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WO2025122558A1 - Petites molécules imitant le pyrazinamide utilisées en tant que traitement de la tuberculose - Google Patents

Petites molécules imitant le pyrazinamide utilisées en tant que traitement de la tuberculose Download PDF

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WO2025122558A1
WO2025122558A1 PCT/US2024/058377 US2024058377W WO2025122558A1 WO 2025122558 A1 WO2025122558 A1 WO 2025122558A1 US 2024058377 W US2024058377 W US 2024058377W WO 2025122558 A1 WO2025122558 A1 WO 2025122558A1
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compound
formula
optionally substituted
alkyl
pharmaceutically acceptable
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Fengtian Xue
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University of Maryland Baltimore
University of Maryland College Park
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University of Maryland Baltimore
University of Maryland College Park
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/60—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in meta- or para- positions
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    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
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    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
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    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
    • C07D249/18—Benzotriazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
    • C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
    • C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/64—Benzothiazoles with only hydrocarbon or substituted hydrocarbon radicals attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D455/00—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/03—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
    • C07D455/04—Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing quinolizine ring systems directly condensed with at least one six-membered carbocyclic ring, e.g. protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine containing a quinolizine ring system condensed with only one six-membered carbocyclic ring, e.g. julolidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis

Definitions

  • PZA pyrazinamide
  • the present disclosure provides a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof: Formula (I) wherein in Formula (I is selected from phenyl and C 6 -C 12 heteroaryl, R 10 is selected from optionally substituted alkyl and -(CH 2 ) m -O-C(O)-R 10a , each R 11 is independently selected from hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, alkoxy, acyl, -NR 12a R 12b , -NR 13 -C(O)-OR 14 , -O-C(O)-NR 15a R 15b , -NR 16 -C(O)-R 17 , -NR 18 -C(O)-N- R 19a R 19b , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted alkeny
  • R10 is n-butyl, n-pentyl, n-hexyl, or .
  • n some embodiments, is phenyl.
  • n is 1 and R 11 is selected from -NR 12a R 12b , -NR 13 -C(O)-OR 14 , -NR 16 -C(O)-R 17 , -NR 18 -C(O)-N- R 19a R 19b , and optionally substituted heterocyclyl.
  • R 11 is selected from -N(CH 3 ) 2 , nd - NH-C(O)-O-(CH 2 ) p -CH 3 , wherein p is 1, 2, or 3. In some embodiments, two or more R 11 bond or fuse to form optionally substituted heterocyclyl.
  • the compound of Formula (I) is a compound of Formula (II), or a stereoisomer or a pharmaceutically acceptable salt thereof: (R Formula (II) wherein in Formula (II) R 20 is selected from optionally substituted alkyl and -(CH 2 ) m -O-C(O)- R 20a , each R 21 is independently selected from hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, alkoxy, acyl, -NR 22a R 22b , -NR 23 -C(O)-OR 24 , -O-C(O)- NR 25a R 25b , -NR 26 -C(O)-R 27 , -NR28-C(O)-N-R 29 a a R 29 b a , optionally substituted alkyl, optionally substituted heteroalkyl,
  • R 20 is unsubstituted C 1 -C 6 alkyl. In some embodiments, R 20 is n- O butyl, n-pentyl, n-hexyl, or . In some embodiments, n is 1. In some embodiments, R 21 is selected from -NR 22a R 22b , -NR 23 -C(O)-OR 24 , -N R 26 -C(O)- R 27 , -NR 28 -C(O)-N- R 29a R 29 b a , and optionally substituted heterocyclyl.
  • R 21 is selected from -N(CH 3 ) 2 , , and -NH-C(O)-O-(CH 2 ) p -CH 3 , wherein p is 1, 2, or 3.
  • two or more R 21 bond or fuse to form optionally substituted heterocyclyl.
  • two or more R 11 bond or fuse to form a compound of Formula (IIa) or a stereoisomer or a pharmaceutically acceptable salt thereof: Formula (IIa).
  • 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:
  • the compound of Formula (I) is a compound of Formula (III), or a stereoisomer or a pharmaceutically acceptable salt thereof: E Formula (III) wherein in Formula (III) R 30 is optionally substituted alkyl and -(CH 2 ) m -O-C(O)-R 30a ; R 30a is optionally substituted alkyl, and n some embodiments, R 30 is unsubstituted C 1 -C 6 alkyl.
  • R 30 is n-butyl, n-pentyl, n- hexyl, [0012]
  • 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:
  • the compound has a minimum inhibitory concentration of less than about 10 ⁇ M against tuberculosis.
  • 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.
  • the pharmaceutical composition is for treating tuberculosis.
  • the pharmaceutical composition is formulated for oral administration.
  • 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.
  • the tuberculosis is drug-resistant tuberculosis.
  • 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.
  • FIG.2 depicts a non-limiting example of the design of new anti-TB agents based on the mechanism of action of PZA.
  • FIG.3 depicts select compounds of the disclosure.
  • 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.
  • MIC Minimum Inhibitory Concentration
  • tuberculosis strains PZA susceptible strain H37Ra (A); PZAR #6 strain (PncA mutation L159P) (B); and PZAR #136 strain (PanD mutation E126*) (C).
  • A PZA susceptible strain H37Ra
  • B PZAR #6 strain
  • B PZAR #136 strain
  • C PZAR #136 strain
  • administer refers 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.
  • co-administration 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.
  • 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.
  • the term “in vivo” refers to an event that takes place in a subject’s body.
  • 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.
  • 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 and disease 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.
  • 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.
  • 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.
  • 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.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • 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.
  • “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 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.
  • 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).
  • 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.
  • the chemical structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms.
  • 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., (C 1-10 )alkyl or C 1-10 alkyl).
  • 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.
  • 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, - OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , - N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C(O)OR a ,
  • 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.
  • 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.
  • 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.
  • An “alkene” moiety refers to a group consisting of at least two carbon atoms and at least one carbon-carbon double bond
  • 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.
  • 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., (C 2-10 )alkenyl or C 2-10 alkenyl).
  • 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.
  • ethenyl i.e., vinyl
  • prop-1-enyl i.e., allyl
  • but-1-enyl i.e., pent-1-enyl and penta-1,4-dienyl.
  • 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, - OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , - N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )
  • 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.
  • 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., (C 2-10 )alkynyl or C 2-10 alkynyl).
  • 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.
  • 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, -OR a , -SR a , -OC(O)-R a , - N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , - N(R a )C(O)R a , -N(R a )C(O)
  • 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.
  • Cyano refers to a -CN radical.
  • Cycloalkyl refers to a monocyclic or polycyclic radical that contains only carbon and hydrogen, and may be saturated, or partially unsaturated. Cycloalkyl groups include groups having from 3 to 10 ring atoms (i.e. (C 3-10 )cycloalkyl or C 3-10 cycloalkyl). 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.
  • 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.
  • 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, -OR a , -SR a , -OC(O)-R a , - N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , - N(R a )C(O)R a , -N(R a )C(
  • 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.
  • 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.
  • 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.
  • 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.
  • substituted alkoxy refers to alkoxy wherein the alkyl constituent is substituted (i.e., -O-(substituted alkyl)).
  • 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, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , - C(O)N(R a ) 2 , -N(R a )C(O)OR a , -N(R a )C(O)OR a , -N(R a )
  • a (C 1 -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.
  • substituted alkoxycarbonyl refers to the group (substituted alkyl)-O-C(O)- wherein the group is attached to the parent structure through the carbonyl functionality.
  • 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, -OR a , -SR a , - OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O
  • 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 hetero ring or chain atoms contribute to the total number of chain or ring atoms.
  • 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, -OR a , -SR a , - OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , -N(R a )C(O)OR a ,
  • 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, -OR a , -SR a , - OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , - N(R a )C(O)R a , -N(R a )C(
  • 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, - OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , - N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )C
  • a -N(R a ) 2 group When a -N(R a ) 2 group has two R a substituents other than hydrogen, they can be combined with the nitrogen atom to form a 4-, 5-, 6- or 7-membered ring.
  • -N(R a ) 2 is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • 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, -OR a , -SR a , -OC(O)-R a , - N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , - N(R a )C(O)R a , -N(R a )C(O)OR a
  • substituted amino also refers to N-oxides of the groups -NHR a , and NR a R a each as described above. N-oxides can be prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid.
  • Amide or “amido” refers to a chemical moiety with formula -C(O)N(R) 2 or -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.
  • R2 of -N(R) 2 of 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.
  • an amido group is optionally substituted independently by one or more of the substituents as described herein for alkyl, 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, 3 rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety.
  • “Aromatic” or “aryl” or “Ar” refers to an aromatic radical with six to ten ring atoms (e.g., C 6 -C 10 aromatic or C 6 -C 10 aryl) 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.
  • 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.
  • 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, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , - OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )
  • aryloxy refers to the group -O-aryl.
  • substituted aryloxy refers to aryloxy wherein the aryl substituent is substituted (i.e., -O-(substituted aryl)).
  • the aryl moiety of an aryloxy 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, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , - C(O)N(R a ) 2 , -N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a
  • “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.
  • “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).
  • 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, 3 rd Ed., John Wiley & Sons, New York, N.Y., 1999, which is incorporated herein by reference in its entirety.
  • 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, -OR a , -SR a , -OC(O)- R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , - N(R a )C(O)R a , -N(R a )C(O)OR a
  • 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.
  • Halo “halide,” or, alternatively, “halogen” is intended to mean fluoro, chloro, bromo or iodo.
  • haloalkyl examples include alkyl, alkenyl, alkynyl and alkoxy structures that are substituted with one or more halo groups or with combinations thereof.
  • fluoroalkyl and “fluoroalkoxy” include haloalkyl and haloalkoxy groups, respectively, in which the halo is fluorine.
  • Heteroalkyl refers 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., C 1 -C 4 heteroalkyl 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, -OR a , -SR a , -OC(O)-R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , - C(O)N(R a ) 2 , -N(R a )C(O)OR a , -N(R a )C(O)OR a , -N(R a )C(O)OR a
  • 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.
  • 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.
  • 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.
  • 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.
  • Heteroaryl or “heteroaromatic” or “HetAr” or “Het” refers to a 5- to 18-membered aromatic radical (e.g., C 5 -C 13 heteroaryl) 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.
  • 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.
  • heteroaryl may be attached to the rest of the molecule through any atom of the ring(s).
  • 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, benz
  • 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, -OR a , -SR a , -OC(O)- R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , -N(R a )C(O)OR a , - N(R a )C(O)R a , -N(R a )C(O)OR
  • Substituted heteroaryl also includes ring systems substituted with one or more oxide (-O-) substituents, such as, for example, pyridinyl N-oxides.
  • “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.
  • “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.
  • 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.
  • 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).
  • 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,
  • 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, -OR a , -SR a , -OC(O)- R a , -N(R a ) 2 , -C(O)R a , -C(O)OR a , -OC(O)N(R a ) 2 , -C(O)N(R a ) 2 , - N(R a )C(O)OR a , -N(R a )C(O)R a , -N(R a )
  • 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.
  • “Nitro” refers to the -NO 2 radical.
  • Oxa refers to the -O- radical.
  • “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.
  • 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 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.
  • 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).
  • HPLC high pressure liquid chromatography
  • 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.
  • 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.
  • “Moiety” refers to a specific segment or functional group of a molecule.
  • 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.
  • keto-enol tautomerization An example of tautomerization is keto-enol tautomerization.
  • keto-enol tautomerization is the interconversion of pentane-2,4-dione and 4- hydroxypent-3-en-2-one tautomers.
  • phenol-keto tautomerization Another example of tautomerization is phenol-keto tautomerization.
  • phenol-keto tautomerization is the interconversion of pyridin-4-ol and pyridin-4(1H)-one tautomers.
  • 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.
  • 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).
  • Solvate refers to a compound in physical association with one or more molecules of a pharmaceutically acceptable solvent.
  • “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, sulfoxy
  • substituents themselves may be substituted, for example, a cycloalkyl substituent may itself have a halide substituent at one or more of its ring carbons.
  • optionally substituted means optional substitution with the specified groups, radicals or moieties.
  • “Sulfanyl” refers to groups that include -S-(optionally substituted alkyl), -S-(optionally substituted aryl), -S-(optionally substituted heteroaryl) and -S-(optionally substituted heterocycloalkyl).
  • “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).
  • “Sulfonyl” refers to groups that include -S(O 2 )-H, -S(O 2 )-(optionally substituted alkyl), -S(O 2 )-(optionally substituted amino), -S(O 2 )-(optionally substituted aryl), -S(O 2 )- (optionally substituted heteroaryl), and -S(O2)-(optionally substituted heterocycloalkyl).
  • a sulfonamido group is optionally substituted by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.
  • a sulfonate group is optionally substituted on R by one or more of the substituents described for alkyl, cycloalkyl, aryl, heteroaryl, respectively.
  • 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.
  • Crystal 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.
  • 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.
  • 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.
  • 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.
  • the small molecule anti-TB agent is a compound of Formula (I), or a stereoisomer or a pharmaceutically acceptable salt thereof: (R 11 Formula (I) wherein in Formula (I): is selected from phenyl and C 6 -C 12 heteroaryl; R 10 is selected from optionally substituted alkyl and -(CH 2 ) m -O-C(O)-R 10a ; each R 11 is independently selected from hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, alkoxy, acyl, -NR 12a R 12b , -NR 13 -C(O)-OR 14 , -O-C(O)- NR 15a R 15b , -NR 16 -C(O)-R 17 , -NR 18 -C(O)-N-R 19a R 19b , optionally substituted alkyl, optionally substituted heteroalkyl, optionally substituted
  • R 10 is unsubstituted C 1 -C 6 alkyl. In one embodiment, R 10 is methyl. In one embodiment, R 10 is ethyl. In one embodiment, R 10 is n-propyl. In one embodiment, R 10 is i-propyl. In one embodiment, R 10 is n-butyl. In one embodiment, R 10 is i- butyl. In one embodiment, R 10 is t-butyl. In one embodiment, R 10 is n-pentyl. In one embodiment, R 10 is i-pentanyl. In one embodiment, R 10 is neopentyl. In one embodiment, R 10 is n-hexyl.
  • R 10 is 2-methylpentyl. In one embodiment, R 10 is 3-methylpentyl. In one embodiment, R 10 is 2,3-dimethylbutyl. In one embodiment, R 10 is 2,2-dimethylbutyl. In one embodiment, R 10 is -(CH 2 ) m -O-C(O)-R 10a . In one embodiment, R 10a is unsubstituted C 1 -C 6 alkyl. In one embodiment, R 10a is methyl. In one embodiment, R 10a is ethyl. In one embodiment, R 10a is n-propyl. In one embodiment, R 10a is i-propyl. In one embodiment, R 10a is n-butyl.
  • R 10a is i-butyl. In one embodiment, R 10a is t-butyl. In one embodiment, R 10a is n-pentyl. In one embodiment, R 10a is i-pentanyl. In one embodiment, R 10a is neopentyl. In one embodiment, R 10a is n-hexyl. In one embodiment, R 10a is 2-methylpentyl. In one embodiment, R 10a is 3-methylpentyl. In one embodiment, R 10a is 2,3-dimethylbutyl. In one embodiment, R 10a is 2,2-dimethylbutyl. [00103] In one embodiment, R 10 is substituted C 1 -C 6 alkyl.
  • R 10 is a C 1 -C 6 alkyl substituted with an ester.
  • the ester is a methyl ester.
  • the ester is an ethyl ester.
  • the ester is an n-propyl ester.
  • the ester is an i-propyl ester.
  • the ester is an n-butyl ester.
  • the ester is an i-butyl ester.
  • the ester is a t-butyl ester.
  • the ester is an n-pentyl ester.
  • the ester is an i-pentanyl ester.
  • 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. [00104] In one embodiment, s phenyl. [00105] In one embodiment, n is 1.
  • n is 1 and R 11 is selected from -NR 12a R 12b , -NR 13 -C(O)-OR 14 , and optionally substituted heterocyclyl.
  • n is 1 and R 11 is selected from -N(CH 3 ) 2 , , nd -NH-C(O)-O-(CH 2 ) p -CH 3 , wherein p is 1, 2, or 3.
  • one or more R 11 bond or fuse to form optionally substituted heterocyclyl.
  • 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): R 20 is selected from optionally substituted alkyl and -(CH 2 ) m -O-C(O)-R 20a ; each R 21 is independently selected from hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, alkoxy, acyl, -NR 22a R 22b , -NR 23 -C(O)-OR 24 , -O-C(O)
  • R 20 is unsubstituted C 1 -C 6 alkyl. In one embodiment, R 20 is unsubstituted C 1 -C 6 alkyl. In one embodiment, R 20 is methyl. In one embodiment, R 20 is ethyl. In one embodiment, R 20 is n-propyl. In one embodiment, R 20 is i-propyl. In one embodiment, R 20 is n-butyl. In one embodiment, R 20 is i-butyl. In one embodiment, R 20 is t-butyl. In one embodiment, R 20 is n-pentyl. In one embodiment, R 20 is i-pentanyl. In one embodiment, R 20 is neopentyl.
  • R 20 is n-hexyl. In one embodiment, R 20 is 2-methylpentyl. In one embodiment, R 20 is 3-methylpentyl. In one embodiment, R 20 is 2,3-dimethylbutyl. In one embodiment, R 20 is 2,2-dimethylbutyl. In one embodiment, R 20 is -(CH 2 ) m -O-C(O)-R 20a . In one embodiment, R 20a is unsubstituted C 1 -C 6 alkyl. In one embodiment, R 20a is methyl. In one embodiment, R 20a is ethyl. In one embodiment, R 20a is n-propyl. In one embodiment, R 20a is i- propyl.
  • R 20a is n-butyl. In one embodiment, R 20a is i-butyl. In one embodiment, R 20a is t-butyl. In one embodiment, R 20a is n-pentyl. In one embodiment, R 20a is i- pentanyl. In one embodiment, R 20a is neopentyl. In one embodiment, R 20a is n-hexyl. In one embodiment, R 20a is 2-methylpentyl. In one embodiment, R 20a is 3-methylpentyl. In one embodiment, R 20a is 2,3-dimethylbutyl. In one embodiment, R 20a is 2,2-dimethylbutyl.
  • R 20 is substituted C 1 -C 6 alkyl. In some embodiments, R 20 is a C 1 -C 6 alkyl 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.
  • 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. [00109] In one embodiment, the compound of Formula (I) is a compound of Formula (II) wherein n is 1.
  • n is 1 and R 21 is selected from -NR 22a R 22b , -NR 23 -C(O)- OR 24 , and optionally substituted heterocyclyl.
  • n is 1 and R 21 is selected from -N(CH 3 ) 2 , and -NH-C(O)-O-(CH 2 ) p -CH 3 , wherein p is 1, 2, or 3.
  • one or more R 21 bond or fuse to the phenyl ring to form one or more optionally substituted heterocyclyls.
  • 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: [00113]
  • s C 6 -C 12 heteroaryl is selected from a compound having any one of formula 1001-1006, or 1013-1020, or a stereoisomer or a pharmaceutically acceptable salt thereof:
  • the C 6 - C 12 heteroaryl comprises a phenyl ring fused to a ring comprising one or more heteroatoms. In one embodiment, the C 6 -C 12 heteroaryl 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 C 6 -C 12 heteroaryl comprises a phenyl ring fused to a ring comprising two or three nitrogen atoms. In one embodiment, the C 6 -C 12 heteroaryl comprises a phenyl ring fused to a ring comprising one nitrogen atom and one oxygen atom.
  • the compound of Formula (I) is a compound of Formula (III) or Formula (IIIa), or a stereoisomer or a pharmaceutically acceptable salt thereof: E Formula (III) Formula (IIIa). wherein in Formula (III) or Formula (IIIa): R 30 is selected from optionally substituted alkyl and -(CH 2 ) m -O-C(O)-R 30a ; R 30a is optionally substituted alkyl, and [00115] In one embodiment, R 30 is unsubstituted C 1 -C 6 alkyl.
  • R 30 is unsubstituted C 1 -C 6 alkyl. In one embodiment, R 30 is methyl. In one embodiment, R 30 is ethyl. In one embodiment, R 30 is n-propyl. In one embodiment, R 30 is i-propyl. In one embodiment, R 30 is n-butyl. In one embodiment, R 30 is i-butyl. In one embodiment, R 30 is t-butyl. In one embodiment, R 30 is n-pentyl. In one embodiment, R 30 is i-pentanyl. In one embodiment, R 30 is neopentyl. In one embodiment, R 30 is n-hexyl. In one embodiment, R 30 is 2-methylpentyl.
  • R 30 is 3-methylpentyl. In one embodiment, R 30 is 2,3-dimethylbutyl. In one embodiment, R 30 is 2,2-dimethylbutyl. In one embodiment, R 30 is -(CH 2 ) m -O-C(O)-R 30a . In one embodiment, R 30a is unsubstituted C 1 -C 6 alkyl. In one embodiment, R 30a is methyl. In one embodiment, R 30a is ethyl. In one embodiment, R 30a is n-propyl. In one embodiment, R 30a is i- propyl. In one embodiment, R 30a is n-butyl. In one embodiment, R 30a is i-butyl.
  • R 30a is t-butyl. In one embodiment, R 30a is n-pentyl. In one embodiment, R 30a is i- pentanyl. In one embodiment, R 30a is neopentyl. In one embodiment, R 30a is n-hexyl. In one embodiment, R 30a is 2-methylpentyl. In one embodiment, R 30a is 3-methylpentyl. In one embodiment, R 30a is 2,3-dimethylbutyl. In one embodiment, R 30a is 2,2-dimethylbutyl. [00116] In one embodiment, R 30 is substituted C 1 -C 6 alkyl.
  • R 30 is a C 1 -C 6 alkyl substituted with an ester.
  • the ester is a methyl ester.
  • the ester is an ethyl ester.
  • the ester is an n-propyl ester.
  • the ester is an i-propyl ester.
  • the ester is an n-butyl ester.
  • the ester is an i-butyl ester.
  • the ester is a t-butyl ester.
  • the ester is an n-pentyl ester.
  • the ester is an i-pentanyl ester.
  • 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. [00117] 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:
  • 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 ⁇ M, less than about 140 ⁇ M, less than about 130 ⁇ M, less than about 120 ⁇ M, less than about 110 ⁇ M, less than about 100 ⁇ M, less than about 90 ⁇ M, less than about 80 ⁇ M, less than about 70 ⁇ M, less than about 60 ⁇ M, less than about 50 ⁇ M, less than about 40 ⁇ M, less than about 30 ⁇ M, less than about 20 ⁇ M, less than about 10 ⁇ M, less than about 5 ⁇ M, or less than about 1 ⁇ M against Mycobacterium tuberculosis.
  • MIC minimum inhibitory concentration
  • 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 ⁇ M, less than about 5 ⁇ M, or less than about 1 ⁇ M against Mycobacterium tuberculosis.
  • MIC minimum inhibitory concentration
  • 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.
  • a compound of Formula (I), Formula (II), and Formula (III) are provided elsewhere herein.
  • the tuberculosis is drug-resistant tuberculosis.
  • 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.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier. Exemplary pharmaceutically acceptable carriers are described elsewhere herein.
  • the method further comprises administering to the subject a therapeutically effective amount of one or more additional anti-TB agents.
  • the one or more additional anti-TB agents comprise the current standard of care for tuberculosis.
  • the one or more additional anti-TB agents are selected from isoniazid, rifampin (rifadin, rimactane), ethambutol (myambutol), and pyrazinamide.
  • 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.
  • the one or more additional anti-TB agents is administered orally to the subject.
  • 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.
  • 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.
  • 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 sequentially to the subject.
  • 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.
  • 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.
  • 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 [00125]
  • the disclosure provides a pharmaceutical composition for use in the treatment of tuberculosis.
  • the tuberculosis is drug resistant tuberculosis.
  • 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.
  • 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.
  • the pharmaceutical composition is formulated for oral administration.
  • the present disclosure relates to a pharmaceutical composition comprising one or more small molecule anti-TB agents described elsewhere herein.
  • 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.
  • 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.
  • 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.
  • 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%,
  • 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%
  • 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 0.0001% 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
  • 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.
  • 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
  • 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
  • Each of the compounds provided according to the disclosure is effective over a wide dosage range.
  • 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.
  • Described below are non-limiting pharmaceutical compositions and methods for preparing the same.
  • compositions 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.
  • 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.
  • the composition further contains (iii) an effective amount of an additional active pharmaceutical ingredient.
  • additional active pharmaceutical ingredients, as used herein may include one or more compounds that are useful in the treatment or prevention of tuberculosis.
  • the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption.
  • 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.
  • 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
  • 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.
  • 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.
  • 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. [00140] The disclosure further encompasses anhydrous pharmaceutical compositions and dosage forms since water can facilitate the degradation of some compounds.
  • 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 prevent exposure to water such that they can be included in suitable formulary kits.
  • suitable packaging include, but are not limited to, hermetically sealed foils, plastic or the like, unit dose containers, blister packs, and strip packs.
  • 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.
  • 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.
  • suitable carriers include powders, capsules, and tablets, with the solid oral preparations.
  • 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.
  • 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 pyrrol
  • 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.
  • 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.
  • a sufficient amount of disintegrant that is neither too little nor too much to detrimentally 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • HLB hydrophilic-lipophilic balance
  • 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.
  • lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10.
  • 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-g
  • 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.
  • 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
  • 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 sterol
  • the polyol may be glycerol, ethylene glycol, polyethylene glycol, sorbitol, propylene glycol, pentaerythritol, or a saccharide.
  • 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
  • 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.
  • 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.
  • 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.
  • 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 te
  • 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.
  • solubilizers include sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol.
  • 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.
  • 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.
  • the composition can further include one or more pharmaceutically acceptable additives and excipients.
  • 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.
  • detackifiers anti-foaming agents
  • buffering agents buffering agents
  • polymers antioxidants
  • preservatives chelating agents
  • viscomodulators tonicifiers
  • flavorants colorants
  • odorants opacifiers
  • suspending agents binders
  • fillers fillers
  • plasticizers plasticizers
  • lubricants lubricants
  • 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.
  • 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.
  • a pharmaceutically acceptable acid such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids
  • Salts of polyprotic acids such as sodium phosphate, disodium hydrogen phosphate, and sodium dihydrogen phosphate can also be used.
  • 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.
  • 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.
  • 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.
  • compositions for Injection [00163]
  • 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.
  • 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.
  • a coating such as lecithin
  • surfactants 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.
  • 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.
  • 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.
  • compositions for Topical 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.
  • 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.
  • DMSO dimethylsulfoxide
  • carriers with higher densities are capable of providing an area with a prolonged exposure to the active ingredients.
  • a solution formulation may provide more immediate exposure of the active ingredient to the chosen area.
  • 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.
  • 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.
  • penetration-enhancing molecules known to those trained in the art of topical formulation.
  • 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 e.g., isopropyl myristate and sodium lauryl sulfate
  • pyrrolidones e.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.
  • transdermal delivery devices 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.
  • transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos.5,023,252; 4,992,445 and 5,001,139.
  • 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.
  • 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.
  • 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 [00173] 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.
  • 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.
  • 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.
  • 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.
  • a compound of the disclosure is admixed with a matrix.
  • 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.
  • lactone-based polyesters or copolyesters such as polylactide, polycaprolactonglycolide, polyorthoesters, polyanhydrides, polyaminoacids, polysaccharides, polyphosphazenes, poly(ether-ester) cop
  • 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.
  • the compound may be located in the body of the stent or graft, for example in microchannels or micropores.
  • stents When implanted, the compound diffuses out of the body of the stent to contact the arterial wall.
  • 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 stent may be removed via an additional brief solvent wash.
  • 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.
  • 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.
  • the disclosure also provides kits.
  • 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.
  • 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.
  • the kit may further contain another active pharmaceutical ingredient.
  • 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 separate compositions in separate containers within the kit.
  • the other active pharmaceutical ingredient comprises one or more additional anti-TB agents.
  • 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.
  • 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. [00178] In embodiments, the kits described above are for use in the treatment of tuberculosis.
  • Dosages and Dosing Regimens [00179] 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.
  • a 70 kg human 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.
  • 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/m 2 of body surface area.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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,
  • 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.
  • 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 [00186] The embodiments encompassed herein are now described with reference to the following examples.
  • Example 1 Small molecule anti-tubercular agents
  • the present disclosure provides PZA-like molecules with low micromolar to nanomolar anti-TB potencies as an improved anti-TB therapy.
  • the present disclosure provides the design, synthesis and characterization of novel PZA-like small molecules that can eradicate the infection in weeks.
  • PZA is a bio-precursor that is activated in vivo by the enzyme amidase to yield the active metabolite pyrazinoic acid (FIG.1).
  • new compounds of Formula (I) have been designed as useful anti-TB agents.
  • the compounds of Formula (I) include two structural moieties: i) a substituted phenyl or 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).
  • 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.
  • HOBt and EDC as the activation reagents.
  • compounds of the disclosure have been prepared (FIG.3).
  • General method for the synthesis of disclosed compounds [00189] 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).
  • DCM dichloromethane
  • DIPEA diisopropylethylamine
  • Example 2 Determination of MICs using broth microdilution method
  • 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 ⁇ 10 7 CFU/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 KH 2 PO 4 , 0.5 g/L MgSO 4 , 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 ZnSO 4 .
  • PZA-S1 minimal media contains 0.5 g/L KH 2 PO 4 , 0.5 g/L MgSO 4 , 0.5 g/L citric acid, 10 mL/L glycerol, 2 g/L
  • the pH of the medium was adjusted to 6.8 with 1 M of sodium hydroxide and sterilized by filtering through a 0.2 ⁇ m membrane filter).
  • the standard inoculum size in each well was ⁇ 1 ⁇ 10 5 CFU/mL to ⁇ 5 ⁇ 10 5 CFU/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.
  • 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 ⁇ M (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. [00205] PZA-resistant TB strains were vulnerable to FX6018.
  • FX6018 did not exhibit cross-resistance to PZA.
  • Example 3 Determination of activity at neutral pH on agar plate [00206]
  • 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.
  • 5 mL of PZA-S1 agar media at 1.5% (w/v) agar is poured into each quadrant of a 100 mm Petri dish.
  • a 50 ⁇ L suspension is spread on each quadrant of the Petri dish using a sterile cotton applicator.
  • sterile Taxo Blank Discs with 0 (DMSO control) 400 ⁇ g, 800 ⁇ g or 1600 ⁇ g of a compound of the disclosure is pressed down at the center of the quadrant on the agar plate.
  • Example 4 Toxicity of FX6018 [00207] 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 ⁇ L per animal in 8- week-old C57BL/6J mice (2 M and 2 F mice/group). FX6018 was suspended in corn oil.
  • 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.
  • 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 ⁇ 10 5 cells/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 % CO 2 .
  • Tox 50 is measured using CellTiter-Glo kit (Promega) and calculated. The compound is selected with Tox50 ⁇ 100 ⁇ M.
  • 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.
  • Example 5 Pharmacokinetic profiles [00209] 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-state plasma concentration.
  • CD-1 outbred mice are given a single intravenous dose at 50 ⁇ g/gram body weight.
  • time points are 0.1, 0.25, 0.5, 1, 2, 4, 6, 12, and 24 hours post- injection.
  • 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.
  • a parallel artificial membrane permeability assay using 96-well plate-based technology is employed.
  • Each well containing a test compound at a concentration of 1 ⁇ g/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 -6 cm/s or more are considered highly permeable.
  • FX6018 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 & eosin stained.
  • mice/group 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 [00212]
  • 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.
  • Drug cocktails are given via oral gavage 5 days/week for 8 weeks (Table 2).
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • FMI Full Market Insights
  • Fadah K. Rivera M., Lingireddy A., Kalas M.A., Ghafouri R.S., and Deoker A.2022.
  • 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.
  • 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.

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Abstract

La présente invention concerne des agents anti-tuberculose à petites molécules et des compositions pharmaceutiques comprenant les agents anti-tuberculeux. L'invention concerne en outre une méthode de traitement de la tuberculose, notamment la tuberculose pharmacorésistante, chez un sujet en ayant besoin, la méthode comprenant l'administration au sujet d'une quantité thérapeutiquement efficace de l'agent anti-tuberculeux.
PCT/US2024/058377 2023-12-05 2024-12-04 Petites molécules imitant le pyrazinamide utilisées en tant que traitement de la tuberculose Pending WO2025122558A1 (fr)

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US2880050A (en) * 1956-01-27 1959-03-31 Celanese Corp Butyl benzoate as a dyeing assistant
US20150018543A1 (en) * 2008-06-17 2015-01-15 Institut Pasteur Korea Anti-infective compounds
US9073941B2 (en) * 2010-06-28 2015-07-07 Academia Sinica Compounds and methods for treating tuberculosis infection
EP4345091A1 (fr) * 2022-09-29 2024-04-03 Faculdade de Farmácia da Universidade de Lisboa Dérivés d'acide benzoïque, procédés et utilisations de ceux-ci

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2880050A (en) * 1956-01-27 1959-03-31 Celanese Corp Butyl benzoate as a dyeing assistant
US20150018543A1 (en) * 2008-06-17 2015-01-15 Institut Pasteur Korea Anti-infective compounds
US9073941B2 (en) * 2010-06-28 2015-07-07 Academia Sinica Compounds and methods for treating tuberculosis infection
EP4345091A1 (fr) * 2022-09-29 2024-04-03 Faculdade de Farmácia da Universidade de Lisboa Dérivés d'acide benzoïque, procédés et utilisations de ceux-ci

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PAIS JOãO P., ANTONIUK OLHA, FREIRE RAQUEL, PIRES DAVID, VALENTE EMíLIA, ANES ELSA, CONSTANTINO LUIS: "Nitrobenzoates and Nitrothiobenzoates with Activity against M. tuberculosis", MICROORGANISMS, MDPI AG, SWITZERLAND, vol. 11, no. 4, Switzerland, pages 969, XP093327047, ISSN: 2076-2607, DOI: 10.3390/microorganisms11040969 *

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