutical compositions are well-known in the art. See, e.g., Anderson, et al., eds., Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002; and Pratt and Taylor, eds., Principles of Drug Action, Third Edition, Churchill Livingston, N.Y., 1990, each of which is incorporated by reference herein in its entirety.

[0174] Administration of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition of these compounds can be effected by any method that enables delivery of the compounds to the site of action. These methods include oral routes, intraduodenal routes, parenteral injection (including intravenous, intraarterial, subcutaneous, intramuscular, intravascular, intraperitonealor infusion), topical (e.g., transdermal application), rectal administration, via local delivery by catheter or stent or through inhalation. The compound of Formula (I), the compound of Formula (II), the compound of Formula (III), or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein, can also be administered intraadiposally or intrathecally.

[0175] The compositions of the disclosure may also be delivered via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer. Such a method of administration may, for example, aid in the prevention or amelioration of restenosis following procedures such as balloon angioplasty. Without being bound by theory, compounds of the disclosure may slow or inhibit the migration and proliferation of smooth muscle cells in the arterial wall which contribute to restenosis. A compound of the disclosure may be administered, for example, by local delivery from the struts of a stent, from a stent graft, from grafts, or from the cover or sheath of a stent. In some embodiments, a compound of the disclosure is admixed with a matrix. Such a matrix may be a polymeric matrix, and may serve to bond the compound to the stent. Polymeric matrices suitable for such use, include, for example, lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly(ether-ester) copolymers (e.g., PEO-PLLA); polydimethylsiloxane, poly(ethylene- vinylacetate), acrylate-based polymers or copolymers (e.g., polyhydroxyethyl methylmethacrylate, polyvinyl pyrrolidinone), fluorinated polymers such as polytetrafluoroethylene and cellulose esters. Suitable matrices may be nondegrading or may degrade with time, releasing the compound or compounds. A compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein, may be applied to the surface of the stent by various methods such as dip / spin coating, spray coating, dip-coating, and / or brush-coating. The compounds may be applied in a solvent and the solvent may be allowed to evaporate, thus forming a layer of compound onto the stent. Alternatively, the compound may be located in the body of the stent or graft, for example in microchannels or micropores. When implanted, the compound diffuses out of the body of the stent to contact the arterial wall. Such stents may be prepared by dipping a stent manufactured to contain such micropores or microchannels into a solution of the compound of the disclosure in a suitable solvent, followed by evaporation of the solvent. Excess drug on the surface of the stentmay be removed via an additional brief solvent wash. In yet other embodiments, compounds of the disclosure may be covalently linked to a stent or graft. A covalent linker may be used which degrades in vivo, leading to the release of the compound of the disclosure. Any bio-labile linkage may be used for such a purpose, such as ester, amide or anhydride linkages. A compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein, may additionally be administered intravascularly from a balloon used during angioplasty. Extravascular administration of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein, via the pericard or via advential application of formulations of the disclosure may also be performed to decrease restenosis.

[0176] Exemplary parenteral administration forms include solutions or suspensions of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired.

[0177] The disclosure also provides kits. The kits include a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein, in suitable packaging, and written material that can include instructions for use, discussion of clinical studies and listing of side effects. Such kits may also include information, such as scientific literature references, package insert materials, clinical trial results, and / or summaries of these and the like, which indicate or establish the activities and / or advantages of the composition, and / or which describe dosing, administration, side effects, drug interactions, or other information useful to the health care provider. Such information may be based on the results of various studies, for example, studies using experimental animals involving in vivo models and studies based on human clinical trials. The kit may further contain another active pharmaceutical ingredient. In some embodiments, the compound of Formula (I), the compound of Formula (II), the compound of Formula (III), or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein, and another active pharmaceutical ingredient are provided as separatecompositions in separate containers within the kit. In one embodiment, the other active pharmaceutical ingredient comprises one or more additional anti-TB agents. In some embodiments, the compound of Formula (I), the compound of Formula (II), the compound of Formula (III), or a stereoisomer or a pharmaceutically acceptable salt thereof, and the agent are provided as a single composition within a container in the kit. Suitable packaging and additional articles for use (e.g., measuring cup for liquid preparations, foil wrapping to minimize exposure to air, and the like) are known in the art and may be included in the kit. Kits described herein can be provided, marketed and / or promoted to health providers, including physicians, nurses, pharmacists, formulary officials, and the like. Kits may also, in some embodiments, be marketed directly to the consumer.

[0178] In embodiments, the kits described above are for use in the treatment of tuberculosis. Dosages and Dosing Regimens

[0179] The amounts of: a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein, administered will be dependent on the human or mammal being treated, the severity of the disorder or condition, the rate of administration, the disposition of the compounds and the discretion of the prescribing physician. However, an effective dosage of each is in the range of about 0.001 to about 100 mg per kg body weight per day, such as about 1 to about 35 mg / kg / day, in single or divided doses. For a 70 kg human, this would amount to about 0.05 to 7 g / day, such as about 0.05 to about 2.5 g / day. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect - e.g., by dividing such larger doses into several small doses for administration throughout the day. The dosage of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein, may be provided in units of mg / kg of body mass or in mg / m2of body surface area.

[0180] In some embodiments, a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer ora pharmaceutically acceptable salt thereof, described herein is administered in multiple doses. In a preferred embodiment, a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein is administered in multiple doses. Dosing may be once, twice, three times, four times, five times, six times, or more than six times per day. Dosing may be once a month, once every two weeks, once a week, or once every other day. In other embodiments, a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein, is administered about once per day to about 6 times per day. In some embodiments, a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein, is administered once daily, while in other embodiments, a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein is administered twice daily, and in other embodiments a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein, is administered three times daily.

[0181] Administration of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein, may continue as long as necessary. In some embodiments, a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein, is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein is administered chronically on an ongoing basis - e.g., for the treatment of chronic effects. Inanother embodiment, the administration of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein, continues for less than about 7 days. In yet another embodiment, the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous dosing is achieved and maintained as long as necessary.

[0182] In some embodiments, an effective dosage of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein, is in the range of about 1 mg to about 500 mg, about 10 mg to about 300 mg, about 20 mg to about 250 mg, about 25 mg to about 200 mg, about 10 mg to about 200 mg, about 20 mg to about 150 mg, about 30 mg to about 120 mg, about 10 mg to about 90 mg, about 20 mg to about 80 mg, about 30 mg to about 70 mg, about 40 mg to about 60 mg, about 45 mg to about 55 mg, about 48 mg to about 52 mg, about 50 mg to about 150 mg, about 60 mg to about 140 mg, about 70 mg to about 130 mg, about 80 mg to about 120 mg, about 90 mg to about 110 mg, about 95 mg to about 105 mg, about 150 mg to about 250 mg, about 160 mg to about 240 mg, about 170 mg to about 230 mg, about 180 mg to about 220 mg, about 190 mg to about 210 mg, about 195 mg to about 205 mg, or about 198 to about 202 mg.

[0183] In some embodiments, an effective dosage of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein, is in the range of about 0.01 mg / kg to about 4.3 mg / kg, about 0.15 mg / kg to about 3.6 mg / kg, about 0.3 mg / kg to about 3.2 mg / kg, about 0.35 mg / kg to about 2.85 mg / kg, about 0.15 mg / kg to about 2.85 mg / kg, about 0.3 mg to about 2.15 mg / kg, about 0.45 mg / kg to about 1.7 mg / kg, about 0.15 mg / kg to about 1.3 mg / kg, about 0.3 mg / kg to about 1.15 mg / kg, about 0.45 mg / kg to about 1 mg / kg, about 0.55 mg / kg to about 0.85 mg / kg, about 0.65 mg / kg to about 0.8 mg / kg, about 0.7 mg / kg to about 0.75 mg / kg, about 0.7 mg / kg to about 2.15 mg / kg, about 0.85 mg / kg to about 2 mg / kg, about 1 mg / kg to about 1.85 mg / kg, about 1.15 mg / kg to about 1.7 mg / kg, about 1.3 mg / kg mg to about 1.6 mg / kg, about 1.35 mg / kg to about 1.5 mg / kg, about 2.15 mg / kg to about 3.6 mg / kg, about 2.3 mg / kg to about 3.4 mg / kg, about 2.4 mg / kg to about 3.3 mg / kg, about 2.6mg / kg to about 3.15 mg / kg, about 2.7 mg / kg to about 3 mg / kg, about 2.8 mg / kg to about 3 mg / kg, or about 2.85 mg / kg to about 2.95 mg / kg.

[0184] In some instances, dosage levels below the lower limit of the aforesaid ranges may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect - e.g., by dividing such larger doses into several small doses for administration throughout the day.

[0185] An effective amount of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of any one of Formula 1001-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof, described herein, may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant. EXAMPLES

[0186] The embodiments encompassed herein are now described with reference to the following examples. These examples are provided for the purpose of illustration only and the disclosure encompassed herein should in no way be construed as being limited to these examples, but rather should be construed to encompass any and all variations which become evident as a result of the teachings provided herein. Example 1: Small molecule anti-tubercular agents

[0187] In one aspect, the present disclosure provides PZA-like molecules with low micromolar to nanomolar anti-TB potencies as an improved anti-TB therapy. In embodiments, the present disclosure provides the design, synthesis and characterization of novel PZA-like small molecules that can eradicate the infection in weeks.

[0188] PZA is a bio-precursor that is activated in vivo by the enzyme amidase to yield the active metabolite pyrazinoic acid (FIG.1). Based on the unique mechanism of action of PZA, new compounds of Formula (I) have been designed as useful anti-TB agents. In a non-limiting example, the compounds of Formula (I) include two structural moieties: i) a substituted phenylor a heterocyclic system that mimics the pyrazine ring of PZA and ii) an ester carrier group that can facilitate cell permeability of compounds and be hydrolytically cleaved by enzymes in the cell to release the carboxylic acid group (FIG.2). In a non-limiting example, the synthesis of the target compounds involves an esterification reaction of the corresponding carboxylic acid precursor with the selected hydroxy compounds using HOBt and EDC as the activation reagents. Using this route, compounds of the disclosure have been prepared (FIG.3). General method for the synthesis of disclosed compounds

[0189] General Method A. To a solution of the carboxylic acid starting material (1.0 mmol) in dichloromethane (DCM, 5 mL) was added 1-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC, 1.5 mmol), HOBt (1.5 mmol), followed by diisopropylethylamine (DIPEA, 2.0 mmol). The reaction mixture was allowed to stir at room temperature for 24 h, and concentrated. The crude product was purified by flash chromatography to yield the ester products 1-4 (50-85%) as white solids.

[0190] General Method B. To a pressure vessel round bottom flask, carboxylic acid starting material (1.0 – 2.0 mmol) was added, followed by n-BuOH (0.18–0.37 mL), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC, 1.1 – 3.0 mmol), 4-dimethylaminopyridine (DMAP, 0.2 – 0.6 mmol), and tetrahydrofuran (THF). The reaction mixture was stirred at 70°C for 48 h, and concentrated. The crude product was purified by flash chromatography to yield the ester product 5-11 as white solids.

[0191] General Method C. To a solution of the carboxylic acid starting material (1.0 mmol) in dichloromethane (DCM, 5 mL) was added to alkylbromide (1.5 mmol) followed by diisopropylethylamine (DIPEA, 2.0 mmol). The reaction mixture was allowed to stir at room temperature for 24 h, and concentrated. The crude product was purified by flash chromatography to yield the ester products 1-4 (50-85%) as white solids. Compound characterization

[0192] Compound 1 (FX6013) was synthesized starting with 1H-benzo[d]imidazole-6- carboxylic acid and n-butylbromide using the General Method C (50%) and the General MethodA (50%):1H NMR (400 MHz, CDCl3): δ 8.50 (s, 1H), 8.43 (s, 1H), 8.05-8.02 (d, J = 8.4 Hz, 1H), 7.71-7.69 (d, J = 8.4 Hz, 1H), 4.40-4.30 (t, J = 6.4 Hz, 2H), 1.80-1.70 (m, 2H), 1.50-1.40 (m, 2H), 1.00-0.90 (t, J = 7.6 Hz, 3H);13C NMR (100 MHz, CDCl3): δ 166.8, 142.5, 139.6, 136.5, 126.0, 124.9, 117.9, 114.9, 65.0, 30.8, 19.3, 13.8.

[0193] Compound 2 (FX6015) was synthesized starting with quinoxaline-6-carboxylic acid and n-butylbromide using the General Method C (85%) and the General Method A (85%):1H NMR (400 MHz, CDCl3): δ 8.93-8.92 (d, J = 1.6 Hz, 1H), 8.84-8.83 (d, J = 1.6 Hz, 1H), 8.38-8.37 (d, J = 6.8 Hz, 1H), 8.17-8.16 (d, J = 6.8 Hz, 1H), 4.40-4.30 (t, J = 6.4 Hz, 2H), 1.80- 1.70 (m, 2H), 1.50-1.40 (m, 2H), 1.00-0.90 (t, J = 7.6 Hz, 3H);13C NMR (100 MHz, CDCl3): δ 165.7, 146.5, 145.9, 144.9, 142.3, 132.0, 129.8, 129.6, 65.5, 30.7, 19.3, 13.7.

[0194] Compound 3 (FX6017) was synthesized starting with 1H-benzo[d][1,2,3]triazole- 6-carboxylic acid and n-butylbromide using the General Method C (55%) and the General Method A (55%):1H NMR (400 MHz, CDCl3): δ 8.74 (s, 1H), 8.21-8.19 (d, J = 8.8 Hz, 1H), 7.91-7.89 (d, J = 8.8 Hz, 1H), 4.40-4.30 (t, J = 7.2 Hz, 2H), 1.80-1.70 (m, 2H), 1.50-1.40 (m, 2H), 1.10-0.95 (t, J = 7.6 Hz, 3H);13C NMR (100 MHz, CDCl3): δ 166.3, 140.2, 139.2, 128.1, 127.4, 119.1, 113.6, 65.5, 30.7, 19.2, 13.7.

[0195] Compound 4 (FX6019) was synthesized starting with 1H-indole-5-carboxylic acid and n-butylbromide using the General Method C (50%) and the General Method A (50%):1H NMR (400 MHz, CDCl3): δ 8.57 (s, 1H), 8.24 (s, 1H), 8.13-8.10 (d, J = 8.8 Hz, 1H), 7.58-7.55 (d, J = 8.8 Hz, 1H), 4.40-4.30 (t, J = 7.2 Hz, 2H), 1.80-1.70 (m, 2H), 1.50-1.40 (m, 2H), 1.10-0.95 (t, J = 7.6 Hz, 3H);13C NMR (100 MHz, CDCl3): δ 166.3, 140.2, 139.2, 128.1, 127.4, 119.1, 113.6, 65.5, 30.7, 19.2, 13.7.

[0196] Compound 5 (FX6039-IW) was synthesized starting with imidazo[1,2-a]pyridine- 6-carboxylic acid and 1-butanol following General Method B (25%):1H NMR (400 MHz, CDCl3): δ 8.97 (s, 2H), 7.88-7.73 (m, 2H), 4.41-4.37 (t, J = 5.6 Hz, 2H), 1.81-1.75 (m, 2H), 1.51-1.45 (m, 2H), 1.01-0.99 (t, J = 6.4 Hz, 3H);13C NMR (100 MHz, CDCl3): δ 164.5, 144.9, 132.8, 130.2, 126.2, 118.4, 116.6, 113.9, 65.8, 30.8, 19.4, 13.9.

[0197] Compound 6 (FX6041-IW) was synthesized starting with 1,2,4-triazolo[4,3- a]pyridine-6-carboxylic acid and 1-butanol following General Method B (13%):1H NMR (400 MHz, CDCl3): δ 8.99-8.96 (d, J = 12 Hz, 2H), 7.83 (s, 2H), 4.39-4.36 (t, J = 6.8 Hz, 2H), 1.79- 1.75 (m, 2H), 1.5-1.44 (m, 2H), 1.00-0.97 (t, J = 7.2 Hz, 3H)

[0198] Compound 7 (FX6043-IW) was synthesized starting with imidazo[1,2- a]pyrimidine-6-carboxylic acid and 1-butanol following General Method B (19%):1H NMR (400 MHz, CDCl3): δ 9.28 (s, 1H), 9.13 (s, 1H), 7.95 (s, 1H), 7.80 (s, 1H), 4.43-4.40 (t, J = 4.8 Hz, 2H), 1.82-1.76 (m, 2H), 1.51-1.46 (m, 2H), 1.01-0.98 (t, J = 6 Hz, 3H);13C NMR (100 MHz, CDCL3): δ 163.3, 151.2, 149.0, 137.5, 135.5, 114.2, 112.4, 66.1, 30.8, 19.3, 13.8.

[0199] Compound 8 (FX6045-IW) was synthesized starting with 4-(1- pyrrolidinyl)benzoic acid and 1-butanol following General Method B (10%):1H NMR (400 MHz, CDCl3): δ 7.91-7.89 (d, J = 8 Hz, 2H), 6.53-6.51 (d, J = 8.8 Hz, 2H), 4.28-4.25 (t, J = 6.4 Hz, 2H), 3.36-3.33 (t, J = 6.4 Hz, 4H), 2.05-2.02 (t, J = 6.4 Hz, 4H), 1.75-1.71 (m, 2H), 1.50- 1.43 (m, 2H), 0.99-0.95 (t, J = 8 Hz, 3H);13C NMR (100 MHz, CDCl3): 167.3, 150.8, 131.5, 117.1, 110.9, 64.1, 47.8, 31.1, 25.6, 19.5, 14.0.

[0200] Compound 9 (FX6047-IW) was synthesized starting with 6- benzoxazolecarboxylic acid and 1-butanol General Method B (29%):1H NMR (400 MHz, CDCl3): δ 8.30 (s, 1H), 8.23 (s, 1H), 8.14-8.12 (d, J = 6.8 Hz, 1H), 7.85-7.83 (d, J = 6.8 Hz, 1H), 4.39-4.37 (t, J = 5.6 Hz, 2H), 1.82-1.76 (m, 2H), 1.55-1.47 (m, 2H), 1.02-0.99 (t, J = 4 Hz, 3H);13C NMR (100 MHz, CDCL3): 166.2, 154.9, 149.9, 143.9, 128.5, 126.4, 120.4, 112.9, 65.4, 30.9, 19.4, 13.9.

[0201] Compound 10 (FX6049-IW) was synthesized starting with 6- benzothiazolecarboxylic acid and 1-butanol General Method B (38%):1H NMR (400 MHz, CDCl3): δ 9.17 (s, 1H), 8.70 (s, 1H), 8.21-8.17 (q, J = 4.4 Hz, 2H), 4.40-4.37 (t, J = 4.8 Hz, 2H), 1.82-1.76 (m, 2H), 1.53-1.47 (m, 2H), 1.02-0.99 (t, J = 5.6 Hz, 3H);13C NMR (100 MHz, CDCL3): 166.2, 157.4, 155.8, 133.8, 128.1, 127.5, 124.3, 123.5, 65.4, 30.9, 19.4, 13.9.

[0202] Compound 11 (FX6051-IW) was synthesized starting with 1H- benzo[d][1,2,3]triazole-6-carboxylic acid and 1-butamine General Method B (38%). Example 2: Determination of MICs using broth microdilution method

[0203] The MIC of the compounds disclosed herein can be determined using broth microdilution, as described in Shi, W., Antibiotics, 2021, 10: 909, which is incorporated by reference herein in its entirety. Briefly, the broth microdilution method was performed as follows. A compound of the disclosure was added to a well and two-fold serial dilutions of the concentration of the compound are performed, arranged from 800 mg / L to 12.5 mg / L or 1000 mg / L to 1 mg / L. A set of media with and without PZA control were included in each experiment. More than six colonies of M. tuberculosis H37Ra or PZA-resistant strains were scraped from the 7H11 agar plates using a sterile inoculating loop into a medium with 10 glass 0.5 mm beads. The sample was vortexed for 30-60 s and settled for 15 min to remove clumps. The supernatant suspensions were diluted in the media to reach a 0.5 McFarland unit, standardized using a densitometer according to the manufacturer’s instructions, corresponding to ∼1 × 107CFU / mL, and then were diluted 1:50 and 1:100 with PZA-S1 minimal medium (wherein PZA-S1 minimal media contains 0.5 g / L KH2PO4, 0.5 g / L MgSO4, 0.5 g / L citric acid, 10 mL / L glycerol, 2 g / L L-Ala, 30 mg / L ferric ammonium citrate, 0.5mg / L biotin, 1 mg / L pyridoxine hydrochloride and 0.5 mg / L ZnSO4. The pH of the medium was adjusted to 6.8 with 1 M of sodium hydroxide and sterilized by filtering through a 0.2 µm membrane filter). The standard inoculum size in each well was ∼1 × 105CFU / mL to ∼5 × 105CFU / mL. There was a good concordance between the McFarland scale and the CFU / mL for M. tuberculosis. There was 0.2 mL of the bacterial suspension per well. The microtiter plates were sealed with parafilm to avoid drying and were incubated at 37 °C. The MICs were read at one, two, and four weeks. The MIC results recorded by the first reader were considered to be the test results. All tests were carried out three times.

[0204] FX6018 had the best potency profile seen with the broth microdilution method (see Table 1). In PZA-S1 (acidic) media against PZA-susceptible strain H37Ra, FX6018 showed an excellent MIC value of 6.25 µM (250x better than PZA). Similar to PZA, the new drug’s activity was much weaker in 7H9 (neutral) media. Table 1. MICs of five novel PZA-class compounds.

[0205] PZA-resistant TB strains were vulnerable to FX6018. The in vitro effectiveness of FX6018 was measured in PZA-S1 (acidic) media against two PZA-resistant TB strains, PZAR #6 (PncA mutation L159P) and PZAR #136 (PanD mutation E126*). H37Ra served as the control (Fig.4, left). FX6018 had the same promising MIC (6.25 µM) against all three strains in PZA-S1 media. PZA’s MIC value for H37Ra was 1,620 µM, but the old drug was ineffective against both resistant strains (Fig.4, right). Therefore, FX6018 does not exhibit cross-resistance to PZA. In Fig.4, the wells in white boxes are those with the lowest concentrations of FX6018 (left) or PZA (right) that were effective in preventing visible growth of M. tuberculosis. PZA did not inhibit the growth of the two resistant TB trains (right, B and C). Example 3: Determination of activity at neutral pH on agar plate

[0206] The antibiotic activity of the compounds disclosed herein can be determined as described in Shi, W., Antibiotics, 2021, 10: 909. The disk diffusion method is a culture-based assay to determine antibiotic activity on solid media by observing the inhibition of visible growth. Four-week-old colonies of M. tuberculosis are taken from 7H11 agar plates and suspended in PZA-S1 minimal media. The turbidity is adjusted to a 0.5 McFarland unit and standardized using a densitometer according to the manufacturer’s instructions. In total, 5 mL of PZA-S1 agar media at 1.5% (w / v) agar is poured into each quadrant of a 100 mm Petri dish. After the agar plate is solidified, a 50 µL suspension is spread on each quadrant of the Petri dish using a sterile cotton applicator. After the surface of the agar plate is dry, sterile Taxo Blank Discs with 0 (DMSO control), 400 µg, 800 µg or 1600 µg of a compound of the disclosure is pressed down at the center of the quadrant on the agar plate. After being sealed in plastic bags, the plates are inverted and placed in an incubator at 37 °C for 3-4 weeks. In this study, the activity of PZA is determined by observing the inhibition of the visible growth of M. tuberculosis at a neutral pH at 37 °C on the agar plate. All tests are carried out three times.Example 4: Toxicity of FX6018

[0207] FX6018 was well-tolerated. The acute toxicity of FX6018 was evaluated with single-dose oral gavage doses16-18 at 2, 1, and 0.5 g / kg at a volume of 300 µL per animal in 8- week-old C57BL / 6J mice (2 M and 2 F mice / group). FX6018 was suspended in corn oil. Clinical observations, measurements of weight, and behavior were conducted for 7 days. Over 7 days. 80% of mice in experimental groups gained weight similar to the control group, and body weight loss of the remainder was modest (<2%). Overall, all mice exhibited no signs of toxicity, behaved normally, and survived the treatment, even with the high dose of 2000 mg / kg.

[0208] Further toxicity testing of the improved compounds is evaluated at three levels: prokaryotic organisms, eukaryotic cells, and animals. The testing includes Ames tests, cytotoxicity assays, and acute toxicity studies. The Ames test evaluates the mutagenic activity of PZA-class candidates as described in previous study histidine-deficient Salmonella typhimurium T98 and T100 strain from Fisher scientific is exposed to the compound at the appropriate concentration, and the number of bacterial colonies that grow on the glucose minimal agar plates is counted to determine mutagenicity. The mutagenicity index (MI) is calculated by comparing the number of colonies in the test plates to the number of colonies in the negative control plates. Cytotoxicity assays use human hepatocarcinoma (HepG2) cells as described in previous studies. Cell suspension will be added to Eagle’s MEM at a final density of 1.0 × 105cells / mL with serial dilution concentration of the compound in 96-well clear-bottom plates and incubated at 37 °C at 90 % relative humidity for 48 h under 5 % CO2. Tox50is measured using CellTiter-Glo kit (Promega) and calculated. The compound is selected with Tox50 ≥ 100 μM. Acute toxicity studies in mice involve eight-week-old male and female C57BL / 6J strain. The compounds are administered by oral gavage at a single dose of 2000, 100 and 500 mg / kg. Signs of toxicity, such as changes in behavior, weight loss, and mortality, are monitored and recorded by comparing them with the vehicle control group for 7 days. These tests provide a comprehensive understanding of potential toxicity related to the FX6018. Example 5: Pharmacokinetic profiles

[0209] The drug clearance rate, volume of distribution, Cmax, and in vivo half-life of FX6018 is determined. These findings aid in estimations of the time needed to reach steady-stateplasma concentration. CD-1 outbred mice are given a single intravenous dose at 50 µg / gram body weight. For the first study, time points are 0.1, 0.25, 0.5, 1, 2, 4, 6, 12, and 24 hours post- injection. At each time point, one group of 3 mice are euthanized per JHU IACUC protocol MO22H147. Concentration of compounds of the disclosure in the blood are determined by LC / MS. Heart, liver, kidney, lung, and brain are collected at necropsy and stored at -80 C for assessment of FX6018 bioavailability. This study is performed twice, with dosage and time points determined on the basis of prior results. The PK profile makes a first estimate of the oral doses. Three studies, each with 9 time points and one control, include 3 mice / group, thus n=90 mice. Example 6: Evaluating the in vitro solubility, stability, lipophilicity, and permeability of the improved PZA-class compounds.

[0210] The solubility, stability and lipophilicity of compounds of the disclosure are evaluated through an integrated assay panel. To assess the permeability of the compounds, a parallel artificial membrane permeability assay (PAMPA) using 96-well plate-based technology is employed. Each well containing a test compound at a concentration of 1 μg / mL in PBS is supplemented with a membrane integrity marker on the apical side of the filter plate, with the bottom portion filled with blank buffer. Samples from both donor and theoretical equilibrium wells are matrix matched with blank buffer and then submitted for LCMS / MS analysis. A portion of the sample containing the marker is analyzed on a microplate absorbance reader to determine the Papp value of each compound. Those compounds exhibiting a Papp value of 14×10-6cm / s or more are considered highly permeable. Example 7: Maximum Tolerated Dose

[0211] FX6018’s small size (MW 219) and high polarity favor high oral bioavailability. FX6018 is well-tolerated in mice at high oral doses (> 2,000 mg / kg). FX6018 is given orally (via gavage) to CD-1 mice. The doses and schedule are determined by prior results; half-log intervals are employed. Each mouse is weighed and observed 3x / week, then euthanized at the 2-week timepoint (earlier on signs of distress or a 20% weight loss). At sacrifice, heart, liver, kidney, lung and brain tissue are formalin-fixed, then embedded, sectioned, and hematoxylin & eosinstained. Each organ is assessed for damage, using the Xue lab’s standard procedures. Four groups (3 FX6018 doses and vehicle control), 5 mice / group, are used giving a total number of mice of 20. Example 8: Evaluation of FX6018 efficacy against M. tuberculosis

[0212] A mouse model such as that described by Fanzblaue et al. is chosen that correctly reflects PZA’s clinical characteristics for the first efficacy study. The virulent PZA-resistant M. tuberculosis strain PZAR #6 (PncA mutation L159P) is grown to late-log phase in 7H9 media. Female BALB / c mice ~5 weeks of age are infected on Day-15 via aerosol exposure. Mice are then randomly assigned to one of four treatment groups (mouse equivalents to standard human doses are used for INH, RIF, and PZA): (1) INH+RIF+PZA, (2) & (3) INH+RIF+FX6018 (oral; ‘high’ & ‘low’ doses TBD) or (4) untreated control. Groups 1 to 3 have 15 mice, while Group 4 has 10 added members, as 5 untreated mice are sacrificed the day after infection (D-14) to quantify the initial M. tuberculosis lung burden, and again on D0 to establish the burden at the start of treatment (n=70 mice). Drug cocktails are given via oral gavage 5 days / week for 8 weeks (Table 2). On D28, D42, and D56, five mice from each group are euthanized. Lungs and spleens are harvested. Lung appearance is characterized, and spleens weighed. Each of the two organs are then homogenized, with homogenates serially diluted (neat to 1:9,999) and plated on 7H11 agar plates (remaining samples are archived at -80°C). Because of the slow-growing nature of M. tuberculosis, plates are incubated for 5 weeks at 37°C, at which point CFUs are determined. As an alternative, guinea pigs are used as a second model (Fonseca, 2017) Table 2. Experimental plan.Example 9: Interactions between improved PZA-class compounds with other TB drugs.

[0213] To determine in vitro interaction between commonly used TB drugs, RIF and INH, and potent PZA-class compounds, a two-dimensional checkerboard microdilutions test is performed. Two-dimensional microdilution checkerboard plates are prepared by dispensing the serially diluted PZA-class compounds on the x-axis and RIF or INH on the y-axis in a 96-well plate with PZA-active media. The improved PZA-class compounds are then dispensed throughout the wells as an overlay at subinhibitory concentrations ranging from 1 / 32 to 1 / 2 of the MIC. Three PZA-resistant strains are included in the test. After inoculation, microplates are incubated for 2-3 weeks at 37 °C until visible growth in growth control wells are visually read. The fractional inhibitory concentration (FIC) are calculated and interpreted based on the FIC index as follows: synergism, ≤ 0.75; indifference, > 0.75–4; and antagonism, > 494.

[0214] A number of patent and non-patent publications are cited herein in order to describe the state of the art to which this disclosure pertains. The entire disclosure of each of these publications is incorporated by reference herein. References 1. Organization, W. H. Treatment of tuberculosis. Guidelines for national programmes. WHO report 2003. 2. Zhang, Y.; Shi, W.; Zhang, W.; Mitchison, D.; “Mechanisms of Pyrazinamide Action and Resistance,” Microbiol. Spectr.2014, 2(4): MGM2-0023-2013. 3. Zhang, Y.; Mitchison, D.; “The curious characteristics of pyrazinamide: a review,” Int. J. Tuberc. Lung Dis., 2003, 7(1): 6-21. 4. INSIGHTS, C. M., Global Pyrazinamide Market.2021. https: / / www.coherentmarketinsights.com / insight / buy-now / 4317 (accessed Feb 10, 2022). 5. Cui, Y.; Shen, H.; Wang, F.; Wen, H.; Zeng, Z.; Wang, Y.; Yu, C., A Long-Term Trend Study of Tuberculosis Incidence in China, India and United States 1992-2017: A Joinpoint and Age-Period-Cohort Analysis. Int J Environ Res Public Health 2020, 17 (9). 6. WHO. Treatment of tuberculosis. Guidelines for national programmes, 4th edition.2010.7. Canetti, G., The tubercle bacillus in the pulmonary lesion of man: histobacteriology and its bearing on the therapy of pulmonary tuberculosis. Springer Publishing Company: 1955. 8. Lenaerts, A.; Barry, C. E., 3rd; Dartois, V., Heterogeneity in tuberculosis pathology, microenvironments and therapeutic responses. Immunol Rev 2015, 264 (1), 288-307. 9. Sarathy, J. P.; Dartois, V., Caseum: a Niche for Mycobacterium tuberculosis Drug- Tolerant Persisters. Clin Microbiol Rev 2020, 33 (3). 10. McDermott, W.; Tompsett, R., Activation of pyrazinamide and nicotinamide in acidic environments in vitro. American review of tuberculosis 1954, 70 (4), 748-754. 11. Kempker, R. R.; Heinrichs, M. T.; Nikolaishvili, et al., Lung Tissue Concentrations of Pyrazinamide among Patients with Drug-Resistant Pulmonary Tuberculosis. Antimicrobial agents and chemotherapy 2017. 12. Shi, W., Activity of Pyrazinamide against Mycobacterium tuberculosis at Neutral pH in PZA-S1 Minimal Medium. Antibiotics 2021, 10 (8), 909. 13. den Hertog, A. L.; Menting, S.; Pfeltz, R.; Warns, M.; Siddiqi, S. H.; Anthony, R. M., Pyrazinamide Is Active against Mycobacterium tuberculosis Cultures at Neutral pH and Low Temperature. Antimicrobial agents and chemotherapy 2016, 60 (8), 4956-60. 14. Peterson, N. D.; Rosen, B. C.; Dillon, N. A.; Baughn, A. D., Uncoupling Environmental pH and Intrabacterial Acidification from Pyrazinamide Susceptibility in Mycobacterium tuberculosis. Antimicrobial agents and chemotherapy 2015, 59 (12), 7320-6. 15. Yeager, R. L.; Munroe, W. G.; Dessau, F. I., Pyrazinamide (aldinamide) in the treatment of pulmonary tuberculosis. Am Rev Tuberc 1952, 65 (5), 523-46. 16. Schwartz, W. S.; Moyer, R. E., The chemotherapy of pulmonary tuberculosis with pyrazinamide used alone and in combination with streptomycin, para-aminosalicylic acid, or isoniazid. Am Rev Tuberc 1954, 70 (3), 413-22. 17. Almeida, D. V.; Tyagi, S.; Li, S.; Wallengren, K.; Pym, A. S.; Ammerman, N. C.; Bishai, W. R.; Grosset, J. H., Revisiting Anti-tuberculosis Activity of Pyrazinamide in Mice. Mycobact Dis 2014, 4, 145. 18. Grosset, J., The sterilizing value of rifampicin and pyrazinamide in experimental short- course chemotherapy. Bull Int Union Tuberc 1978, 53 (1), 5-12. 19. Chinedu, E.; Arome, D.; Solomon Ameh, F., A new method for determining acute toxicity in animal models. Toxicology international 2013, 20 (3).20. Erhirhie, E. O.; Ihekwereme, C. P.; Ilodigwe, E. E., Advances in acute toxicity testing: strengths, weaknesses and regulatory acceptance. Interdiscip Toxicol 2018, 11 (1), 5-12. 21. Roy, R.; Liya, I. J.; Roy, J.; Basher, M. A., Acute and subchronic toxicity profile of methanol extract of leaves of Fimbristylis miliacea (L.) Vahl. Toxicol Rep 2023, 10, 301-307. 22. OA, A.-S.; TM, E.-H.; AA, A.-M., Effect of prolonged vigabatrin treatment on hematological and biochemical parameters in plasma, liver and kidney of Swiss albino mice. Scientia Pharmaceutica 2002, 70 (2), 135-145. 23. Teo, S.; Stirling, D.; Thomas, S.; Hoberman, A.; Kiorpes, A.; Khetani, V., A 90-day oral gavage toxicity study of d-methylphenidate and d,l-methylphenidate in Sprague-Dawley rats. Toxicology 2002, 179 (3), 183-196. 24. FMI (Future Market Insights), TB Therapeutics Market.2021. 25. Coherent Market Insights, Pyrazinamide Market Size, Trends, and Forecast to 2030. 2020. 26. Ivek I., Knotek T., Ivičić T., Rubinić B., Bajlo P., and Hamzić J.2022. Methemoglobinemia–a Case Report and Literature Review. Acta clinica Croatica 61: 93-98. 27. Fadah K., Rivera M., Lingireddy A., Kalas M.A., Ghafouri R.S., and Deoker A.2022. A Rare Culprit of Methemoglobinemia. J Investig Med High Impact Case Rep 10: 23247096221117919. 28. Gopal P., Gruber G., Dartois V., and Dick T.2019. Pharmacological and Molecular Mechanisms Behind the Sterilizing Activity of Pyrazinamide. Trends Pharmacol Sci 40: 930- 940. 29. Coleman D., Waddell S.J., and Mitchison D.A.2011. Effects of low incubation temperatures on the bactericidal activity of anti-tuberculosis drugs. J Antimicrob Chemother 66: 146-50. 30. Kushner S., Dalalian H., Sanjurjo J., Bach Jr F., Safir S., Smith Jr V., and Williams J. 1952. Experimental chemotherapy of tuberculosis. II. The synthesis of pyrazinamides and related compounds. Journal of the American Chemical Society 74: 3617-3621. 31. Bernstein J., Lott W.A., Steinberg B.A., and Yale H.L.1952. Chemotherapy of experimental tuberculosis. V. Isonicotinic acid hydrazide (nydrazid) and related compounds. Am Rev Tuberc 65: 357-64.32. Almeida D.V., Tyagi S., Li S., Wallengren K., Pym A.S., Ammerman N.C., Bishai W.R., and Grosset J.H.2014. Revisiting Anti-tuberculosis Activity of Pyrazinamide in Mice. Mycobact Dis 4: 145. 33. McCune R.M., Jr., and Tompsett R.1956. Fate of Mycobacterium tuberculosis in mouse tissues as determined by the microbial enumeration technique. I. The persistence of drug- susceptible tubercle bacilli in the tissues despite prolonged antimicrobial therapy. J Exp Med 104: 737-62. 34. McCune R.M., Jr., McDermott W., and Tompsett R.1956. The fate of Mycobacterium tuberculosis in mouse tissues as determined by the microbial enumeration technique. II. The conversion of tuberculous infection to the latent state by the administration of pyrazinamide and a companion drug. J Exp Med 104: 763-802. 35. Forgacs P., Wengenack N.L., Hall L., Zimmerman S.K., Silverman M.L., and Roberts G.D.2009. Tuberculosis and trimethoprim-sulfamethoxazole. Antimicrobial agents and chemotherapy 53: 4789-93. 36. Alsaad N., van der Laan T., van Altena R., Wilting K.R., van der Werf T.S., Stienstra Y., van Soolingen D., and Alffenaar J.W.2013. Trimethoprim / sulfamethoxazole susceptibility of Mycobacterium tuberculosis. Int J Antimicrob Agents 42: 472-4. 37. Organization W.H.2016. WHO treatment guidelines for drug-resistant tuberculosis. World Health Organization. 38. Organization W.H.2021. Treatment of drug-susceptible tuberculosis: rapid communication. 39. Lamont E.A., and Baughn A.D.2019. Impact of the host environment on the antitubercular action of pyrazinamide. EBioMedicine 49: 374-380. 40. Heifets L., and Lindholm-Levy P.1992. Pyrazinamide sterilizing activity in vitro against semidormant Mycobacterium tuberculosis bacterial populations. Am Rev Respir Dis 145: 1223- 5. 41. Lanoix J.P., Ioerger T., Ormond A., Kaya F., Sacchettini J., Dartois V., and Nuermberger E.2016. Selective Inactivity of Pyrazinamide against Tuberculosis in C3HeB / FeJ Mice Is Best Explained by Neutral pH of Caseum. Antimicrobial agents and chemotherapy 60: 735-43. 42. Sarathy J.P., and Dartois V.2020. Caseum: a Niche for Mycobacterium tuberculosis Drug-Tolerant Persisters. Clin Microbiol Rev 33.43. Tharakan S.M.2022. Global Tuberculosis: Background and Issues for Congress. 44. WHO.2021. Global tuberculosis report 2021. 45. McGrath M., Gey van Pittius N.C., van Helden P.D., Warren R.M., and Warner D.F. 2014. Mutation rate and the emergence of drug resistance in Mycobacterium tuberculosis. J Antimicrob Chemother 69: 292-302. 46. Castro R.A.D., Borrell S., and Gagneux S.2020. The within-host evolution of antimicrobial resistance in Mycobacterium tuberculosis. FEMS Microbiol Rev. 47. Whitfield M.G., Soeters H.M., Warren R.M., York T., Sampson S.L., Streicher E.M., van Helden P.D., and van Rie A.2015. A Global Perspective on Pyrazinamide Resistance: Systematic Review and Meta-Analysis. PloS one 10: e0133869. 48. Köser C.U., Cirillo D.M., and Miotto P.2020. How to optimally combine genotypic and phenotypic drug susceptibility testing methods for pyrazinamide. Antimicrobial agents and chemotherapy 64. 49. ASSOCIATION OF PUBLIC HEALTH L.2022. Issues in Mycobacterium tuberculosis Complex Drug Susceptibility Testing: Pyrazinamide. Infectious disease. 50. Anthony R.M., Cynamon M., Hoffner S., Werngren J., den Hertog A.L., and van Soolingen D.2017. Protecting Pyrazinamide, a Priority for Improving Outcomes in Multidrug- Resistant Tuberculosis Treatment. Antimicrobial agents and chemotherapy 61. 51. Fofana M.O., Shrestha S., Knight G.M., Cohen T., White R.G., Cobelens F., and Dowdy D.W.2017. A Multistrain Mathematical Model To Investigate the Role of Pyrazinamide in the Emergence of Extensively Drug-Resistant Tuberculosis. Antimicrobial agents and chemotherapy 61. 52. Kwon B.S., Kim Y., Lee S.H., Lim S.Y., Lee Y.J., Park J.S., Cho Y.-J., Yoon H.I., Lee C.-T., and Lee J.H.2020. The high incidence of severe adverse events due to pyrazinamide in elderly patients with tuberculosis. PloS one 15: e0236109. 53. WHO.2017. Guidelines for treatment of drug-susceptible tuberculosis and patient care. 54. Organization W.H.2018. Latent tuberculosis infection: updated and consolidated guidelines for programmatic management. World Health Organization. 55. Control C.f.D., and Prevention.2014. Latent Tuberculosis Infection: A Guide for Primary Health Care Providers. Atlanta, GA, Centers for Disease Control and Prevention, 2013.56. Centers for Disease C., and Prevention.2002. Update: Fatal and severe liver injuries associated with rifampin and pyrazinamide treatment for latent tuberculosis infection. MMWR Morb Mortal Wkly Rep 51: 998-9. 57. Centers for Disease C., and Prevention.2001. Fatal and severe hepatitis associated with rifampin and pyrazinamide for the treatment of latent tuberculosis infection--New York and Georgia, 2000. MMWR Morb Mortal Wkly Rep 50: 289-91. 58. Parish T.2020. In vitro drug discovery models for Mycobacterium tuberculosis relevant for host infection. Expert Opin Drug Discov 15: 349-358. 59. WHO.2022. Global tuberculosis report 2022. 60. Schildknecht KR P.R., Feng PI, Price SF, Self JL.2023. Tuberculosis — United States, 2022. MMWR Morb Mortal Wkly Rep 297-303. 67. INSIGHTS C.M.2021. Global Pyrazinamide Market. 68. Early J., Ollinger J., Darby C., Alling T., Mullen S., Casey A., Gold B., Ochoada J., Wiernicki T., Masquelin T. and others.2019. Identification of Compounds with pH-Dependent Bactericidal Activity against Mycobacterium tuberculosis. ACS Infect Dis 5: 272-280. 69. Early J.V., Mullen S., and Parish T.2019. A rapid, low pH, nutrient stress, assay to determine the bactericidal activity of compounds against non-replicating Mycobacterium tuberculosis. PloS one 14: e0222970. 70. Gold B., Warrier T., and Nathan C.2015. A multi-stress model for high throughput screening against non-replicating Mycobacterium tuberculosis. Methods Mol Biol 1285: 293- 315. 71. Rinder H., Mieskes K.T., and Loscher T.2001. Heteroresistance in Mycobacterium tuberculosis. Int J Tuberc Lung Dis 5: 339-45. 72. Koul A., Arnoult E., Lounis N., Guillemont J., and Andries K.2011. The challenge of new drug discovery for tuberculosis. Nature 469: 483-90. 73. Payne D.J., Gwynn M.N., Holmes D.J., and Pompliano D.L.2007. Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat Rev Drug Discov 6: 29-40. 74. Craggs P.D., and de Carvalho L.P.S.2022. Bottlenecks and opportunities in antibiotic discovery against Mycobacterium tuberculosis. Curr Opin Microbiol 69: 102191.75. Fernandes G.F.S., Thompson A.M., Castagnolo D., Denny W.A., and Dos Santos J.L. 2022. Tuberculosis Drug Discovery: Challenges and New Horizons. J Med Chem 65: 7489- 7531. 76. Yuan T., and Sampson N.S.2018. Hit Generation in TB Drug Discovery: From Genome to Granuloma. Chem Rev 118: 1887-1916. 77. Koller F.a.L., F..1934. Nekrose und Autolyse Beitrag zur Kenntnis der Dystrophischen Verkalkung. Klin Wochenschr 13: 1527-1529. 78. Canetti G.1955. The tubercle bacillus in the pulmonary lesion of man: histobacteriology and its bearing on the therapy of pulmonary tuberculosis. Springer Publishing Company. 79. Sarathy J.P., Via L.E., Weiner D., Blanc L., Boshoff H., Eugenin E.A., Barry C.E., 3rd, and Dartois V.A.2018. Extreme Drug Tolerance of Mycobacterium tuberculosis in Caseum. Antimicrobial agents and chemotherapy 62. 80. Johansen F.A.1927. Benzocaine-Chaulmoogra Oil in the Treatment of Leprosy: Preliminary Note on the Use of an Oil-Soluble Analgesic Which Renders Intramuscular Injections of Chaulmoogra Chaulmoogra Oil Painless. Public Health Reports (1896-1970): 3005- 3010. 81. Murray M.F.2003. Nicotinamide: an oral antimicrobial agent with activity against both Mycobacterium tuberculosis and human immunodeficiency virus. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 36: 453-60. 82. Chakraborty S., and Rhee K.Y.2015. Tuberculosis Drug Development: History and Evolution of the Mechanism-Based Paradigm. Cold Spring Harb Perspect Med 5: a021147. 83. Yeager R.L., Munroe W.G., and Dessau F.I.1952. Pyrazinamide (aldinamide) in the treatment of pulmonary tuberculosis. Am Rev Tuberc 65: 523-46. 84. Malone L., Schurr A., Lindh H., Mc K.D., Kiser J.S., and Williams J.H.1952. The effect of pyrazinamide (aldinamide) on experimental tuberculosis in mice. Am Rev Tuberc 65: 511-8. 85. Schwartz W.S., and Moyer R.E.1954. The chemotherapy of pulmonary tuberculosis with pyrazinamide used alone and in combination with streptomycin, para-aminosalicylic acid, or isoniazid. Am Rev Tuberc 70: 413-22. 86. Grosset J.1978. The sterilizing value of rifampicin and pyrazinamide in experimental short-course chemotherapy. Bull Int Union Tuberc 53: 5-12.87. Grosset J.2003. Mycobacterium tuberculosis in the extracellular compartment: an underestimated adversary. Antimicrobial agents and chemotherapy 47: 833-6. 88. Flynn J.L., and Chan J.2001. Tuberculosis: latency and reactivation. Infect Immun 69: 4195-201. 89. Lenaerts A., Barry C.E., 3rd, and Dartois V.2015. Heterogeneity in tuberculosis pathology, microenvironments and therapeutic responses. Immunol Rev 264: 288-307. 90. Kempker R.R., Heinrichs M.T., Nikolaishvili K., Sabulua I., Bablishvili N., Gogishvili S., Avaliani Z., Tukvadze N., Little B., Bernheim A. and others.2017. Lung Tissue Concentrations of Pyrazinamide among Patients with Drug-Resistant Pulmonary Tuberculosis. Antimicrobial agents and chemotherapy. 91. Almeida D., Nuermberger E., Tasneen R., Rosenthal I., Tyagi S., Williams K., Peloquin C., and Grosset J.2009. Paradoxical effect of isoniazid on the activity of rifampin-pyrazinamide combination in a mouse model of tuberculosis. Antimicrobial agents and chemotherapy 53: 4178-84. 92. Development Therapeutics Program, National Cancer Institute (NCI), National Institutes of Health (NIH). 93. Chinedu E., Arome D., and Solomon Ameh F.2013. A new method for determining acute toxicity in animal models. Toxicology international 20. 94. Erhirhie E.O., Ihekwereme C.P., and Ilodigwe E.E.2018. Advances in acute toxicity testing: strengths, weaknesses and regulatory acceptance. Interdiscip Toxicol 11: 5-12. 95. Roy R., Liya I.J., Roy J., and Basher M.A.2023. Acute and subchronic toxicity profile of methanol extract of leaves of Fimbristylis miliacea (L.) Vahl. Toxicol Rep 10: 301-307. 96. OA A.-S., TM E.-H., and AA A.-M.2002. Effect of prolonged vigabatrin treatment on hematological and biochemical parameters in plasma, liver and kidney of Swiss albino mice. Scientia Pharmaceutica 70: 135-145. 97. Teo S., Stirling D., Thomas S., Hoberman A., Kiorpes A., and Khetani V.2002. A 90- day oral gavage toxicity study of d-methylphenidate and d, l-methylphenidate in Sprague– Dawley rats. Toxicology 179: 183-196. 98. Chorine V.1945. Action de l’amide nicotinique sur les bacilles du genre Mycobacterium. Comptes rendus de l'Académie des Sciences 220: 150-151.99. Huant E.1945. Note sur l’action de très fortes doses d`amide nicotinique dans les lésions bacillaires. Gazette des Hopitau 118: 259-260. 100. FOX H.H.1953. SECTION OF PHYSICS AND CHEMISTRY: THE CHEMICAL ATTACK ON TUBERCULOSIS. Transactions of the New York Academy of Sciences 15: 234- 242. 101. Woods G.L., Brown-Elliott B.A., Conville P.S., Desmond E.P., Hall G.S., Lin G., Pfyffer G.E., Ridderhof J.C., Siddiqi S.H., and Wallace Jr R.J.2011. Susceptibility testing of mycobacteria, nocardiae, and other aerobic actinomycetes. 102. ISO.2006. ISO 20776‐1: 2006 Clinical laboratory testing and in vitro diagnostic test systems–Susceptibility testing of infectious agents and evaluation of performance of antimicrobial susceptibility test devices–Part 1: Reference method for testing the in vitro activity of antimicrobial agents against rapidly growing aerobic bacteria involved in infectious diseases. International Organization for Standardization: 19. 103. Bax H.I., Bakker-Woudenberg I., de Vogel C.P., van der Meijden A., Verbon A., and de Steenwinkel J.E.M.2017. The role of the time-kill kinetics assay as part of a preclinical modeling framework for assessing the activity of anti-tuberculosis drugs. Tuberculosis 105: 80- 85. 104. Collins L., and Franzblau S.G.1997. Microplate alamar blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrobial agents and chemotherapy 41: 1004-9. 105. Heinrichs M.T., May R.J., Heider F., Reimers T., SK B.S., Peloquin C.A., and Derendorf H.2018. Mycobacterium tuberculosis Strains H37ra and H37rv have equivalent minimum inhibitory concentrations to most antituberculosis drugs. Int J Mycobacteriol 7: 156-161. 106. Fisher R.A., Gollan B., and Helaine S.2017. Persistent bacterial infections and persister cells. Nat Rev Microbiol 15: 453-464. 107. Amato S.M., and Brynildsen M.P.2015. Persister Heterogeneity Arising from a Single Metabolic Stress. Curr Biol 25: 2090-8. 108. Rohde K., Yates R.M., Purdy G.E., and Russell D.G.2007. Mycobacterium tuberculosis and the environment within the phagosome. Immunological reviews 219: 37-54.109. Dalberto P.F., de Souza E.V., Abbadi B.L., Neves C.E., Rambo R.S., Ramos A.S., Macchi F.S., Machado P., Bizarro C.V., and Basso L.A.2020. Handling the Hurdles on the Way to Anti-tuberculosis Drug Development. Front Chem 8: 586294. 110. Kumar A., Chettiar S., and Parish T.2017. Current challenges in drug discovery for tuberculosis. Expert Opin Drug Discov 12: 1-4. 111. Wernevik J., Bergstrom F., Noven A., Hulthe J., Fredlund L., Addison D., Holmgren J., Stromstedt P.E., Rehnstrom E., and Lundbock T.2020. A Fully Integrated Assay Panel for Early Drug Metabolism and Pharmacokinetics Profiling. Assay Drug Dev Technol 18: 157-179. 112. Lakshminarayana S.B., Huat T.B., Ho P.C., Manjunatha U.H., Dartois V., Dick T., and Rao S.P.2015. Comprehensive physicochemical, pharmacokinetic and activity profiling of anti- TB agents. J Antimicrob Chemother 70: 857-67. 113. Wohnsland F., and Faller B.2001. High-throughput permeability pH profile and high- throughput alkane / water log P with artificial membranes. J Med Chem 44: 923-30. 114. Volpe D.A., Faustino P.J., Ciavarella A.B., Asafu-Adjaye E.B., Ellison C.D., Yu L.X., and Hussain A.S.2007. Cl3assification of drug permeability with a Caco-2 cell monolayer assay. Clinical Research and Regulatory Affairs 24: 39-47. 115. Fatima R., Ashraf M., Ejaz S., Rasheed M.A., Altaf I., Afzal M., Batool Z., Saleem U., and Anwar K.2013. In vitro toxic action potential of anti tuberculosis drugs and their combinations. Environmental toxicology and pharmacology 36: 501-513. 116. Cumming B.M., Baig Z., Addicott K.W., Chen D., and Steyn A.J.C.2021. Host Bioenergetic Parameters Reveal Cytotoxicity of Antituberculosis Drugs Undetected Using Conventional Viability Assays. Antimicrobial agents and chemotherapy 65: e0093221. 117. Ahmed S., Manning A., Flint L., Awasthi D., Ovechkina Y., and Parish T.2021. Identification of Novel Chemical Scaffolds that Inhibit the Growth of Mycobacterium tuberculosis in Macrophages. Front Pharmacol 12: 790583. 118. Bhusal Y., Shiohira C.M., and Yamane N.2005. Determination of in vitro synergy when three antimicrobial agents are combined against Mycobacterium tuberculosis. Int J Antimicrob Agents 26: 292-7. 119. Omollo C., Singh V., Kigondu E., Wasuna A., Agarwal P., Moosa A., Ioerger T.R., Mizrahi V., Chibale K., and Warner D.F.2021. Developing synergistic drug combinations torestore antibiotic sensitivity in drug-resistant Mycobacterium tuberculosis. Antimicrobial agents and chemotherapy. 120. Ioerger T.R., O'Malley T., Liao R., Guinn K.M., Hickey M.J., Mohaideen N., Murphy K.C., Boshoff H.I., Mizrahi V., Rubin E.J. and others.2013. Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis. PloS one 8: e75245. 121. Mugumbate G., Mendes V., Blaszczyk M., Sabbah M., Papadatos G., Lelievre J., Ballell L., Barros D., Abell C., Blundell T.L. and others.2017. Target Identification of Mycobacterium tuberculosis Phenotypic Hits Using a Concerted Chemogenomic, Biophysical, and Structural Approach. Front Pharmacol 8: 681. 122. Rosenthal I.M., Zhang M., Williams K.N., Peloquin C.A., Tyagi S., Vernon A.A., Bishai W.R., Chaisson R.E., Grosset J.H., and Nuermberger E.L.2007. Daily dosing of rifapentine cures tuberculosis in three months or less in the murine model. PLoS Med 4: e344. 123. Dorman S.E., Nahid P., Kurbatova E.V., Phillips P.P.J., Bryant K., Dooley K.E., Engle M., Goldberg S.V., Phan H.T.T., Hakim J. and others.2021. Four-Month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis. N Engl J Med 384: 1705-1718.

[0215] While certain embodiments of the present disclosure have been described and / or exemplified above, various other embodiments will be apparent to those skilled in the art from the foregoing disclosure. The present disclosure is, therefore, not limited to the particular embodiments described and / or exemplified, but is capable of considerable variation and modification without departure from the scope and spirit of the appended claims.

Claims

CLAIMS 1. A compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof: (R11Formula (I) wherein in Formula (I):is selected from phenyl and C6-C12heteroaryl; R10is selected from optionally substituted alkyl and -(CH2)m-O-C(O)-R10a; each R11is independently selected from hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, alkoxy, acyl, -NR12aR12b, -NR13-C(O)-OR14, -O-C(O)- NR15aR15b, -NR16-C(O)-R17, -NR18-C(O)-N-R19aR19b, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, and optionally substituted heterocyclyl, wherein two or more R11can bond or fuse to form optionally substituted heterocyclyl; R12a,R13, R15a, R15b, R16, R17, R18, R19a, and R19bare each independently selected from H and optionally substituted alkyl; R10ais optionally substituted alkyl; R12bis optionally substituted alkyl; m is 1, 2, 3, or 4; and n is 0, 1, 2, 3, 4, or 5. O2. The compound of claim 1, wherein R10is n-butyl, n-pentyl, n-hexyl, or.

3. The compound of claim 1 or 2, whereinphenyl.

4. The compound of claim 3, wherein n is 1 and R11is selected from -NR12aR12b, -NR13- C(O)-OR14, -NR16-C(O)-R17, -NR18-C(O)-N-R19aR19b, and optionally substituted heterocyclyl.

5. The compound of claim 4, wherein R11is selected from -N(CH3)2,, nd -NH- C(O)-O-(CH2)p-CH3, wherein p is 1, 2, or 3.

6. The compound of claim 3, wherein two or more R11bond or fuse to form optionally substituted heterocyclyl.

7. The compound of claim 6, wherein two or more R11, together with, rm8. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (II), or a stereoisomer or a pharmaceutically acceptable salt thereof:Formula (II) wherein in Formula (II): R20is selected from optionally substituted alkyl and -(CH2)m-O-C(O)-R20a; each R21is independently selected from hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, alkoxy, acyl, -NR22aR22b, -NR23-C(O)-OR24, -O-C(O)- NR25aR25b, -NR26-C(O)-R27, -NR28-C(O)-N-R29aR29b, optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionallysubstituted carbocyclyl, and optionally substituted heterocyclyl, wherein two or more R21can bond or fuse to form optionally substituted heterocyclyl; R22a,R23, R25a, R25b, R26, R27, R28, R29a, and R29bare each independently selected from H and optionally substituted alkyl; R20ais optionally substituted alkyl; R22bis optionally substituted alkyl; m is 1, 2, 3, or 4; and n is 1, 2, 3, 4, or 5.

9. The compound of claim 8, wherein R20is unsubstituted C1-C6alkyl or10. The compound of claim 8 or 9, wherein R20is n-butyl.

11. The compound of any one of claims 8-10, wherein n is 1.

12. The compound of claim 11, wherein R21is selected from -NR22aR22b, -NR23-C(O)- OR24, -NR26-C(O)-R27, -NR28-C(O)-N-R29aR29b, and optionally substituted heterocyclyl.

13. The compound of claim 12, wherein R21is selected from -N(CH3)2,, d - NH-C(O)-O-(CH2)p-CH3, wherein p is 1, 2, or 3.

14. The compound of any one of claims 8-10, wherein two or more R21bond or fuse to form optionally substituted heterocyclyl.

15. The compound of claim 14, wherein two or more R11bond or fuse to form a compound of Formula (IIa) or a stereoisomer or a pharmaceutically acceptable salt thereof:Formula (IIa).

16. The compound of any one of claims 8-15, wherein the compound of Formula (I) or Formula (II) is selected from a compound having any one of formula 1001-1006, 1013-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof:.

17. The compound of claim 1 or 2, whereinC6-C12heteroaryl.

19. The compound of claim 17 or 18, wherein n is 0.

20. The compound of claim 1, wherein the compound of Formula (I) is a compound of Formula (III), or a stereoisomer or a pharmaceutically acceptable salt thereof: EFormula (III) wherein in Formula (III): R30is selected from optionally substituted alkyl and -(CH2)m-O-C(O)-R20a; R30ais optionally substituted alkyl: m is 1, 2, 3, or 4; and21. The compound of claim 20, wherein R30is unsubstituted C1-C6alkyl or.

22. The compound of claim 20 or 21, wherein R30is n-butyl.

23. The compound of any one of claims 17-22, wherein the compound of Formula (III) is selected from a compound having any one of formula 1007-1012, or a stereoisomer or a pharmaceutically acceptable salt thereof:.

24. The compound of any one of claims 1-23, wherein the compound has a minimum inhibitory concentration of less than about 10 µM against tuberculosis.

25. A pharmaceutical composition comprising one or more compounds of any one of claims 1-24, or a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

26. A pharmaceutical composition for treating tuberculosis, the pharmaceutical composition comprising one or more compounds of any one of claims 1-24, or a stereoisomer or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

27. The pharmaceutical composition of claim 25 or 26, wherein the pharmaceutical composition is formulated for oral administration.

28. A method of treating tuberculosis in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-24.

29. The method of claim 28, wherein the tuberculosis is drug-resistant tuberculosis.

Images