Iron compounds

Abstract

Provided herein, in part, are compounds and compositions useful for administering an effective amount of iron to a subject in need thereof.

Description

IRON COMPOUNDSCROSS REFERENCE

[0001] This application claims priority to and the benefit of U.S. Provisional Patent Application Number 63 / 580,101 filed September 1, 2023 and U.S. Provisional Patent Application Number 63 / 552,587 filed February 12, 2024, each of which is incorporated herein by reference in its entirety.BACKGROUND

[0002] The current standard of care for treatment of iron deficiency is grossly inadequate. Conventional oral iron drugs are associated with poor tolerability due to, for example, a slew of gastrointestinal side effects, ranging from dyspepsia, constipation, nausea, and diarrhea. In addition, oral iron supplements have low bioavailability and poor systemic absorption. Intravenous iron infusions are expensive, invasive, and are associated with safety issues due to the risk of hypersensitivity reactions from an anaphylactic shock, necessitating medical supervision in a hospital setting. In addition, small molecule iron compounds are generally associated with poor aqueous solubility. To improve formulation challenges, soluble iron complexes with carbohydrate moieties have been developed; however, these complexes have large molecular weights and sizes, for example, in thousands of Da, and are not suitable for certain routes of delivery that need to circumvent the gastrointestinal tract and first-pass metabolism, for example, through the skin. Thus, there is a need for alternatives that reduce the side effects and increase absorbance, bioavailability of iron, exhibit smaller molecular sizes, higher solubility, and higher stability, for example, across a wide pH range. Disclosed herein are compounds and compositions directed towards this end.SUMMARY

[0003] Disclosed herein, in part, are compounds and compositions useful for administering an effective amount of iron to a subject in need thereof. In some embodiments, the compounds and compositions described herein reduce side effects associated with conventional iron supplements, and / or provide high absorbance and / or bioavailability of iron.

[0004] In an aspect, provided herein is a compound of Formula I, II, III, or IV:or a pharmaceutically acceptable salt thereof, wherein: R1is each independently selected from the group consisting of -OS(=O)2-, -NH-, - OC(=O)-, and amino acid;L is an optionally substituted C1-6alkylene; and R2is each independently selected from the group consisting of amino, carboxylic acid, sulfonic acid, and amino acid.

[0005] In some embodiments, the compound of Formula I, II, III, or IV is selected from the group consisting of:

[0006] In another aspect, provided herein is a pharmaceutical composition comprising a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0007] In another aspect, provided herein is a method of administering an effective amount of iron to a subject in need thereof, comprising administering to the subject a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0008] In another aspect, provided herein is a method of treating or preventing iron deficiency in a subject in need thereof, comprising administering to the subject a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, or a compositioncomprising a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0009] In another aspect, provided herein is a method of providing higher absorbance of iron in a subject in need thereof, comprising administering to the subject a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0010] In another aspect, provided herein is a method of providing higher bioavailability of iron in a subject in need thereof, comprising administering to the subject a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0011] In other embodiments, the Fe of a compound of Formula I, II, III, or IV is replaced with Group 3-12 or Period 4 transition metals, including Sc, Ti, V, Cr, Mn, Co, Ni, Cu, or Zn.BRIEF DESCRIPTION OF THE DRAWINGS

[0012] FIG. 1 shows a comparative1H-NMR spectra (in D2O solvent) of Tau and FeCit-Tau complex, which indicates complexation of Tau with FeCit.

[0013] FIG. 2 shows a comparative solid-state NMR spectra of taurine, FeCit-Tau complex, FeCit, and CitAc.

[0014] FIG. 3 shows an X-ray Powder Diffraction (XRPD) pattern of the FeCit-Tau complex.

[0015] FIG. 4 shows a differential scanning calorimetry (DSC) curve of the FeCit- Tau complex.

[0016] FIG. 5 shows a Fourier transform infrared (FTIR) spectrometry curve of the FeCit-Tau complex.

[0017] FIG. 6 shows comparative X-ray absorption spectroscopy spectra and X-ray absorption fine structures (EXAFS) of the samples.

[0018] FIG. 7 shows exemplary in vivo data showing comparative hematological profiles in Fe-deficient rats injected intradermally for 15 days either with test compound (FeCit-Tau complex) or commercial (iron dextran).

[0019] FIG. 8 shows an exemplary pharmacokinetic profile showing systemic iron absorption with resorbable buccal patches in Fe-deficient hamsters.DETAILED DESCRIPTION

[0020] As generally described herein, the present disclosure provides compounds and compositions useful for administering an effective amount of iron to a subject in need thereof. In some embodiments, the compounds and compositions described herein reduce side effects associated with conventional iron supplements, and / or provide high absorbance and / or bioavailability of iron.Compounds

[0021] In an aspect, provided herein is a compound of Formula I, II, III, or IV:or a pharmaceutically acceptable salt thereof, wherein: R1is each independently selected from the group consisting of -OS(=O)2-, -NH-, - OC(=O)-, and amino acid;L is an optionally substituted C1-6alkylene; and R2is each independently selected from the group consisting of amino, carboxylic acid, sulfonic acid, and amino acid.

[0022] In some embodiments, the compound is of Formula I, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula II, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of FormulaIll, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is of Formula IV, or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, R1is each independently selected from the group consisting of -OS(=O)2-, -NH-, and -OC(=O)-. In some embodiments, R1is each independently -OS(=O)2- or -NH-. In some embodiments, R1is each -OS(=O)2-. In other embodiments, R1is each -NH-. In other embodiments, R1is each -OC(=O)-. In other embodiments, R1is each an amino acid.

[0024] In some embodiments, L is an unsubstituted C1-6alkylene. In some embodiments, L is an unsubstituted C1-3alkylene. In some embodiments, L is an unsubstituted C1-2alkylene. In some embodiments, L is an unsubstituted C1alkylene. In some embodiments, L is an unsubstituted C2alkylene. In some embodiments, L is an unsubstituted C3alkylene. In some embodiments, L is an unsubstituted C4alkylene. In some embodiments, L is an unsubstituted C5alkylene. In some embodiments, L is an unsubstituted C6alkylene.

[0025] In some embodiments, L is an optionally substituted C1-3alkylene. In some embodiments, L is an optionally substituted C1-2alkylene. In some embodiments, L is an optionally substituted C1alkylene. In some embodiments, L is an optionally substituted C2alkylene. In some embodiments, L is an optionally substituted C3alkylene. In some embodiments, L is an optionally substituted C4alkylene. In some embodiments, L is an optionally substituted C5alkylene. In some embodiments, L is an optionally substituted C6alkylene.

[0026] In some embodiments, R2is each independently selected from the group consisting of amino, carboxylic acid, and sulfonic acid. In some embodiments, R2is each independently amino or sulfonic acid. In some embodiments, R2is each amino. In other embodiments, R2is each sulfonic acid. In other embodiments, R2is each carboxylic acid. In other embodiments, R2is each an amino acid.

[0027] In some embodiments, the compound of Formula I, II, III, or IV is selected from the group consisting of:or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments, the compounds of Formula I, II, III, IV, or a pharmaceutically acceptable salt thereof, have aqueous solubility of greater than about 100 mg / mL. In some embodiments, the compounds of Formula I, II, III, IV, or a pharmaceutically acceptable salt thereof, have aqueous solubility of greater than about 200 mg / mL. In some embodiments, the compounds of Formula I, II, III, IV, or a pharmaceutically acceptable salt thereof, have aqueous solubility of greater than about 300 mg / mL. In some embodiments, the compounds of Formula I, II, III, IV, or a pharmaceutically acceptable salt thereof, have aqueous solubility of greater than about 400 mg / mL. In some embodiments, the compounds of Formula I, II, III, IV, or a pharmaceutically acceptable salt thereof, have aqueous solubility of greater than about 500 mg / mL. In some embodiments, the compounds of Formula I, II, III,IV, or a pharmaceutically acceptable salt thereof, have aqueous solubility of greater than about 600 mg / mL. In some embodiments, the compounds of Formula I, II, III, IV, or a pharmaceutically acceptable salt thereof, have aqueous solubility of greater than about 700 mg / mL. In some embodiments, the compounds of Formula I, II, III, IV, or a pharmaceutically acceptable salt thereof, have aqueous solubility of greater than about 800 mg / mL. In some embodiments, the compounds of Formula I, II, III, IV, or a pharmaceutically acceptable salt thereof, have aqueous solubility of greater than about 900 mg / mL. In some embodiments, the compounds of Formula I, II, III, IV, or a pharmaceutically acceptable salt thereof, have aqueous solubility of greater than about 1000 mg / mL. In some embodiments, the compounds of Formula I, II, III, IV, or a pharmaceutically acceptable salt thereof, have aqueous solubility of greater than about 1200 mg / mL. In some embodiments, the compounds of Formula I, II, III, IV, or a pharmaceutically acceptable salt thereof, have aqueous solubility of greater than about 1400 mg / mL. In some embodiments, the compounds of Formula I, II, III, IV, or a pharmaceutically acceptable salt thereof, have aqueous solubility of greater than about 1600 mg / mL. In some embodiments, the compounds of Formula I, II, III, IV, or a pharmaceutically acceptable salt thereof, have aqueous solubility of greater than about 1800 mg / mL. In some embodiments, the compounds of Formula I, II, III, IV, or a pharmaceutically acceptable salt thereof, have aqueous solubility of greater than about 2000 mg / mL.

[0029] In some embodiments, the compounds of Formula I, II, III, IV, or a pharmaceutically acceptable salt thereof, facilitates direct uptake by transferrin without intermediate redox cycles.

[0030] In other embodiments, the Fe of a compound of Formula I, II, III, or IV is replaced with Group 3-12 or Period 4 transition metals, including Sc, Ti, V, Cr, Mn, Co, Ni, Cu, or Zn.

[0031] In some embodiments, the compound is oror a pharmaceutically acceptable salt thereof.

[0032] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a ferric-carboxylic acid-amino acid complex. For example, the ferric-carboxylic acid-amino acid complex is a ferric citrate-taurate mixed ligand complex.

[0033] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof is prepared in the molar ratio of Fe3+ : carboxylic acid : amino acid = 1 : 1 : 1. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof is synthesized in the molar ratio of Fe3+ : carboxylic acid : amino acid = 1 : 1.5: 1. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof is prepared in the molar ratio of Fe3+ : carboxylic acid : amino acid = 1: 2: 1.

[0034] In some embodiments, the carboxylic acid ligand of the compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of citric acid, monoacetyl citric acid, tricarballylic acid, aconitic acid, acetonedicarboxylic acid, tartaricacid, oxalic acid, malic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, and any other monocarboxylic, dicarboxylic, tricarboxylic and hydroxy acid.

[0035] In some embodiments, the amino acid ligand of the compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of α-, β- or γ- amino acids, proteinogenic amino acids, and non-proteinogenic amino acids.

[0036] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is amorphous.

[0037] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is stable in solution. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is stable in solution without crystallizing out of the solution.

[0038] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is characterized as having XRPD peaks substantially the same as shown in FIG. 3. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is characterized as having a melting point of about 200 to about 300 °C as determined by differential scanning calorimetry. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is characterized as having a melting point of about 200 to about 250 °C. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is characterized as having a melting point of about 225 to about 235 °C. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is characterized as having a melting point of about 230 °C. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is characterized as having a melting point of about 231 °C.

[0039] In some embodiments, iron content ranges from about 1% to about 20%. In some embodiments, iron content ranges from about 5% to about 15%. In some embodiments, iron content ranges from about 5% to about 10%. In some embodiments, iron content ranges from about 10% to about 15%.

[0040] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has a molecular weight of about 100 to about 800 g / mol. In some embodiments, thecompound, or a pharmaceutically acceptable salt thereof, has a molecular weight of about 200 to about 700 g / mol. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has a molecular weight of about 300 to about 600 g / mol. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has a molecular weight of about 300 to about 400 g / mol. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has a molecular weight of about 500 to about 600 g / mol. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, has a molecular weight of about 400 to about 500 g / mol.

[0041] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is stable at a pH of up to about 10. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is stable at a pH of about 2 to about 10. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is stable at a pH of about 3 to about 10. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is stable at a pH of about 4 to about 10. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is stable at a pH of about 5 to about 10. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is stable at a pH of about 7 to about 10. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is stable at a pH of about 8 to about 10.Pharmaceutical Compositions and Routes of Administration

[0042] In an aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof), and a pharmaceutically acceptable excipient. The pharmaceutical compositions provided herein can be administered by enteral means comprising oral, gastric, duodenal, intestinal or rectal routes. In some embodiments, the pharmaceutical compositions provided herein can be administered as a resorbable buccal patchThe pharmaceutical compositions provided herein can be administered by parenteral (e.g., intradermal, subcutaneous, intramuscular, intravenous, intraperitoneal as well as transdermal and transmucosal (including oral, nasal, ocular, vaginal and rectal mucosa) routes of administration.

[0043] The pharmaceutical compositions disclosed herein may be administered alone or in combination with other therapeutic agents.

[0044] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation. General considerations in the formulation and / or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21sted., Lippincott Williams & Wilkins, 2005.

[0045] Generally, the compounds and compositions provided herein are administered in an effective amount. The amount of the compound or composition actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like.Methods of Use

[0046] As disclosed herein, the compounds and compositions are useful for increasing absorbance and / or bioavailability of iron.

[0047] Thus, in an aspect, provided herein is a method of administering an effective amount of iron to a subject in need thereof, comprising administering to the subject a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0048] In another aspect, provided herein is a method of treating or preventing iron deficiency in a subject in need thereof, comprising administering to the subject a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, or a compositioncomprising a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0049] In another aspect, provided herein is a method of providing higher absorbance of iron in a subject in need thereof, comprising administering to the subject a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0050] In another aspect, provided herein is a method of providing higher bioavailability of iron in a subject in need thereof, comprising administering to the subject a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, or a composition comprising a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0051] In some embodiments, the methods described herein reduce side effects associated with administration of a conventional iron supplement.

[0052] In some embodiments, the methods described herein further comprises administering one or more additional therapeutic agents.

[0053] In some embodiments, the methods descried herein comprises orally administering the compound or composition.

[0054] In some embodiments, the methods descried herein comprises parenterally administering the compound or composition.DefinitionsChemical definitions

[0055] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well as specific functional moietiesand reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March ’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0056] Isomers, e.g., stereoisomers, 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 isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ, of Notre Dame Press, Notre Dame, IN 1972). The disclosure additionally encompasses compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0057] Stereoisomers”: It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers.” Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non- superimposable mirror images of each other are termed “enantiomers.” When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0058] As used herein, a pure enantiomeric compound is substantially free from other enantiomers or stereoisomers of the compound (i.e., in enantiomeric excess). In other words, an “S” form of the compound is substantially free from the “R” form of the compound and is, thus, in enantiomeric excess of the “R” form. The term “enantiomerically pure” or “pureenantiomer” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the enantiomer. In certain embodiments, the weights are based upon total weight of all enantiomers or stereoisomers of the compound.

[0059] As used herein, the term “diastereomeric purity” refers to the amount of a compound having the depicted absolute stereochemistry, expressed as a percentage of the total amount of the depicted compound and its diastereomers. The term “diastereomerically pure” denotes that the compound comprises more than 75% by weight, more than 80% by weight, more than 85% by weight, more than 90% by weight, more than 91% by weight, more than 92% by weight, more than 93% by weight, more than 94% by weight, more than 95% by weight, more than 96% by weight, more than 97% by weight, more than 98% by weight, more than 98.5% by weight, more than 99% by weight, more than 99.2% by weight, more than 99.5% by weight, more than 99.6% by weight, more than 99.7% by weight, more than 99.8% by weight or more than 99.9% by weight, of the diastereomer. Methods for determining diastereomeric and enantiomeric purity are well-known in the art. Diastereomeric purity can be determined by any analytical method capable of quantitatively distinguishing between a compound and its diastereomers, such as high performance liquid chromatography (HPLC).

[0060] In the compositions provided herein, an enantiomerically pure compound can be present with other active or inactive ingredients. For example, a pharmaceutical composition comprising enantiomerically pure R-position / center / carbon compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure R- compound. In certain embodiments, the enantiomerically pure R-compound in such compositions can, for example, comprise, at least about 95% by weight R-compound and at most about 5% by weight S-compound, by total weight of the compound. For example, a pharmaceutical composition comprising enantiomerically pure S-compound can comprise, for example, about 90% excipient and about 10% enantiomerically pure S-compound. Incertain embodiments, the enantiomerically pure S-compound in such compositions can, for example, comprise, at least about 95% by weight S-compound and at most about 5% by weight R-compound, by total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipient or carrier.

[0061] The articles “a” and “an” may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue.

[0062] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example “C1-6alkyl” is intended to encompass, C1, C2, C3, C4, c5, c6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6alkyl.

[0063] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present disclosure.

[0064] “Alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C1-20alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C1-12alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C1-10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6alkyl”, also referred to herein as “lower alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6alkyl”). Examples of C1-6alkyl groups include methyl (C1), ethyl (C2), n-propyl (C3), isopropyl (C3), n-butyl (C4), tert-butyl (C4), sec-butyl (C4), iso-butyl (C4), n-pentyl (C5), 3-pentanyl (C5), amyl (C5), neopentyl (C5), 3-methyl-2- butanyl (C5), tertiary amyl (C5), and n-hexyl (C6). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstitutedalkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C1-10alkyl (e.g., -CH3). In certain embodiments, the alkyl group is substituted C1-10alkyl. Common alkyl abbreviations include Me (-CH3), Et (-CH2CH3), iPr (-CH(CH3)2), nPr (-CH2CH2CH3), n-Bu (-CH2CH2CH2CH3), or i-Bu (-CH2CH(CH3)2).

[0065] “Alkylene” refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), pentylene (-CH2CH2CH2CH2CH2- ), hexylene (-CH2CH2CH2CH2CH2CH2-), and the like. Exemplary substituted alkylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted methylene (-CH(CH3)-, (-C(CH3)2-), substituted ethylene (-CH(CH3)CH2-,- CH2CH(CH3)-, -C(CH3)2CH2-,-CH2C(CH3)2-), substituted propylene (-CH(CH3)CH2CH2-, - CH2CH(CH3)CH2-, -CH2CH2CH(CH3)-, -C(CH3)2CH2CH2-, -CH2C(CH3)2CH2-, - CH2CH2C(CH3)2-), and the like. When a range or number of carbons is provided for a particular alkylene group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. Alkylene groups may be substituted or unsubstituted with one or more substituents as described herein.

[0066] “Alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds), and optionally one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds) (“C2-20alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C2-10alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C2-10alkenyl. In certain embodiments, the alkenyl group is substituted C2-10alkenyl.

[0067] “Alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triple bonds), and optionally one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon double bonds) (“C2-20alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2alkynyl”). The one or more carboncarbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl groupis unsubstituted C2-10alkynyl. In certain embodiments, the alkynyl group is substituted C2-10alkynyl.

[0068] The term “heteroalkyl,” as used herein, refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and / or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1io alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-9alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-8alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC1-7alkyl”). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC1-6alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC1-5alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms (“heteroC1-4alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC1-3alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroC1-2alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms (“heteroC2-6alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1io alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-10alkyl.

[0069] “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (c.g, having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ringsystem (“C6-14aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C6aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C10aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C14aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted C6-14aryl. In certain embodiments, the aryl group is substituted C6-14aryl.

[0070] In certain embodiments, an aryl group is substituted with one or more of groups selected from halogen, C1-C8alkyl, C1-C8haloalkyl, cyano, hydroxy, C1-C8alkoxy, and amino.

[0071] Examples of representative substituted aryls include the followingwherein one of R56and R57may be hydrogen and at least one of R56and R57is each independently selected from C1-C8alkyl, C1-C8haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C1-C8alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR58COR59, NR58SOR59NR58SO2R59, COOalkyl, COOaryl, CONR58R59, CONR58OR59, NR58R59, SO2NR58R59, S-alkyl, SOalkyl, SO2alkyl, Saryl, SOaryl, SO2aryl; or R56and R57may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S. R60and R61areindependently hydrogen, C1-C8alkyl, C1-C4haloalkyl, C3-C10cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, substituted C6-C10aryl, 5-10 membered heteroaryl, or substituted 5- 10 membered heteroaryl .

[0072] “Fused aryl” refers to an aryl having two of its ring carbon in common with a second aryl or heteroaryl ring or with a carbocyclyl or heterocyclyl ring.

[0073] “Heteroaryl” refers to a radical of a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5-10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl / heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

[0074] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.

[0075] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotri azolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothi azolyl, benzthiadi azolyl, indolizinyl, and purinyl. Exemplary 6,6- bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0076] Examples of representative heteroaryls include the following:wherein each Z is selected from carbonyl, N, NR65, O, and S; and R65is independently hydrogen, C1-C8alkyl, C3-C10cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, and 5-10 membered heteroaryl.

[0077] “Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3-10carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10carbocyclyl”). Exemplary C3-6carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8carbocyclyl groups include, without limitation, the aforementioned C3-6carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10carbocyclyl groups include, without limitation, the aforementioned C3-8carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro- 1H-in denyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicycliccarbocyclyl”) and can be saturated or can be partially unsaturated. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C3-10carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-10carbocyclyl.

[0078] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10cycloalkyl”). Examples of C5-6cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6cycloalkyl groups include the aforementioned C5-6cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8cycloalkyl groups include the aforementioned C3-6cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C3-10cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C3-10cycloalkyl.

[0079] “Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ringsystems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl.

[0080] In some embodiments, a heterocyclyl group is a 5-10 membered nonaromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5- 8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0081] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5- dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include,without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8- membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C6aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like.

[0082] “Nitrogen-containing heterocyclyl” group means a 4- to 7- membered nonaromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, morpholine, piperidine (e.g. 2-piperidinyl, 3 -piperidinyl and 4-piperidinyl), pyrrolidine (e.g. 2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N- methyl piperazine. Particular examples include azetidine, piperidone and piperazone.

[0083] “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g.,. heteroaryl, cycloalkenyl, e.g.,. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms.

[0084] “Acyl” refers to a radical -C(O)R20, where R20is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, as defined herein. “Alkanoyl”is an acyl group wherein R20is a group other than hydrogen. Representative acyl groups include, but are not limited to, formyl (-CHO), acetyl (-C(=O)CH3), cyclohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl (-C(=O)Ph), benzyl carbonyl (-C(=O)CH2Ph), — C(O)- C1-C8alkyl, -C(O)-(CH2)t(C6-C10aryl), -C(O)-(CH2)t(5-10 membered heteroaryl), -C(O)- (CH2)t(C3-C10cycloalkyl), and -C(O)-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4. In certain embodiments, R21is C1-C8alkyl, substituted with halogen or hydroxy; or C3-C10cycloalkyl, 4-10 membered heterocyclyl, C6-C10aryl, arylalkyl, 5-10 membered heteroaryl or heteroarylalkyl, each of which is substituted with unsubstituted C1- C4alkyl, halogen, unsubstituted C1-C4alkoxy, unsubstituted C1-C4haloalkyl, unsubstituted C1-C4hydroxyalkyl, or unsubstituted C1-C4haloalkoxy or hydroxy.

[0085] “Alkoxy” refers to the group -OR29where R29is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n- hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms.

[0086] In certain embodiments, R29is a group that has 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C6-C10aryl, aryloxy, carboxyl, cyano, C3-C10cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl-S(O)-, alkyl-S(O)2- and aryl-S(O)2-. Exemplary ‘substituted alkoxy’ groups include, but are not limited to, -O -(CH2)t(C6-C10aryl), -O-(CH2)t(5-10 membered heteroaryl), -O -(CH2)t(C3-C10cycloalkyl), and -O-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-C4alkyl, halogen, unsubstituted C1-C4alkoxy, unsubstituted C1-C4haloalkyl, unsubstituted C1-C4hydroxyalkyl, or unsubstituted C1-C4haloalkoxy or hydroxy. Particular exemplary ‘substituted alkoxy’ groups are -OCF3, -OCH2CF3, -OCH2Ph, -OCH2-cyclopropyl, -OCH2CH2OH, and -OCH2CH2NMe2.

[0087] “Amino” refers to the radical -NH2.

[0088] Oxo group” refers to -C(=O)-.

[0089] Substituted amino” refers to an amino group of the formula -N(R38)2wherein R38is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or an amino protecting group, wherein at least one of R38is not a hydrogen. In certain embodiments, each R38is independently selected from hydrogen, C1-C8alkyl, C3-C8alkenyl, C3-C8alkynyl, C6-C10aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, or C3-C10cycloalkyl; or C1-C8alkyl, substituted with halogen or hydroxy; C3-C8alkenyl, substituted with halogen or hydroxy; C3-C8alkynyl, substituted with halogen or hydroxy, or - (CH2)t(C6-C10aryl), -(CH2)t(5-10 membered heteroaryl), -(CH2)t(C3-C10cycloalkyl), or - (CH2)t(4-10 membered heterocyclyl), wherein t is an integer between 0 and 8, each of which is substituted by unsubstituted C1-C4alkyl, halogen, unsubstituted C1-C4alkoxy, unsubstituted C1-C4haloalkyl, unsubstituted C1-C4hydroxyalkyl, or unsubstituted C1-C4haloalkoxy or hydroxy; or both R38groups are joined to form an alkylene group.

[0090] Exemplary “substituted amino” groups include, but are not limited to, -NR39- C1-C8alkyl, -NR39-(CH2)t(C6-C10aryl), -NR39-(CH2)t(5-10 membered heteroaryl), -NR39- (CH2)t(C3-C10cycloalkyl), and -NR39-(CH2)t(4-10 membered heterocyclyl), wherein t is an integer from 0 to 4, for instance 1 or 2, each R39independently represents H or C1-C8alkyl; and any alkyl groups present, may themselves be substituted by halogen, substituted or unsubstituted amino, or hydroxy; and any aryl, heteroaryl, cycloalkyl, or heterocyclyl groups present, may themselves be substituted by unsubstituted C1-C4alkyl, halogen, unsubstituted C1-C4alkoxy, unsubstituted C1-C4haloalkyl, unsubstituted C1-C4hydroxyalkyl, or unsubstituted C1-C4haloalkoxy or hydroxy. For the avoidance of doubt the term ‘substituted amino’ includes the groups alkylamino, substituted alkylamino, alkylarylamino, substituted alkylarylamino, arylamino, substituted arylamino, dialkylamino, and substituted dialkylamino as defined below. Substituted amino encompasses both monosubstituted amino and disubstituted amino groups.

[0091] “Cyano” refers to the radical -CN.

[0092] “Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halogen group is either fluoro or chloro.

[0093] “Haloalkyl” refers to an alkyl radical in which the alkyl group is substituted with one or more halogens. Typical haloalkyl groups include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, dichloromethyl, dibromoethyl, tribromomethyl, tetrafluoroethyl, and the like.

[0094] “Hydroxy” refers to the radical -OH.

[0095] “Nitro” refers to the radical -NO2.

[0096] Thioketo” refers to the group =S.

[0097] Sulfonic acid” as used herein refers to -S(=O)2OH.

[0098] “Carboxylic acid” as used herein refers to -C(O)OH.

[0099] “Amino acid” as used herein refers to a radical of a molecule containing both an amino group and a carboxyl group bound to a carbon which is designated the a-carbon. Suitable amino acids include, without limitation, both the D-and L-isomers of the naturally- occurring amino acids, as well as non-naturally occurring amino acids prepared by organic synthesis or other metabolic routes. Unless the context specifically indicates otherwise, the term amino acid, as used herein, is intended to include amino acid analogs.[000100] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen may have hydrogen substituentsand / or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.[000101] Exemplary carbon atom substituents include, but are not limited to, halogen, - CN, -NO2, -N3, -SO2H, -SO3H, -OH, -ORaa, -ON(Rbb)2, -N(Rbb)2, -N(Rbb)3+X , - N(ORcc)Rbb, -SH, -SRaa, -SSRcc, -C(=O)Raa, -CO2H, -CHO, -C(ORcc)2, -CO2Raa, - OC(=O)Raa, -OCO2Raa, -C(=O)N(Rbb)2, -OC(=O)N(Rbb)2, -NRbbC(=O)Raa, -NRbbCO2Raa, - NRbbC(=O)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, - C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=O)NRbbSO2Raa, - NRbbSO2Raa, -SO2N(Rbb)2, -SO2Raa, -SO2ORaa, -OSO2Raa, -S(=O)Raa, -OS(=O)Raa, - Si(Raa)3, -OSi(Raa)3-C(=S)N(Rbb)2, -C(=O)SRaa, -C(=S)SRaa, -SC(=S)SRaa, -SC(=O)SRaa, -OC(=O)SRaa, -SC(=O)ORaa, -SC(=O)Raa, -P(=O)2Raa, -OP(=O)2Raa, -P(=O)(Raa)2, - OP(=O)(Raa)2, -OP(=O)(ORcc)2, -P(=O)2N(Rbb)2, -OP(=O)2N(Rbb)2, -P(=O)(NRbb)2, - OP(=O)(NRbb)2, -NRbbP(=O)(ORcc)2, -NRbbP(=O)(NRbb)2, -P(Rcc)2, -P(Rcc)3, -OP(Rcc)2, - OP(Rcc)3, -B(Raa)2, -B(ORcc)2, -BRaa(ORcc), C1-10alkyl, C1-10haloalkyl, C2-10alkenyl, C2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; each instance of Raais, independently, selected from C1-10alkyl, C1-10haloalkyl, C2-10alkenyl, C2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, -OH, -ORaa, - N(Rcc)2, -CN, -C(=O)Raa, -C(=O)N(Rcc)2, -CO2Raa, -SO2Raa, -C(=NRcc)ORaa, - C(=NRcc)N(Rcc)2, -SO2N(Rcc)2, -SO2Rcc, -SO2ORcc, -SORaa, -C(=S)N(Rcc)2, -C(=O)SRcc, - C(=S)SRcc, -P(=O)2Raa, -P(=O)(Raa)2, -P(=O)2N(Rcc)2, -P(=O)(NRcc)2, CI 10 alkyl, C1-10haloalkyl, C2-10alkenyl, C2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl,carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rccis, independently, selected from hydrogen, C1-10alkyl, C1-10haloalkyl, C2-10alkenyl, C2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, -CN, -NO2, -N3, - SO2H, -SO3H, -OH, -ORee, -O N(Rff)2, -N(Rff)2, -N(Rff)3+X , -N(ORee)Rff, -SH, -SRee, - SSRee, -C(=O)Ree, -CO2H, -CO2Ree, -OC(=O)Ree, -OCO2Ree, -C(=O)N(Rff)2, - OC(=O)N(Rff)2, -NRffC(=O)Ree, -NRffCO2Ree, -NRffC(=O)N(Rff)2, -C(=NRff)ORee, - OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, - NRffC(=NRff)N(Rff)2,-NRffSO2Ree, -SO2N(Rff)2, -SO2Ree, -SO2ORee, -OSO2Ree, -S(=O)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=O)SRee, -C(=S)SRee, -SC(=S)SRee, -P(=O)2Ree, - P(=O)(Ree)2, -OP(=O)(Ree)2, -OP(=O)(ORee)2, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups, or two geminal Rddsubstituents can be joined to form =O or =S; each instance of Reeis, independently, selected from C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocyclyl, 3-10 membered heterocyclyl, C6-10aryl and 5-10 membered heteroaryl, or two Rffgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgggroups; and each instance of Rggis, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, - OH, -OC1-6alkyl, -ON(C1-6alkyl)2, -N(C1-6alkyl)2, -N(C1-6alkyl)3+X-, -NH(C1-6alkyl)2+X-, -NH2(C1-6alkyl)+X-, -NH3+X , -N(0C1-6alkyl)(C1-6alkyl), -N(0H)(C1-6alkyl), -NH(OH), -SH, -SC1-6alkyl, -SS(C1-6alkyl), -C(=O)(C1-6alkyl), -CO2H, -CO2(C1-6alkyl), -OC(=O)(C1-6alkyl), -OCO2(C1-6alkyl), -C(=O)NH2, -C(=O)N(C1-6alkyl)2, - OC(=O)NH(C1-6alkyl), -NHC(=O)( C1-6alkyl), -N(C1-6alkyl)C(=O)( C1-6alkyl), - NHCO2(C1-6alkyl), -NHC(=O)N(C1-6alkyl)2, -NHC(=O)NH(C1 6alkyl), -NHC(=O)NH2, -C(=NH)O(C1-6alkyl), -OC(=NH)(C1-6alkyl), -OC(=NH)OC1-6alkyl, -C(=NH)N(C1-6alkyl)2, -C(=NH)NH(C1-6alkyl), -C(=NH)NH2, -OC(=NH)N(C1-6alkyl)2, - OC(NH)NH(C1-6alkyl), -OC(NH)NH2, -NHC(NH)N(C1-6alkyl)2, -NHC(=NH)NH2, - NHSO2(C1-6alkyl), -SO2N(C1-6alkyl)2, -SO2NH(CI6alkyl), -SO2NH2-SO2C1-6alkyl, - SO2OC1-6alkyl, -OSO2C1-6alkyl, -SOC1-6alkyl, -Si(C1-6alkyl)3, -OSi(C1-6alkyl)3- C(=S)N(C1-6alkyl)2, C(=S)NH(C1-6alkyl), C(=S)NH2, -C(=O)S(C1-6alkyl), -C(=S)SC1-6alkyl, -SC(=S)SC1-6alkyl, -P(=O)2(C1-6alkyl), -P(=O)(C1-6alkyl)2, -OP(=O)(C1-6alkyl)2, - OP(=O)(OC1-6alkyl)2, C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C2-6alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; wherein X is a counterion.[000102] In some embodiments, carbon atom substituents include halogen, -CN, -OH, -ORaa,-N(Rbb)2, -CO2H, -CO2Raa, -OC(=O)Raa,-C(=O)N(Rbb)2, -SO2Raa, C1-6alkyl, C1-6haloalkyl, C3-10carbocyclyl, 5-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl, wherein each instance of Raais, independently, selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-10alkenyl, C2-10alkynyl, C3-10carbocyclyl, 5-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl; and each instance of Rbbis, independently, selected from hydrogen, C1-6alkyl, C1-6haloalkyl, C2-10alkenyl, C2-10alkynyl, C3-10carbocyclyl, 5-6 membered heterocyclyl, phenyl, and 5-6 membered heteroaryl.Other definitions[000103] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans.[000104] “Pharmaceutically acceptable salt” refers to a salt of a compound of the disclosure that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non-toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2- naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4- methylbicyclo[2.2.2]-oct-2-ene-l-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N- methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate and the like. The term “pharmaceutically acceptable cation” refers to an acceptable cationic counterion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1): 1-79.[000105] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. Incertain embodiments, the subject is a human. In certain embodiments, the subject is a nonhuman animal.[000106] Disease, disorder, and condition are used interchangeably herein.[000107] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition (also “therapeutic treatment”).[000108] In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the disclosure may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject.[000109] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.[000110] In an alternate embodiment, the present disclosure contemplates administration of the compounds of the present disclosure or a pharmaceutically acceptable salt or a pharmaceutically acceptable composition thereof, as a prophylactic before a subject begins to suffer from the specified disease, disorder or condition. As used herein, “prophylactic treatment” contemplates an action that occurs before a subject begins to suffer from the specified disease, disorder or condition. As used herein, and unless otherwise specified, a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically effective amountof a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.EXAMPLES[000111] In order that the disclosure described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.Materials and Methods[000112] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization.[000113] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein.[000114] The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). The following schemes are presented with details as to the preparation of representative oxysterols that have been listed herein. The compounds provided herein may be prepared from known or commercially available starting materials and reagents by one skilled in the art of organicsynthesis. Exemplary chiral columns available for use in the separation / purification of the enantiomers / diastereomers provided herein include, but are not limited to, CHIRALPAK® AD- 10, CHIRALCEL® OB, CHIRALCEL® OB-H, CHIRALCEL® OD, CHIRALCEL® OD-H, CHIRALCEL® OF, CHIRALCEL® OG, CHIRALCEL® OJ and CHIRALCEL® OK.[000115]1H-NMR reported herein (e.g., for the region between 5 (ppm) of about 0.5 to about 4 ppm) will be understood to be an exemplary interpretation of the NMR spectrum (e.g., exemplary peak integratations) of a compound.Example 1. Synthesis of CompoundsSynthesis Scheme for mixed ligand iron complex:[000116] Step 1: To a heated beaker of DI H2O at 60C, FeCl3:CitAc was added in 1:2 molar ratio. The pH was adjusted to 4 by adding NaOH or KOH in steps. Reddish browncloudy solution changed to greenish-yellow transparent solution forming Fe(Cit)2or Ferric Citrate. The mixture was filtered and the filtrate was used for the next step.[000117] Step 2 : Filtrate containing Fe(Cit)2was dried in a rotavapor under vacuum at60C, to produce dry chips, which were washed in methanol and dried in filter paper.[000118] Step 3 : Dried Fe(Cit)2from Step 2 was used here. To a heated beaker of DI H2O at 90 °C, Tau:Fe(Cit)2was added in 1 : 1 molar ratio. The pH was adjusted to 8 by adding NaOH or KOH in steps. Colorless solution changed to brownish yellow with effervescence and vigorous reaction with Fe(Cit)2particles. The mixture was filtered and the filtrate was used for the next step.[000119] Step 4 : Filtrate containing Ferric-Citrate-Taurine [Fex(Cit)yTau] complex was dried and washed as in Step 2.Formulae / Abbreviations used:[000120] FeCl3= ferric chloride, CitAc = Citric Acid, Fe(Cit)2= Ferric citrate, Tau = Taurine, [Fex(Cit)yTau] = Ferric citrate taurine complex, DI = deionizedPhysicochemical characterization data:[000121] An exemplary compound of the disclosure is C6H10O7Fe(C2SO3NH2) (alsoreferred to as FeCit-Tau and having the structure: ). Provided are physicochemical characterization spectroscopic data of C6H10O7Fe(C2SO3NH2). See FIG. 1-6. FIG. 1 provides comparative1H-NMR spectra (in D2O solvent) of Tau and FeCit-Tau, which indicates complexation of Tau with FeCit as inferred from a shift in the peaks. ‘R’ refers to Taurine, while DI refers to the FeCit-Tau complex. NMR of FeCit is unavailable due to poor solubility of FeCit in D2O. FIG. 2 provides comparative solid-state NMR spectra of Taurine (green), FeCit-Tau complex (blue), FeCit (violet) and CitAc (orange). This datasuggests FeCit-Tau is the resulting new complex, showing signature peaks from the complexing moieties. Peak broadening is observed in the iron compounds, FeCit-Tau and FeCit (typically due to paramagnetism) and can be contrasted with narrower line widths of the organic compounds, taurine and citric acid. FIG. 3 shows comparative X-ray Powder Diffraction (XRPD) pattern of taurine, iron citrate, and the taurine-iron citrate complex, which indicates formation of the complex of FeCit and Tau. FIG. 4. shows a Differential Scanning Calorimetry (DSC) curve of the taurine-iron citrate complex. The analysis was performed to determine melting point (MP) of the FeCit-Tau complex. MP was observed to be unique at 231.09 °C. Both taurine and ferric citrate have MPs > 300 °C each. Typically, MP requirement for a transdermal drug candidate is less than 250°C which is satisfied by the FeCit-Tau complex. FIG. 5 shows Fourier Transform Infrared (FTIR) spectrometry curves, which shows K7 (FeCit-Tau) is significantly different from each K6 (FeCit) and K10 (taurine), indicating formation of a new complex. FIG. 6 (top) shows X-ray absorption spectroscopy (XAS) curve at the Fe K-edge which shows a characteristic ‘taurine’ shoulder in the primary peak observed in compounds K9, K12, K7 which are missing in KI 1, K8 and K6 (instead replaced by a signature ‘tooth’), indicating that taurine moiety is participating in the complexation. FIG. 6 (bottom) shows extended X-ray absorption fine structures (EXAFS) which denote the radial distance at the first peak for all compounds except KI 1, at around 1.55 A, which is the signature length of an Fe-0 bond, proving complexation of Fe with taurine occurs at O of SO3H, and not NH2.[000122] FIG. 7 shows comparative hematological profiles in Fe-deficient rats injected intradermally for 15 days either with test compound (FeCit-Tau complex) or commercial (iron dextran). Primary endpoint hemoglobin exhibited 40% and secondary endpoint ferritin exhibited 3.5x mean improvements over baseline, respectively, with FeCit-Tau complex. Significant serum iron elevation was observed in test group but not in commercial group. TIBC graph denoting a decrease over treatment duration proves the validity of the rodent model. No systemic toxicity was noted (post repeat administrations) in the gross histopathological evaluation in test group while significant inflammation in spleen was observed in the commercial group.[000123] FIG. 8 shows pharmacokinetic profile showing systemic iron absorption with resorbable buccal patches in Fe-deficient hamsters. FeCit-Tau complex denotes patch made with FeCit-Tau complex and control denotes patch made with commercially availableiron(III) citrate. The successful systemic uptake of iron with FeCit-Tau complex infused buccal patch, and not with the Control suggests that FeCit-Tau complex is uniquely tailored to a transdermal delivery route unlike other commercially available iron forms.[000124] Acronyms: Fe-Cit = ferric citrate; Tau = taurine (K10), CitAc = Citric acid; FeC or FeCit = Ferric citrate (K6); FeCit-Tau = C6H6O7Fe(C2SO3NH2) (K7).

Claims

CLAIMS1. A compound of F ormula I, II, III, or IV :or a pharmaceutically acceptable salt thereof, wherein: R1is each independently selected from the group consisting of -OS(=O)2-, -NH-, - OC(=O)-, and amino acid;L is an optionally substituted C1-6alkylene; and R2is each independently selected from the group consisting of amino, carboxylic acid, sulfonic acid, and amino acid.

2. The compound of claim 1, wherein the compound is of Formula I, or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein the compound is of Formula II, or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1, wherein the compound is of Formula III, or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1, wherein the compound is of Formula IV, or a pharmaceutically acceptable salt thereof.

6. The compound of any one of claims 1-5, wherein R1is each independently selected from the group consisting of -OS(=O)2-, -NH-, and -OC(=O)-.

7. The compound of claim 6, wherein R1is each independently -OS(=O)2- or -NH-.

8. The compound of claim 7, wherein R1is each -OS(=O)2-.

9. The compound of any one of claims 1-8, wherein L is an unsubstituted C1-6alkylene.

10. The compound of claim 9, wherein L is an unsubstituted C1-3alkylene.

11. The compound of any one of claims 1-10, wherein R2is each independently selected from the group consisting of amino, carboxylic acid, and sulfonic acid.

12. The compound of claim 11, wherein R2is each independently amino or sulfonic acid.

13. The compound of claim 12, wherein R2is each amino.

14. The compound of claim 1, wherein the compound is selected from the group consisting of:or a pharmaceutically acceptable salt thereof.

15. The compound of claim 1, wherein the compound is:or a pharmaceuticallyacceptable salt thereof.

16. The compound of claim 15, wherein the compound, or a pharmaceutically acceptable salt thereof, is a ferric-carboxylic acid-amino acid complex.

17. The compound of claim 16, wherein the ferric-carboxylic acid-amino acid complex is a ferric citrate-taurate mixed ligand complex.

18. The compound of claim 16, wherein the compound, or a pharmaceutically acceptable salt thereof is prepared in the molar ratio of Fe3+ : carboxylic acid : amino acid = 1: 1 : 1.

19. The compound of claim 16, wherein the compound, or a pharmaceutically acceptable salt thereof is prepared in the molar ratio of Fe3+ : carboxylic acid : amino acid = 1: 1.5: 1.

20. The compound of claim 16, wherein the compound, or a pharmaceutically acceptable salt thereof is prepared in the molar ratio of Fe3+ : carboxylic acid : amino acid = 1: 2: 1.

21. The compound of any one of claims 15-20, wherein the carboxylic acid ligand of the compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of citric acid, monoacetyl citric acid, tricarballylic acid, aconitic acid, acetonedicarboxylic acid, tartaric acid, oxalic acid, malic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, and any other monocarboxylic, dicarboxylic, tricarboxylic and hydroxy acid.

22. The compound of any one of claims 15-21, wherein the amino acid ligand of the compound, or a pharmaceutically acceptable salt thereof, is selected from the groupconsisting of α-, β- or γ- amino acids, proteinogenic amino acids, and non-proteinogenic amino acids.

23. The compound of any one of claims 1-22, wherein the compound, or a pharmaceutically acceptable salt thereof, has an aqueous solubility of greater than about 1000 mg / mL.

24. The compound of any one of claims 1-23, wherein the compound, or a pharmaceutically acceptable salt thereof, is amorphous.

25. The compound of any one of claims 1-24, wherein the compound, or a pharmaceutically acceptable salt thereof, is stable in solution.

26. The compound of any one of claims 1-25, wherein the compound, or a pharmaceutically acceptable salt thereof, exhibits a melting point of about 200 °C to about 300 °C as determined by differential scanning calorimetry.

27. The compound of any one of claims 1-25, wherein the compound, or a pharmaceutically acceptable salt thereof, exhibits a melting point of about 230 °C as determined by differential scanning calorimetry.

28. The compound of any one of claims 1-27, wherein the compound, or a pharmaceutically acceptable salt thereof, facilitates direct uptake by transferrin without intermediate redox cycles.

29. The compound of any one of claims 1-28, wherein the Fe of the compound, or a pharmaceutically acceptable salt thereof, is replaced with a Group 3-12 or Period 4 transition metal.

30. The compound of any one of claims 1-29, wherein the Fe of the compound, or a pharmaceutically acceptable salt thereof, is replaced with Sc, Ti, V, Cr, Mn, Co, Ni, Cu, or Zn.

31. A pharmaceutical composition, comprising a compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

32. The pharmaceutical composition of claim 31 suitable for enteral administration (e.g., oral, gastric, duodenal, intestinal, or rectal administration).

33. The pharmaceutical composition of claim 31 suitable for parenteral administration (e.g., intradermal, subcutaneous, intramuscular, intravenous, or intraperitoneal administration).

34. The pharmaceutical composition of claim 31 suitable for transdermal and transmucosal administration (e.g., administration through oral, nasal, ocular, vaginal and rectal mucosa).

35. A method of administering an effective amount of iron to a subject in need thereof, comprising administering to the subject a compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 31-34.

36. A method of treating or preventing iron deficiency in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 31-34.

37. A method of providing higher absorbance of iron in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 31-34, relative to a subject administered not administered the compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of any one of claims 31-34.

38. A method of providing higher bioavailability of iron in a subject in need thereof, comprising administering to the subject a compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 31-34, relative to a subject administered not administered the compound of any one of claims 1-30, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim any one of claims 31-34.

39. The method of any one of claims 35-38, wherein the method reduces side effects associated with administration of a conventional iron supplement.

Images