WO2022221182A1 - Small molecule inhibitors of mammalian slc34a1 function - Google Patents

Abstract

Disclosed are compounds, compositions, and methods useful for treating or preventing a disease or disorder associated with elevated serum phosphate levels in a subject.

Description

SMALL MOLECULE INHIBITORS OF MAMMALIAN SLC34A1 FUNCTION RELATED APPLICATION This application claims the benefit of priority to U.S. Provisional Patent Application No.63/173,781, filed April 12, 2021. BACKGROUND Phosphorus is an essential mineral that is responsible for maintaining cellular energy and mineralizing the skeleton. In humans, the majority of phosphorus resides within bone and teeth as hydroxyapatite and within cells as a component of nucleic acids and phospholipid membranes. A small proportion of phosphate circulates in the serum under tight regulation by the complex actions of specialized ion transporters and regulatory hormones, which balance gastrointestinal phosphorus absorption, bone uptake, cellular flux, and excretion through the kidneys. The three members of the NaPi2 family of solute carrier (SLC) sodium-phosphate cotransporters play a key role in phosphate homeostasis. NaPi2a/SLC34A1 and NaPi2c/SLC34A3 are located on the apical membrane of the kidney proximal tubule and function to re-absorb glomerular-filtered phosphate. NaPi2b/SLC34A2 is present on the apical membrane of the small intestine where it absorbs a proportion of dietary phosphate. The bone- derived hormone, fibroblast growth factor 23 (FGF23) and parathyroid-derived parathyroid hormone (PTH) downregulate NaPi2a/SLC34A1 and NaPi2c/SLC34A3 to increase urinary phosphate excretion, when there is phosphate overload, and 1,25(OH)2-vitamin D3 increases intestinal absorption of phosphate by upregulating NaPi2b/SLC34A2 when there is a nadir. Phosphate homeostasis is tightly controlled to maintain appropriate bone function while limiting the undesirable effects of vascular and non-osseus tissue calcification brought about by an excess of circulating phosphate. One of the major life-threating complications in patients with chronic kidney disease (CKD) is hyperphosphatemia that is manifested by impaired renal excretion of phosphate with declining renal function. Hyperphosphatemia in the end-stage renal disease (ESRD) patient is a significant risk factor for cardiovascular events and in the CKD patient it is an independent risk factor for further renal function decline as well as increased cardiovascular burden. FGF- 23 levels become elevated with renal function decline and this precedes the development of overt hyperphosphatemia. FGF-23 controls the cell surface expression of NaPi2a/SLC34A1 and NaPi2c/SLC34A3, reducing the level of phosphate re-absorption and facilitating phosphate excretion. This role of FGF-23 is especially important in individuals with decreased renal function to prevent hyperphosphatemia, but one of the deleterious consequences of high levels of systemic FGF-23 is also promotion of left ventricular hypertrophy and cardiac insufficiency. Genetic studies and experiments support the role of NaPi2a/SLC34A1 & NaPi2c/SLC34A3 in modifying both serum and excreted phosphate. Individuals with predicted loss-of-function variants of NaPi2a/SLC34A1 and NaPi2c/SLC34A3 present with hypophosphatemia and hyperphosphaturia. Additionally, deletion of the NaPi2a/SLC34A1 gene, the most prominent renal phosphate transporter in human & mice, leads to marked urinary phosphorus wasting and impaired skeletal development in mice, as well as diminished levels of FGF-23. Common and loss-of-function variants in the FGF23 gene are also associated with phosphate levels, suggesting a genetic hypothesis that links alteration in NaPi2a/SLC34A1 activity, an increase in phosphate excretion, and lowering of FGF-23 levels. High levels of FGF-23 are an independent predictor of cardiovascular mortality in the CKD and non-CKD patient populations. Given the relationship between phosphate excretion and FGF-23 there is a belief that further diminishing phosphate re-uptake will result in a lowering of FGF-23 levels as well, leading to a lowering in CKD progression and cardiovascular events. While limiting dietary phosphate intake as well as the use of parenteral phosphate chelators are important clinical approaches to limiting phosphate burden in the renally impaired individual, the limited toleration and clinical efficacy of these sorts of regimens, especially in the non-ESRD patient, means that there is a still significant unmet need and desire for more effective approaches to regulating systemic phosphate levels. Pharmocological inhibition of NaPi2a/SLC34A1 is a pathway to therapeutically increase phosphate excretion in patients suffering from CKD, lowering the potential cardiorenal risk in those patients by normalizing phosphate balance and FGF-23 levels. SUMMARY One aspect of the invention provides compounds, compositions, and methods useful for inhibiting mammalian SLC34A1 function.Another aspect of the invention provides compounds, compositions, and methods useful for treating or preventing a disease or disorder associated with elevated phosphates levels in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I). Another aspect of the invention provides compounds, compositions, and methods useful for treating or preventing a disease or disorder associated with elevated FGF-23 levels in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I). Accordingly, provided herein is a compound having the structure of Formula (I):

X₁ is a absent or is selected from –O–, –SO₂–, –C(O)–, –N(X₂)–, and –C(X₃)₂–; X₂ is selected from –H, alkyl, and –SO₂–X₂''; X2'' is alkyl; each X₃ is independently selected from –H and alkyl; R₁ is selected from an optionally substituted aminoalkyl, optionally substituted alkylaminoalkyl, optionally substituted alkoxyalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and R2 is selected from –H, halogen (e.g., chloro), nitrile, and alkyl; R2' is selected from an alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, and aryl; R₂'' is selected from H, alkyl, and acyl; provided that when X₁ is –O– or –N(X₂)– and R₁ is a nitrogen-containing heterocyclyl, then the –O– or –N(X2)– is not directly bonded to a nitrogen on the heterocyclyl; provided that when X₁ is absent, R₂ is –Cl, R₂' is –CH₃, and R₂'' is –H, then R₁ is not

or a pharmaceutically acceptable salt thereof. Another aspect of the invention relates to a method of treating or preventing chronic kidney disease (CKD), comprising administering to the subject an effective amount of a compound of Formula (I). Another aspect of the invention relates to a method method of treating or preventing media calcification, comprising administering to the subject an effective amount of a compound of Formula (I). Another aspect of the invention relates to a method of treating or preventing vascular calcification, comprising administering to the subject an effective amount of a compound of Formula (I). Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting. Other features, objects, and advantages of the invention will be apparent from the detailed description, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS FIG.1 is a table summarizing SLC34A1 transport inhibition activity for exemplary compounds of the invention. A+ = <0.5; A = 0.5-0.99; B = 1-4.99; C = 5-9.99; D = ≥10 ( μM). FIG.2 is a table summarizing SLC34A1 transport inhibition activity for exemplary compounds of the invention. A+ = <0.5; A = 0.5-0.99; B = 1-4.99; C = 5-9.99; D = ≥10 ( μM). DETAILED DESCRIPTION Definitions For convenience, before further description of the present invention, certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and as understood by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. In order for the present invention to be more readily understood, certain terms and phrases are defined below and throughout the specification. The articles “a” and “an” are used herein to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article. By way of example, “an element” means one element or more than one element. The phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and/or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc. As used herein in the specification and in the claims, “or” should be understood to have the same meaning as “and/or” as defined above. For example, when separating items in a list, “or” or “and/or” shall be interpreted as being inclusive, i.e., the inclusion of at least one, but also including more than one, of a number or list of elements, and, optionally, additional unlisted items. Only terms clearly indicated to the contrary, such as “only one of” or “exactly one of,” or, when used in the claims, “consisting of,” will refer to the inclusion of exactly one element of a number or list of elements. In general, the term “or” as used herein shall only be interpreted as indicating exclusive alternatives (i.e., “one or the other but not both”) when preceded by terms of exclusivity, such as “either,” “one of,” “only one of,” or “exactly one of.” “Consisting essentially of,” when used in the claims, shall have its ordinary meaning as used in the field of patent law. As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, as a non-limiting example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and/or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc. It should also be understood that, unless clearly indicated to the contrary, in any methods claimed herein that include more than one step or act, the order of the steps or acts of the method is not necessarily limited to the order in which the steps or acts of the method are recited. In the claims, as well as in the specification above, all transitional phrases such as “comprising,” “including,” “carrying,” “having,” “containing,” “involving,” “holding,” “composed of,” and the like are to be understood to be open-ended, i.e., to mean including but not limited to. Only the transitional phrases “consisting of” and “consisting essentially of” shall be closed or semi-closed transitional phrases, respectively, as set forth in the United States Patent Office Manual of Patent Examining Procedures, Section 2111.03. Certain compounds contained in compositions of the present invention may exist in particular geometric or stereoisomeric forms. In addition, polymers of the present invention may also be optically active. The present invention contemplates all such compounds, including cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D)-isomers, (L)- isomers, the racemic mixtures thereof, and other mixtures thereof, as falling within the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in this invention. “Geometric isomer" means isomers that differ in the orientation of substituent atoms in relationship to a carbon-carbon double bond, to a cycloalkyl ring, or to a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides of the carbon- carbon double bond) or Z (substituents are oriented on the same side) configuration. "R," "S," "S*," "R*," "E," "Z," "cis," and "trans," indicate configurations relative to the core molecule. Certain of the disclosed compounds may exist in “atropisomeric” forms or as “atropisomers.” Atropisomers are stereoisomers resulting from hindered rotation about single bonds where the steric strain barrier to rotation is high enough to allow for the isolation of the conformers. The compounds of the invention may be prepared as individual isomers by either isomer-specific synthesis or resolved from a mixture of isomers. Conventional resolution techniques include forming the salt of a free base of each isomer of an isomeric pair using an optically active acid (followed by fractional crystallization and regeneration of the free base), forming the salt of the acid form of each isomer of an isomeric pair using an optically active amine (followed by fractional crystallization and regeneration of the free acid), forming an ester or amide of each of the isomers of an isomeric pair using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary), or resolving an isomeric mixture of either a starting material or a final product using various well known chromatographic methods. If, for instance, a particular enantiomer of compound of the present invention is desired, it may be prepared by asymmetric synthesis, or by derivation with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group cleaved to provide the pure desired enantiomers. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically-active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic means well known in the art, and subsequent recovery of the pure enantiomers. Percent purity by mole fraction is the ratio of the moles of the enantiomer (or diastereomer) or over the moles of the enantiomer (or diastereomer) plus the moles of its optical isomer. When the stereochemistry of a disclosed compound is named or depicted by structure, the named or depicted stereoisomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure relative to the other stereoisomers. When a single enantiomer is named or depicted by structure, the depicted or named enantiomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure. When a single diastereomer is named or depicted by structure, the depicted or named diastereomer is at least about 60%, about 70%, about 80%, about 90%, about 99% or about 99.9% by mole fraction pure. When a disclosed compound is named or depicted by structure without indicating the stereochemistry, and the compound has at least one chiral center, it is to be understood that the name or structure encompasses either enantiomer of the compound free from the corresponding optical isomer, a racemic mixture of the compound or mixtures enriched in one enantiomer relative to its corresponding optical isomer. When a disclosed compound is named or depicted by structure without indicating the stereochemistry and has two or more chiral centers, it is to be understood that the name or structure encompasses a diastereomer free of other diastereomers, a number of diastereomers free from other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomers in which one diastereomer is enriched relative to the other diastereomer(s) or mixtures of diastereomers in which one or more diastereomer is enriched relative to the other diastereomers. The invention embraces all of these forms. Structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a ¹³C- or ¹⁴C- enriched carbon are within the scope of this invention. The term “prodrug” as used herein encompasses compounds that, under physiological conditions, are converted into therapeutically active agents. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal. The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying or transporting the subject chemical from one organ or portion of the body, to another organ or portion of the body. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation, not injurious to the patient, and substantially non-pyrogenic. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. In certain embodiments, pharmaceutical compositions of the present invention are non-pyrogenic, i.e., do not induce significant temperature elevations when administered to a patient. The term “pharmaceutically acceptable salts” refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound(s). These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound(s) in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and laurylsulphonate salts, and the like. (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci.66:1-19.) In other cases, the compounds useful in the methods of the present invention may contain one or more acidic functional groups and, thus, are capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term “pharmaceutically acceptable salts” in these instances refers to the relatively non-toxic inorganic and organic base addition salts of a compound(s). These salts can likewise be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting the purified compound(s) in its free acid form with a suitable base, such as the hydroxide, carbonate, or bicarbonate of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, or tertiary amine. Representative alkali or alkaline earth salts include the lithium, sodium, potassium, calcium, magnesium, and aluminum salts, and the like. Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like (see, for example, Berge et al., supra). The term “pharmaceutically acceptable cocrystals” refers to solid coformers that do not form formal ionic interactions with the small molecule. A “therapeutically effective amount” (or “effective amount”) of a compound with respect to use in treatment, refers to an amount of the compound in a preparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human) alleviates a symptom, ameliorates a condition, or slows the onset of disease conditions according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, e.g., at a reasonable benefit/risk ratio applicable to any medical treatment. The term “prophylactic or therapeutic” treatment is art-recognized and includes administration to the host of one or more of the subject compositions. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, (i.e., it protects the host against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof). The term “patient” or “subject” refers to a mammal in need of a particular treatment. In certain embodiments, a patient is a primate, canine, feline, or equine. In certain embodiments, a patient is a human. An aliphatic chain comprises the classes of alkyl, alkenyl and alkynyl defined below. A straight aliphatic chain is limited to unbranched carbon chain moieties. As used herein, the term “aliphatic group” refers to a straight chain, branched-chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkenyl group, or an alkynyl group. “Alkyl” refers to a fully saturated cyclic or acyclic, branched or unbranched carbon chain moiety having the number of carbon atoms specified, or up to 30 carbon atoms if no specification is made. For example, alkyl of 1 to 8 carbon atoms refers to moieties such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those moieties which are positional isomers of these moieties. Alkyl of 10 to 30 carbon atoms includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tricosyl and tetracosyl. In certain embodiments, a straight chain or branched chain alkyl has 30 or fewer carbon atoms in its backbone (e.g., C1-C30 for straight chains, C₃-C₃₀ for branched chains), and more preferably 20 or fewer. Alkyl goups may be substituted or unsubstituted. As used herein, the term “heteroalkyl” refers to an alkyl moiety as hereinbefore defined which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms. As used herein, the term “haloalkyl” refers to an alkyl group as hereinbefore defined substituted with at least one halogen. As used herein, the term “hydroxyalkyl” refers to an alkyl group as hereinbefore defined substituted with at least one hydroxyl. As used herein, the term “alkylene” refers to an alkyl group having the specified number of carbons, for example from 2 to 12 carbon atoms, that contains two points of attachment to the rest of the compound on its longest carbon chain. Non-limiting examples of alkylene groups include methylene -(CH2)-, ethylene -(CH2CH2)-, n-propylene - (CH2CH2CH2)-, isopropylene -(CH2CH(CH3))-, and the like. Alkylene groups can be cyclic or acyclic, branched or unbranched carbon chain moiety, and may be optionally substituted with one or more substituents. "Cycloalkyl" means mono- or bicyclic or bridged or spirocyclic, or polycyclic saturated carbocyclic rings, each having from 3 to 12 carbon atoms. Preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 3-6 carbons in the ring structure. Cycloalkyl groups may be substituted or unsubstituted. As used herein, the term “halocycloalkyl” refers to a cycloalkyl group as hereinbefore defined substituted with at least one halogen. "Cycloheteroalkyl" refers to an cycloalkyl moiety as hereinbefore defined which contain one or more oxygen, sulfur, nitrogen, phosphorus, or silicon atoms in place of carbon atoms. Preferred cycloheteroalkyls have from 4-8 carbon atoms and heteroatoms in their ring structure, and more preferably have 4-6 carbons and heteroatoms in the ring structure. Cycloheteroalkyl groups may be substituted or unsubstituted. Unless the number of carbons is otherwise specified, “lower alkyl,” as used herein, means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six carbon atoms in its backbone structure such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Likewise, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyls. In certain embodiments, a substituent designated herein as alkyl is a lower alkyl. “Alkenyl” refers to any cyclic or acyclic, branched or unbranched unsaturated carbon chain moiety having the number of carbon atoms specified, or up to 26 carbon atoms if no limitation on the number of carbon atoms is specified; and having one or more double bonds in the moiety. Alkenyl of 6 to 26 carbon atoms is exemplified by hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tricosenyl, and tetracosenyl, in their various isomeric forms, where the unsaturated bond(s) can be located anywhere in the moiety and can have either the (Z) or the (E) configuration about the double bond(s). “Alkynyl” refers to hydrocarbyl moieties of the scope of alkenyl, but having one or more triple bonds in the moiety. The term “aryl” as used herein includes 3- to 12-membered substituted or unsubstituted single-ring aromatic groups in which each atom of the ring is carbon (i.e., carbocyclic aryl) or where one or more atoms are heteroatoms (i.e., heteroaryl). Preferably, aryl groups include 5- to 12-membered rings, more preferably 6- to 10-membered rings The term “aryl” also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjoining rings wherein at least one of the rings is aromatic, e.g., the other cyclic rings can be cycloalkyls, cycloalkenyls, cycloalkynyls, aryls, heteroaryls, and/or heterocyclyls. Carboycyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Heteroaryl groups include substituted or unsubstituted aromatic 3- to 12-membered ring structures, more preferably 5- to 12- membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like. Aryl and heteroaryl can be monocyclic, bicyclic, or polycyclic. The term “halo”, “halide”, or “halogen” as used herein means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms. In a preferred embodiment, halo is selected from the group consisting of fluoro, chloro and bromo. The terms “heterocyclyl” or “heterocyclic group” refer to 3- to 12-membered ring structures, more preferably 5- to 12-membered rings, more preferably 5- to 10-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can be monocyclic, bicyclic, spirocyclic, or polycyclic. Heterocyclyl groups include, for example, thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphate, phosphonate, phosphinate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic moiety, -CF3, -CN, and the like. The term “substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons of the backbone. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds. For purposes of this invention, the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms. Substituents can include any substituents described herein, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxy, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. In preferred embodiments, the substituents on substituted alkyls are selected from C1-6 alkyl, C3-6 cycloalkyl, halogen, carbonyl, cyano, or hydroxyl. In more preferred embodiments, the substituents on substituted alkyls are selected from fluoro, carbonyl, cyano, or hydroxyl. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate. Unless specifically stated as “unsubstituted,” references to chemical moieties herein are understood to include substituted variants. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants. As used herein, the definition of each expression, e.g., alkyl, m, n, etc., when it occurs more than once in any structure, is intended to be independent of its definition elsewhere in the same structure. As used herein, “small molecules” refers to small organic or inorganic molecules of molecular weight below about 3,000 Daltons. In general, small molecules useful for the invention have a molecular weight of less than 3,000 Daltons (Da). The small molecules can be, e.g., from at least about 100 Da to about 3,000 Da (e.g., between about 100 to about 3,000 Da, about 100 to about 2500 Da, about 100 to about 2,000 Da, about 100 to about 1,750 Da, about 100 to about 1,500 Da, about 100 to about 1,250 Da, about 100 to about 1,000 Da, about 100 to about 750 Da, about 100 to about 500 Da, about 200 to about 1500, about 500 to about 1000, about 300 to about 1000 Da, or about 100 to about 250 Da). In some embodiments, a “small molecule” refers to an organic, inorganic, or organometallic compound typically having a molecular weight of less than about 1000. In some embodiments, a small molecule is an organic compound, with a size on the order of 1 nm. In some embodiments, small molecule drugs of the invention encompass oligopeptides and other biomolecules having a molecular weight of less than about 1000. An “effective amount” is an amount sufficient to effect beneficial or desired results. For example, a therapeutic amount is one that achieves the desired therapeutic effect. This amount can be the same or different from a prophylactically effective amount, which is an amount necessary to prevent onset of disease or disease symptoms. An effective amount can be administered in one or more administrations, applications or dosages. A therapeutically effective amount of a composition depends on the composition selected. The compositions can be administered from one or more times per day to one or more times per week; including once every other day. The skilled artisan will appreciate that certain factors may influence the dosage and timing required to effectively treat a subject, including but not limited to the severity of the disease or disorder, previous treatments, the general health and/or age of the subject, and other diseases present. Moreover, treatment of a subject with a therapeutically effective amount of the compositions described herein can include a single treatment or a series of treatments. The terms “decrease,” “reduce,” “reduced”, “reduction”, “decrease,” and “inhibit” are all used herein generally to mean a decrease by a statistically significant amount relative to a reference. However, for avoidance of doubt, “reduce,” “reduction” or “decrease” or “inhibit” typically means a decrease by at least 10% as compared to a reference level and can include, for example, a decrease by at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, up to and including, for example, the complete absence of the given entity or parameter ascompared to the reference level, or any decrease between 10-99% as compared to the absence of a given treatment. The terms “increased”, “increase” or “enhance” or “activate” are all used herein to generally mean an increase by a statically significant amount; for the avoidance of any doubt, the terms “increased”, “increase” or “enhance” or “activate” means an increase of at least 10% as compared to a reference level, for example an increase of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 90% or up to and including a 100% increase or any increase between 10-100% as compared to a reference level, or at least about a 2-fold, or at least about a 3-fold, or at least about a 4-fold, or at least about a 5-fold or at least about a 10-fold increase, or any increase between 2-fold and 10-fold or greater as compared to a reference level. As used herein, the term “modulate” includes up-regulation and down-regulation, e.g., enhancing or inhibiting a response. A “radiopharmaceutical agent,” as defined herein, refers to a pharmaceutical agent which contains at least one radiation-emitting radioisotope. Radiopharmaceutical agents are routinely used in nuclear medicine for the diagnosis and/or therapy of various diseases. The radiolabelled pharmaceutical agent, for example, a radiolabelled antibody, contains a radioisotope (RI) which serves as the radiation source. As contemplated herein, the term “radioisotope” includes metallic and non-metallic radioisotopes. The radioisotope is chosen based on the medical application of the radiolabeled pharmaceutical agents. When the radioisotope is a metallic radioisotope, a chelator is typically employed to bind the metallic radioisotope to the rest of the molecule. When the radioisotope is a non-metallic radioisotope, the non-metallic radioisotope is typically linked directly, or via a linker, to the rest of the molecule. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87, inside cover. Compounds of the Invention One aspect of the invention relates to a compound having the structure of Formula (I):

X₁ is a absent or is selected from –O–, –SO₂–, –C(O)–, –N(X₂)–, and –C(X₃)₂–; X₂ is selected from –H, alkyl, and –SO₂–X₂''; X2'' is alkyl; each X₃ is independently selected from –H and alkyl; R₁ is selected from an optionally substituted aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and R2 is selected from –H, halogen (e.g., chloro), and alkyl; R₂' is selected from an alkyl, alkenyl, alkynyl, cycloalkyl, and aryl; and R2'' is selected from H, alkyl, and acyl; provided that when X1 is –O– or –N(X2)– and R1 is a nitrogen-containing heterocyclyl, then the –O– or –N(X₂)– is not directly bonded to a nitrogen on the heterocyclyl; provided that when X1 is absent, R2 is –Cl, R2' is –CH3, and R2'' is –H, then R1 is not

or a pharmaceutically acceptable salt thereof. Another aspect of the invention relates to a compound having the structure of Formula (I):

X1 is a absent or is selected from –O–, –SO2–, –C(O)–, –N(X2)–, and –C(X3)2–; X2 is selected from –H, alkyl, and –SO2–X2''; X₂'' is alkyl; each X3 is independently selected from –H and alkyl; R1 is selected from an optionally substituted aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and R2 is selected from –H, halogen (e.g., chloro), and alkyl; R2' is selected from an alkyl, alkenyl, alkynyl, cycloalkyl, and aryl; and R₂'' is selected from H, alkyl, and acyl; provided that when X1 is –O– or –N(X2)– and R1 is a nitrogen-containing heterocyclyl, then the –O– or –N(X₂)– is not directly bonded to a nitrogen on the heterocyclyl; provided that when X1 is absent, R2 is –Cl, R2' is –CH3, and R2'' is –H, then R1 is not

or a pharmaceutically acceptable salt thereof. In certain embodiments, X1 is absent, or is selected from –SO2–, –C(O)–, and – C(X3)2–. In certain embodiments, X1 is absent. In certain embodiments, R₁ is an unsubstituted heterocyclyl. In certain embodiments, wherein R₁ is selected from an unsubstituted azetidinyl, unsubstituted pyrrolidinyl, unsubstituted piperazinyl, unsubstituted piperazinonyl, unsubstituted morpholinyl, unsubstituted dioxothiomorpholinyl, unsubstituted tetrahydrofuranyl, and unsubstituted tetrahydropyranyl, e.g. R1 is selected from

, ,

In certain embodiments, R₁ is a substituted heterocyclyl. In certain embodiments, R₁ is –NR₃R₄; and R3 and R4 combine to form a substituted azetidinyl, substituted pyrrolidinyl, substituted piperazinyl, substituted piperazinonyl, substituted morpholinyl, or substituted dioxothiomorpholinyl. In certain embodiments,

Ra, Rb, Ri and Rj are independently selected from -H, halogen, -CN, -CF3, and alkyl; R_c, R_d, R_e, R_f, R_g and R_h are independently selected from -H, halogen, -CN, -CF₃, - OH, -CO₂H, -NH₂, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -OR5, -C(O)NR5R6, -NR5C(O)R6, C(O)R7, - NR5C(O)NR5R6, -SO2R7, -NHSO2R7, -SO2NR5R6, alkyl-C(O)NR5R6, alkyl-NR5C(O)R6, alkyl-C(O)R₇, alkyl-NR₅C(O)NR₅R_6, alkyl-SO₂R₇, alkyl-SO₂NR₅R₆, and -NHC(O)NR₇, or Rc taken together with Rd and the carbon atom to which they are bonded form an unsubstituted or substituted C3-C6 cycloalkyl or C4-C6 heterocyclyl, or R_e taken together with R_f and the carbon atom to which they are bonded form an unsubstituted or substituted C₃-C₆ cycloalkyl or C₄-C₆ heterocyclyl, or Rc taken together with Re and the carbon atoms to which they are bonded form an unsubstituted or substituted C₃-C₆ cycloalkyl, or R_d taken together with R_f and the carbon atoms to which they are bonded form an unsubstituted or substituted C3-C6 cycloalkyl, or Rc taken together with Ri form a methylene bridge, or R_d taken together with R_j form a methylene bridge, or Rc taken together with Rg form a methylene bridge, or Rd taken together with Rh form a methylene bridge; each occurrence of R₅ and R₆ is independently selected from -H, -CF₃, alkyl, aminoalkyl, hydroxyalkyl, methoxyalkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl, or provided that in the case of -C(O)NR₅R₆, -NR₅C(O)NR₅R_6, alkyl-C(O)NR₅R₆, and alkyl-NR₅C(O)NR₅R₆ the R₅ taken together with R₆ and the nitrogen atom to which they are bonded may form an unsubstituted or substituted C4-C6 heterocyclyl; and each occurrence of R₇ is selected from alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl; provided that at least one of R_a, R_b, R_c, R_d, R_e, R_f, R_g, R_h, R_i, and R_j is not -H.In

Ra, Rb, Ri and Rj are independently selected from -H, halogen, -CN, -CF3, and alkyl; R_c, R_d, R_e, R_f, R_g and R_h are independently selected from -H, halogen, -CN, -CF₃, - OH, -CO₂H, -NH₂, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -C(O)NR5R6, -NR5C(O)R6, C(O)R7, - NR5C(O)NR5R6, -SO2R7, -SO2NR5R6, alkyl-C(O)NR5R6, alkyl-NR5C(O)R6, alkyl-C(O)R7, alkyl-NR₅C(O)NR₅R_6, alkyl-SO₂R₇, and alkyl-SO₂NR₅R₆, or R_c taken together with R_d and the carbon atom to which they are bonded form an unsubstituted or substituted C3-C6 cycloalkyl or C4-C6 heterocyclyl, or Re taken together with Rf and the carbon atom to which they are bonded form an unsubstituted or substituted C3-C6 cycloalkyl or C₄-C₆ heterocyclyl; each occurrence of R5 and R6 is independently selected from -H, alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl, or provided that in the case of -C(O)NR5R6, -NR5C(O)NR5R6, alkyl-C(O)NR₅R₆, and alkyl-NR₅C(O)NR₅R₆ the R₅ taken together with R₆ and the nitrogen atom to which they are bonded may form an unsubstituted or substituted C₄-C₆ heterocyclyl; and each occurrence of R₇ is selected from alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl; provided that at least one of R_a, R_b, R_c, R_d, R_e, R_f, R_g, R_h, R_i, and R_j is not -H. In certain embodiments, Ra, Rb, Ri and Rj are independently selected from -H, halogen, -CN, -CF₃, and alkyl; and R_c, R_d, R_e, R_f, R_g and R_h are independently selected from - H, halogen, -CN, -CF3, -OH, -CO2H, -NH2, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, -C(O)NR5R6, -NR5C(O)R6, C(O)R7, alkyl-C(O)NR₅R₆, alkyl-NR₅C(O)R₆, and alkyl-C(O)R₇. In certain embodiments, Ra, Rb, Ri and Rj are each –H; and Rc, Rd, Re, Rf, Rg and Rh are independently selected from -H, halogen, -OH, -CO2H, - alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkyl, -C(O)NR₅R₆, -NR₅C(O)R₆, C(O)R₇, alkyl-C(O)NR₅R₆, and alkyl- NR₅C(O)R₆. In certain embodiments, Ra, Rb, Ri and Rj are each –H; and Rc, Rd, Re, Rf, Rg and Rh are independently selected from -H, -F, -OH, -CH₂OH, CH₂OCH₃, -CH₂NH₂, -CO₂H, -CH₃, -CH(CH₃)₂, -CH₂CH(CH₃)₂, -C(O)NH₂, -C(O)N(H)(CH₃), -C(O)N(CH₃)₂, alkyl- C(O)N(H)(CH3), -CH2-C(O)N(CH3)2, -N(H)C(O)CH3, -N(CH3)C(O)CH3, -CH2-

In certain embodiments, R_a, R_b, R_i and R_j are each –H; and R_c, R_d, R_e, R_f, R_g and R_h are independently selected from -H, -F, -OH, -CH3, -CF3, -OCH3, -OCF3, -CH2CH3, - CH₂OH, -CH₂CH₂OH, -CH₂OCH₃,-CH₂CH₂CH₃, -CH₂F, -NHSO₂CH₃, -NHSO₂CH₂CH₃, - NHC(O)NHCH₃, -NHC(O)CH₃, -C(O)NH₂, -C(O)NHCH₃, -C(O)NHCH₂CH₃, - C(O)NHCH(CH3)2, -C(O)NHCH2CH2OCH3, -CH2NHC(O)CH3, -CH2NHC(O)CH2CH3, - CH2NHC(O)CH2NH2, -CH2NHC(O)C(CH3)2CH3, -CH2NHC(O)C(CH3)2NH2, - CH₂NHC(O)C(CH₃)₂CH₂OH, -CH₂NHC(O)C(CH₃)₂CH₂OCH₃, -CH₂NHC(O)C(CH₃)₂OCH₃, -CH₂C(O)NH₂, -CH₂C(O)NHCH₃, and -CH₂C(O)N(CH₃)₂. In certain embodiments, Ra, Rb, Ri and Rj are each –H; and Rc, Rd, Re, Rf, Rg and Rh are independently selected from -H, -F, -OH, -CH3, -CF3, -OCH3, -OCF3, -CH2CH3, - CH₂OH, -CH₂CH₂OH, -CH₂OCH₃,-CH₂CH₂CH₃, -CH₂F, -O-cyclopropyl, -C(O)NH- cyclopropyl, -C(O)NH-oxatenyl, -C(O)NH-tetrahydofuranyl, -C(O)NH-tetrahydopyranyl, - CH2NHC(O)-cyclopropyl,

, , .In certain embodiments, R1 is selected from:

certain embodiments, R₁ is selected from:

. In other embodiments, R₁ is selected from:

In certain embodiments, R₁ is selected from:

In certain embodiments, R1 is selected from:

,

In certain embodiments, R1 is selected from:

and.

In certain embodiments, R1 is selected from:

In certain embodiments, R1 is selected from:

. In certain embodiments, R1 is R1 is selected from:

In certain embodiments, R₁ is selected from:

In certain embodiments, Ra, Rb, Re, Rf, Rg, Rh, Ri, and Rj are independently selected from -H, halogen, -CN, -CF3, and alkyl; and Rc taken together with Rd and the carbon atom to which they are bonded form an unsubstituted or substituted C3-C6 cycloalkyl or C4-C6 heterocyclyl. In certain embodiments, R_c taken together with R_d and the carbon atom to which they are bonded form an unsubstituted or substituted azetidinyl, pyrrolidinyl, piperazinyl, oxatenyl, tetrahydrofuranyl, tetrahydropyranyl, or sulfolanyl. In certain embodiments, each substituent is independently selected from halogen, - OH, -CN, -CF3, alkyl, and acetyl. In certain embodiments, Ra, Rb, Rc, Rd, Rg, Rh, Ri, and Rj are independently selected from -H, halogen, -CN, -CF₃, and alkyl; and R_e taken together with R_f and the carbon atom to which they are bonded form an unsubstituted or substituted C₃-C₆ cycloalkyl or C₄-C₆ heterocyclyl. In certain embodiments, R_e taken together with R_r and the carbon atom to which they are bonded form an unsubstituted or substituted azetidinyl, pyrrolidinyl, piperazinyl, oxatenyl, tetrahydrofuranyl, tetrahydropyranyl, and sulfolanyl. In certain embodiments, each substituent is independently selected from halogen, - OH, -CN, -CF₃, alkyl, and acetyl. In certain embodiments, R1 is selected from

In certain embodiments, R_a, R_b, R_g, R_h, R_i, and R_j are each -H; one of R_e and R_f is -H and the other of Re and Rf is -OH; and Rc taken together with Rd and the carbon atom to which they are bonded form an unsubstituted or substituted C3-C6 cycloalkyl or C4-C6 heterocyclyl. In certain embodiments, R_a, R_b, R_d, R_g, R_h, R_i, and R_j are each -H; R_f is -OH; and R_c taken together with Re and the carbon atoms to which they are bonded form an unsubstituted or substituted C3-C6 cycloalkyl. In certain embodiments, R_a, R_b, R_c, R_g, R_h, R_i, and R_j are each -H; R_e is -OH; and R_d taken together with Rf and the carbon atoms to which they are bonded form an unsubstituted or substituted C3-C6 cycloalkyl. In certain embodiments, R_a, R_b, R_d, R_g, R_h, and R_j are each -H; one of R_e and R_f is -H and the other of R_e and R_f is -OH; and R_c taken together with R_i form a methylene bridge. In certain embodiments, Ra, Rb, Rc, Rg, Rh, and Ri are each -H; one of Re and Rf is -H and the other of R_e and R_f is -OH; and R_d taken together with R_j form a methylene bridge. In certain embodiments, R_a, R_b, R_c, R_g, R_h, and R_i are each -H; one of R_e and R_f is -H and the other of Re and Rf is -OH; and Rj taken together with Rd form a methylene bridge. In certain embodiments, Ra, Rb, Rd, Rf, Rh, and Ri are each -H; one of Re and Rf is -H and the other of R_e and R_f is -OH; and R_c taken together with R_g form a methylene bridge. In certain embodiments, Ra, Rb, Rc, Rg, Rh, and Ri are each -H; one of Re and Rf is -H and the other of Re and Rf is -OH; and Rd taken together with Rh form a methylene bridge. In certain embodiments, R1 is selected from

Ra, Rb, Ri and Rj are independently selected from -H, halogen, -CN, -CF3, and alkyl; Rc, Rd, Rg and Rh are independently selected from -H, halogen, -CN, -CF3, -CO2H, - alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -C(O)NR5R6, -NR5C(O)R6, C(O)R7, -NR5C(O)NR5R6, -SO2R7, - SO2N R5R6, alkyl-C(O)NR5R6, alkyl-NR5C(O)R6, alkyl-C(O)R7, alkyl-NR5C(O)NR5R6, alkyl-SO₂R₇, and alkyl-SO₂N R₅R₆, or R_c taken together with R_d and the carbon atom to which they are bonded form an unsubstituted or substituted C3-C6 cycloalkyl or C4-C6 heterocyclyl; each occurrence of R5 and R6 is independently selected from -H, alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl, or provided that in the case of -C(O)NR₅R₆, -NR₅C(O)NR₅R_6, alkyl-C(O)NR5R6, and alkyl-NR5C(O)NR5R6 the R5 taken together with R6 and the nitrogen atom to which they are bonded may form an unsubstituted or substituted C4-C6 heterocyclyl; and each occurrence of R₇ is selected from alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl; provided that at least one of R_a, R_b, R_c, R_d, R_g, R_h, R_i, and R_j is not -H. In certain embodiments, R_a, R_b, R_i and R_j are independently selected from -H, halogen, -CN, -CF3, and alkyl; Rc, Rd, Rg and Rh are independently selected from -H, halogen, -CN, -CF3, -CO2H, - alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, -C(O)NR5R6, -NR5C(O)R6, C(O)R7, alkyl-C(O)NR5R6, alkyl-NR5C(O)R6, and alkyl-C(O)R7. In certain embodiments, R_a, R_b, R_i and R_j are each –H; and Rc, Rd, Rg and Rh are independently selected from -H, halogen, -CO2H, - alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkyl, -C(O)NR5R6, -NR5C(O)R6, C(O)R7, alkyl-C(O)NR₅R₆, and alkyl-NR₅C(O)R₆. In certain embodiments, R_a, R_b, R_i and R_j are each –H; and Rc, Rd, Rg and Rh are independently selected from -H, -F, -CH2OH, -CH2OCH3, - CH₂NH₂, -CO₂H, -CH₃, -CH(CH₃)₂, -CH₂CH(CH₃)₂, -C(O)NH₂, -C(O)N(H)(CH₃), - C(O)N(CH₃)₂, alkyl-C(O)N(H)(CH₃), -CH₂-C(O)N(CH₃)₂, -N(H)C(O)CH₃, - N(CH3)C(O)CH3, -CH2-N(H)C(O)CH3, -CH2-N(CH3)C(O)CH3, -CH(CH2)2, and

In certain embodiments, R₁ is selected from:

other embodiments, R₁ is selected from:

In certain embodiments, R₁ is selected from:

In certain embodiments, R_a, R_b, R_g, R_h, R_i, and R_j are independently selected from -H, halogen, -CN, -CF3, and alkyl; and Rc taken together with Rd and the carbon atom to which they are bonded form an unsubstituted or substituted C3-C6 cycloalkyl or C4-C6 heterocyclyl. In certain embodiments, R_c taken together with R_d and the carbon atom to which they are bonded form an unsubstituted or substituted azetidinyl, pyrrolidinyl, piperazinyl, oxatenyl, tetrahydrofuranyl, tetrahydropyranyl, or sulfolanyl. In certain embodiments, each substituent is independently selected from halogen, - OH, -CN, -CF₃, alkyl, and acetyl. In certain embodiments, R1 is selected from:

and

. In certain embodiments,

R_a, R_b, R_i and R_j are independently selected from -H, halogen, -CN, -CF₃, and alkyl; Rc, Rd, Rg and Rh are independently selected from -H, halogen, -CN, -CF3, -CO2H, - alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -C(O)NR₅R₆, -NR₅C(O)R₆, C(O)R₇, -NR₅C(O)NR₅R₆, -SO₂R₇, - SO2NR5R6, alkyl-C(O)NR5R6, alkyl-NR5C(O)R6, alkyl-C(O)R7, alkyl-NR5C(O)NR5R6, alkyl- SO2R7, and alkyl-SO2NR5R6; R_k is selected from –H, alkyl, and cycloalkyl; each occurrence of R₅ and R₆ is independently selected from -H, alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl, or provided that in the case of -C(O)NR5R6, -NR5C(O)NR5R6, alkyl-C(O)NR5R6, and alkyl-NR5C(O)NR5R6 the R5 taken together with R6 and the nitrogen atom to which they are bonded may form an unsubstituted or substituted C₄-C₆ heterocyclyl; and each occurrence of R7 is selected from alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl; provided that at least one of Ra, Rb, Rc, Rd, Rg, Rh, Ri, Rj, and Rk is not -H. In certain embodiments, Ra, Rb, Rc, Rd, Rg, Rh, Ri, and Rj are each -H; and Rk is selected from alkyl and cycloalkyl. In certain embodiments, R₁ is selected from:

In certain embodiments,

selected from alkyl and cycloalkyl, e.g. R1 is:

. In certain embodiments, R1 is

R_a, R_b, R_i, and R_j are independently selected from -H, halogen, -CN, -CF₃, and alkyl; R_c, R_d, R_g, and R_h are independently selected from -H, halogen, -CN, -CF₃, -OH, - CO2H, -NH2, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -OR5, -C(O)NR5R6, -NR5C(O)R6, C(O)R7, - NR₅C(O)NR₅R₆, -SO₂R₇, -NHSO₂R₇, -SO₂NR₅R₆, alkyl-C(O)NR₅R₆, alkyl-NR₅C(O)R₆, alkyl-C(O)R7, alkyl-NR5C(O)NR5R6, alkyl-SO2R7, alkyl-SO2NR5R6, and -NHC(O)NR7, or Rc taken together with Rd and the carbon atom to which they are bonded form an unsubstituted or substituted C₃-C₆ cycloalkyl or C₄-C₆ heterocyclyl, or Rc taken together with Rg or Rd taken together with Rh, and the carbon atoms to which they are bonded form an unsubstituted or substituted C3-C6 cycloalkyl or C4-C6 heterocyclyl; each occurrence of R₅ and R₆ is independently selected from -H, -CF₃, alkyl, aminoalkyl, hydroxyalkyl, methoxyalkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl, or provided that in the case of -C(O)NR5R6, -NR5C(O)NR5R6, alkyl-C(O)NR5R6, and alkyl-NR₅C(O)NR₅R₆ the R₅ taken together with R₆ and the nitrogen atom to which they are bonded may form an unsubstituted or substituted C4-C6 heterocyclyl; and each occurrence of R7 is selected from alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl; provided that at least one of Ra, Rb, Rc, Rd, Rg, Rh, Ri, and Rj is not -H. In certain embodiments, R₁ is

R_a, R_b, R_i, and R_j are independently selected from -H, halogen, -CN, -CF₃, and alkyl; Rc, Rd, Rg, and Rh are independently selected from -H, halogen, -CN, -CF3, -OH, - CO2H, -NH2, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -C(O)NR₅R₆, -NR₅C(O)R₆, C(O)R₇, - NR5C(O)NR5R6, -SO2R7, -SO2NR5R6, alkyl-C(O)NR5R6, alkyl-NR5C(O)R6, alkyl-C(O)R7, alkyl-NR5C(O)NR5R6, alkyl-SO2R7, and alkyl-SO2NR5R6, or Rc taken together with Rd and the carbon atom to which they are bonded form an unsubstituted or substituted C₃-C₆ cycloalkyl or C₄-C₆ heterocyclyl; each occurrence of R₅ and R₆ is independently selected from -H, alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl, or provided that in the case of -C(O)NR5R6, -NR5C(O)NR5R6, alkyl-C(O)NR5R6, and alkyl-NR5C(O)NR5R6 the R5 taken together with R6 and the nitrogen atom to which they are bonded may form an unsubstituted or substituted C₄-C₆ heterocyclyl; and each occurrence of R7 is selected from alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl; provided that at least one of R_a, R_b, R_c, R_d, R_g, R_h, R_i, and R_j is not -H. In certain embodiments, Ra, Rb, Ri and Rj are independently selected from -H, halogen, -CN, -CF₃, and alkyl; and R_c, R_d, R_g and R_h are independently selected from -H, halogen, -CN, -CF₃, -OH, -CO₂H, -NH₂, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, -C(O)NR5R6, -NR5C(O)R6, C(O)R7, alkyl-C(O)NR5R6, alkyl-NR5C(O)R6, and alkyl-C(O)R7. In certain embodiments, R_c, R_d, R_g and R_h are independently selected from –H, alkyl, hydroxyalkyl, aminoalkyl, and alkoxyalkyl.In certain embodiments, Ra, Rb, Ri and Rj are each –H; and Rc, Rd, Rg and Rh are independently selected from –H, alkyl, hydroxyalkyl, aminoalkyl, and alkoxyalkyl. In certain embodiments, R₁ has the structure:

In certain embodiments, R₁ is selected from: and

In certain embodiments, R1 is selected from:

In certain embodiments, R1 is selected from:

In certain embodiments, Ra, Rb, Rg, Rh, Ri, and Rj are each -H; and Rc taken together with R_d and the carbon atom to which they are bonded form an unsubstituted or substituted C3-C6 cycloalkyl or C4-C6 heterocyclyl. In certain embodiments, Rc taken together with Rd and the carbon atom to which they are bonded form an unsubstituted or substituted azetidinyl, pyrrolidinyl, piperazinyl, oxatenyl, tetrahydrofuranyl, tetrahydropyranyl, or sulfolanyl. In certain embodiments, each substituent is independently selected from halogen, - OH, -CN, -CF₃, alkyl, and acetyl. In certain embodiments, R1 is selected from:

. In certain embodiments, Rd and Rh are each -H; and Rc taken together with Rg and the carbon atom to which they are bonded form a substituted C₃-C₆ cycloalkyl. In certain embodiments, Rc and Rg are each -H; and Rd taken together with Rh and the carbon atom to which they are bonded form a substituted C₃-C₆ cycloalkyl. In certain embodiments, the substituted C3-C6 cycloalkyl is substituted with halo (e.g. fluoro) or hydroxyl. In certain embodiments, R1 is selected from:

In certain embodiments, wherein

R_a, R_b, R_e and R_f are independently selected from -H, halogen, -CN, -CF₃, and alkyl; Rc and Rd are independently selected from -H, halogen, -CN, -CF3, -OH, -CO2H, - NH2, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -C(O)NR₅R₆, -NR₅C(O)R₆, C(O)R₇, -NR₅C(O)NR₅R₆, -SO₂R₇, - SO2NR5R6, alkyl-C(O)NR5R6, alkyl-NR5C(O)R6, alkyl-C(O)R7, alkyl-NR5C(O)NR5R6, alkyl- SO2R7, and alkyl-SO2NR5R6, or R_c taken together with R_d and the carbon atom to which they are bonded form an unsubstituted or substituted C₃-C₆ cycloalkyl or C₄-C₆ heterocyclyl; each occurrence of R5 and R6 is independently selected from -H, alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl, or provided that in the case of -C(O)NR₅R₆, -NR₅C(O)NR₅R_6, alkyl-C(O)NR₅R₆, and alkyl-NR₅C(O)NR₅R₆ the R₅ taken together with R₆ and the nitrogen atom to which they are bonded may form an unsubstituted or substituted C4-C6 heterocyclyl; and each occurrence of R₇ is selected from alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl, provided that one of Ra, Rb, Rc, Rd, Re and Rf is not –H. In certain embodiments, R_a, R_b, R_e, and R_f are each –H; and R_c and R_d are independently selected from –H, alkyl, hydroxyalkyl, aminoalkyl, and alkoxyalkyl. In certain embodiments, Ra, Rb, Re, and Rf are each -H; and Rc taken together with Rd and the carbon atom to which they are bonded form an unsubstituted or substituted C₃-C₆ cycloalkyl or C₄-C₆ heterocyclyl. In certain embodiments, Rc taken together with Rd and the carbon atom to which they are bonded form an unsubstituted or substituted azetidinyl, pyrrolidinyl, piperazinyl, oxatenyl, tetrahydrofuranyl, tetrahydropyranyl, or sulfolanyl. In certain embodiments, each substituent is independently selected from halogen, - OH, -CN, -CF3, alkyl, and acetyl. In certain embodiments, R1 is selected from:

. In certain embodiments, R₁ is selected from:

In certain embodiments, R1 is an unsubstituted heteroaryl. In certain embodiments, R₁ is selected from unsubstituted oxazolyl, unsubstitutedpyrazolyl, and unsubstituted triazolyl. In certain embodiments, R₁ is selected from

certain embodiments, wherein X1 is absent, or is selected from –O–, –SO2–, –C(O)–, –N(X2)–, and – C(X3)2–. In certain embodiments, wherein X₁ is absent. In certain embodiments, R1 is an unsubstituted cycloalkyl, e.g. R1 is

. In certain embodiments, R₁ is a substituted cycloalkyl. In certain embodiments, each substituent is independently selected from halogen, - OH, -CN, -CF3, and alkyl. In certain embodiments,

In certain embodiments, R1 is selected from

In certain embodiments, X1 is –N(X2)–, wherein X2 is –H or –CH3. In certain embodiments, R₁ is selected from an optionally substituted alkylaminoalkyl, alkoxyalkyl, and cycloalkyl. In certain embodiments, each substituent is independently selected from halogen, - OH, -CN, -CF3, and alkyl. In certain embodiments, R₁ is –NH-(alkyl)-N(CH₃)₂, –N(CH₃)-(alkyl)-N(CH₃)₂, –NH- (alkyl)-OCH3, and –N(CH3)-(alkyl)-OCH3. In certain embodiments,

In certain embodiments, R₂ is halogen or alkyl, e.g. R₂ is –CH₃, –Cl, or –F. In certain embodiments, R2 is selected from –Br and -CN. In certain embodiments, R2 is –Cl. In other embodiments, R2 is –Br. In other embodiments, R₂ is –F. In other embodiments, R2 is –CH3. In other embodiments, R2 is –CN. In certain embodiments, R₂' is alkyl, e.g. R₂' is –CH₃. In certain embodiments, R2' is hydroxyalkyl, e.g. R2' is –CH2-OH. In certain embodiments, R2'' is –H. In certain embodiments, R₂'' is alkyl, e.g. R₂'' is –CH₃. In certain embodiments, R₂'' is acyl, e.g. R₂'' is –C(O)CH₃. In certain embodiments, R2'' is –H, –CH3, or –C(O)CH3. In certain embodiments, the compound has the Formula (

In certain embodiments, the compound has the Formula (

In certain embodiments, the compound has the Formula (

In certain embodiments, the compound has the Formula

In certain embodiments, the compound has the Formula (

(Ie). In certain embodiments, the compound is selected from the following Table 1:

In certain embodiments, the compound is selected from Table 1A disclosed herein. In certain embodiments, the compound is selected from Table 2 disclosed herein.In some embodiments, the compounds are atropisomers. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds produced by the replacement of a hydrogen with deuterium or tritium, or of a carbon with a ¹³C- or ¹⁴C- enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention. For example, in the case of variable R¹, the (C1- C₄)alkyl or the -O-(C₁-C₄)alkyl can be suitably deuterated (e.g., -CD₃, -OCD₃). Any compound of the invention can also be radiolabed for the preparation of a radiopharmaceutical agent. Methods of Treatment One aspect of the invention provides compounds, compositions, and methods useful for inhibiting mammalian SLC34A1 function. Another aspect of the invention provides compounds, compositions, and methods useful for treating or preventing a disease or disorder associated with elevated phosphates levels in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I). Another aspect of the invention provides compounds, compositions, and methods useful for treating or preventing a disease or disorder associated with elevated FGF-23 levels in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I). Another aspect of the invention relates to a method of treating or preventing chronic kidney disease (CKD), comprising administering to the subject an effective amount of a compound of Formula (I). In certain embodiments, the chronic kidney disease is selected from Alport syndrome, C3-glomerulopathy, tubulointerstitial nephritis, diabetic nephropathy, idiopathic nephrosclerosis, hemolytic uremic syndrome, focal segmental glomerulosclerosis, ApoL1 nephropathy, hypertensive nephrosclerosis, IgA nephropathy, membraneous nephropathy, and acute phosphate nephropathy. Another aspect of the invention relates to a method of treating or preventing media calcification, comprising administering to the subject an effective amount of a compound of Formula (I). Another aspect of the invention relates to a method of treating or preventing vascular calcification, comprising administering to the subject an effective amount of a compound of Formula (I). In certain embodiments, the media or vascular calcification is associated with chronic kidney disease in the subject. In other embodiment, the media or vascular calcification is associated with heart disease in the subject. In certain embodiments, the media or vascular calcification is associated with chronic kidney disease. In other embodiments, the media or vascular calcification is associated with Moenckeberg's medial sclerosis, atherosclerosis, intima calcification, postmenopausal osteoporosis, type II diabetes, aging, hypophosphaturia, hyperparathyroidism, Vitamin D disorders, Vitamin K deficiency, Kawasaki disease, arterial calcification due to lack of CD73 (ACDC), generalized arterial calcification of infancy (GACI), idiopathic basal ganglia calcification (IBGC), pseudoxanthoma elasticum (PXE), morbus fahr ferrocalcinosis, Singleton-Merten syndrome, P-thalassemia, calciphylaxis, heterotrophic ossification, pre- term placental calcification, uterine calcification, calcified uterine fibroma, idiopathic basal ganglia calcification (FIBGC), morbus fahr ferrocalcinosis, idiopathic basal ganglia calcification, aortic valve calcification, cerebral calcification, tumor calcinosis, or tumor lysis syndrome. Another aspect of the invention relates to a method of treating or preventing acromegaly, rhabdomyolysis, hemolysis, hyperphosphatemia, familial hyperphosphatemia, hypoparathyroidism, pseudohypoparathyroidism, secondary hyperparathyroidism, osteodystrophy, CKD-mineral and bone disorder, diabetic ketoacidosis, metabolic acidosis, respiratory acidosis, fulminant hepatitis, hepatic osteodystrophy, hyperthermia, malignant hyperthermia, sarcoidosis, arterial hypertension, peripheral artery disease, rheumatoid arthritis, calcium-phosphate-mediated inflammasomopathies, pulmonary alveolar microlithiasis, or heart disease, comprising administering to the subject an effective amount of a compound of Formula (I). In certain embodiments, the hyperphosphatemia or familial hyperphosphatemia is associated with a GALNT3, CaSR, Klotho, or FGF23 mutation. In certain embodiments, the heart disease is associated with chronic kidney disease. In other embodiments, the heart disease is associated with elevated FGF-23 levels in the subject. In other embodiments, the heart disease is heart failure with preserved ejection fraction. In other embodiments, the heart disease is CKD-related cardiac hypertrophy, CKD-related renal dystrophy, congestive heart failure, left-ventricular hypertrophy, or atrial fibrillation. Another aspect of the invention relates to a method of treating or preventing elevated magnesium deficiency in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I). Another aspect of the invention relates to a method of treating or preventing elevated plasma FGF-23 levels in a subject in need thereof, comprising administering to the subject an effective amount of a compound of Formula (I). Another aspect of the invention relates to a method of treating or preventing a disease or disorder asscociated with elevated FGF-23 levels, comprising administering to a subject in need thereof an effective amount of a compound of Formula (I). In certain embodiment, the disease or disorder asscociated with elevated FGF-23 levels is heart disease. In some embodiments of any one of the disclosed methods, the compound of Formula (I) is defined as:

X₁ is a absent or is selected from –O–, –SO₂–, –C(O)–, –N(X₂)–, and –C(X₃)₂–; X2 is selected from –H, alkyl, and –SO2–X2''; X2'' is alkyl; each X₃ is independently selected from –H and alkyl; R1 is selected from an optionally substituted aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl; and R₂ is selected from –H, halogen (e.g., chloro), and alkyl; R₂' is selected from an alkyl, alkenyl, alkynyl, cycloalkyl, and aryl; and R2'' is selected from H, alkyl, and acyl; provided that when X₁ is –O– or –N(X₂)– and R₁ is a nitrogen-containing heterocyclyl, then the –O– or –N(X₂)– is not directly bonded to a nitrogen on the heterocyclyl; or a pharmaceutically acceptable salt thereof. In some embodiments of any one of the disclosed methods, the compound is represented by Formula (I), as defined immediately above, provided that when X1 is absent,

Pharmaceutical Compositions, Routes of Administration, and Dosing In certain embodiments, the invention is directed to a pharmaceutical composition, comprising a compound of the invention and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the invention and a pharmaceutically acceptable carrier. In certain embodiments, a pharmaceutical composition of the invention further comprises at least one additional pharmaceutically active agent other than a compound of the invention. The at least one additional pharmaceutically active agent can be an agent useful in the treatment of ischemia-reperfusion injury. Pharmaceutical compositions of the invention can be prepared by combining one or more compounds of the invention with a pharmaceutically acceptable carrier and, optionally, one or more additional pharmaceutically active agents. As stated above, an “effective amount” refers to any amount that is sufficient to achieve a desired biological effect. Combined with the teachings provided herein, by choosing among the various active compounds and weighing factors such as potency, relative bioavailability, patient body weight, severity of adverse side-effects and mode of administration, an effective prophylactic or therapeutic treatment regimen can be planned which does not cause substantial unwanted toxicity and yet is effective to treat the particular subject. The effective amount for any particular application can vary depending on such factors as the disease or condition being treated, the particular compound of the invention being administered, the size of the subject, or the severity of the disease or condition. One of ordinary skill in the art can empirically determine the effective amount of a particular compound of the invention and/or other therapeutic agent without necessitating undue experimentation. A maximum dose may be used, that is, the highest safe dose according to some medical judgment. Multiple doses per day may be contemplated to achieve appropriate systemic levels of compounds. Appropriate systemic levels can be determined by, for example, measurement of the patient’s peak or sustained plasma level of the drug. “Dose” and “dosage” are used interchangeably herein. In certain embodiments, intravenous administration of a compound may typically be from 0.1 mg/kg/day to 20 mg/kg/day. In one embodiment, intravenous administration of a compound may typically be from 0.1 mg/kg/day to 2 mg/kg/day. In one embodiment, intravenous administration of a compound may typically be from 0.5 mg/kg/day to 5 mg/kg/day. In one embodiment, intravenous administration of a compound may typically be from 1 mg/kg/day to 20 mg/kg/day. In one embodiment, intravenous administration of a compound may typically be from 1 mg/kg/day to 10 mg/kg/day. Generally, daily oral doses of a compound will be, for human subjects, from about 0.01 milligrams/kg per day to 1000 milligrams/kg per day. It is expected that oral doses in the range of 0.5 to 50 milligrams/kg, in one or more administrations per day, will yield therapeutic results. Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. For example, it is expected that intravenous administration would be from one order to several orders of magnitude lower dose per day. In the event that the response in a subject is insufficient at such doses, even higher doses (or effective higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of the compound. For any compound described herein the therapeutically effective amount can be initially determined from animal models. A therapeutically effective dose can also be determined from human data for compounds which have been tested in humans and for compounds which are known to exhibit similar pharmacological activities, such as other related active agents. Higher doses may be required for parenteral administration. The applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. Adjusting the dose to achieve maximal efficacy based on the methods described above and other methods as are well-known in the art is well within the capabilities of the ordinarily skilled artisan. The formulations of the invention can be administered in pharmaceutically acceptable solutions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, and optionally other therapeutic ingredients. For use in therapy, an effective amount of the compound can be administered to a subject by any mode that delivers the compound to the desired surface. Administering a pharmaceutical composition may be accomplished by any means known to the skilled artisan. Routes of administration include but are not limited to intravenous, intramuscular, intraperitoneal, intravesical (urinary bladder), oral, subcutaneous, direct injection (for example, into a tumor or abscess), mucosal (e.g., topical to eye), inhalation, and topical. For intravenous and other parenteral routes of administration, a compound of the invention can be formulated as a lyophilized preparation, as a lyophilized preparation of liposome-intercalated or -encapsulated active compound, as a lipid complex in aqueous suspension, or as a salt complex. Lyophilized formulations are generally reconstituted in suitable aqueous solution, e.g., in sterile water or saline, shortly prior to administration. For oral administration, the compounds can be formulated readily by combining the active compound(s) with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated. Pharmaceutical preparations for oral use can be obtained as solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Optionally the oral formulations may also be formulated in saline or buffers, e.g., EDTA for neutralizing internal acid conditions or may be administered without any carriers. Also specifically contemplated are oral dosage forms of the above component or components. The component or components may be chemically modified so that oral delivery of the derivative is efficacious. Generally, the chemical modification contemplated is the attachment of at least one moiety to the component molecule itself, where said moiety permits (a) inhibition of acid hydrolysis; and (b) uptake into the blood stream from the stomach or intestine. Also desired is the increase in overall stability of the component or components and increase in circulation time in the body. Examples of such moieties include: polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinyl pyrrolidone and polyproline. Abuchowski and Davis, “Soluble Polymer-Enzyme Adducts”, In: Enzymes as Drugs, Hocenberg and Roberts, eds., Wiley-Interscience, New York, N.Y., pp.367-383 (1981); Newmark et al., J Appl Biochem 4:185-9 (1982). Other polymers that could be used are poly-1,3-dioxolane and poly-1,3,6-tioxocane. For pharmaceutical usage, as indicated above, polyethylene glycol moieties are suitable. For the component (or derivative) the location of release may be the stomach, the small intestine (the duodenum, the jejunum, or the ileum), or the large intestine. One skilled in the art has available formulations which will not dissolve in the stomach, yet will release the material in the duodenum or elsewhere in the intestine. Preferably, the release will avoid the deleterious effects of the stomach environment, either by protection of the compound of the invention (or derivative) or by release of the biologically active material beyond the stomach environment, such as in the intestine. To ensure full gastric resistance a coating impermeable to at least pH 5.0 is essential. Examples of the more common inert ingredients that are used as enteric coatings are cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCP 50, HPMCP 55, polyvinyl acetate phthalate (PVAP), Eudragit L30D, Aquateric, cellulose acetate phthalate (CAP), Eudragit L, Eudragit S, and shellac. These coatings may be used as mixed films. A coating or mixture of coatings can also be used on tablets, which are not intended for protection against the stomach. This can include sugar coatings, or coatings which make the tablet easier to swallow. Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutic (e.g., powder); for liquid forms, a soft gelatin shell may be used. The shell material of cachets could be thick starch or other edible paper. For pills, lozenges, molded tablets or tablet triturates, moist massing techniques can be used. The therapeutic can be included in the formulation as fine multi-particulates in the form of granules or pellets of particle size about 1 mm. The formulation of the material for capsule administration could also be as a powder, lightly compressed plugs or even as tablets. The therapeutic could be prepared by compression. Colorants and flavoring agents may all be included. For example, the compound of the invention (or derivative) may be formulated (such as by liposome or microsphere encapsulation) and then further contained within an edible product, such as a refrigerated beverage containing colorants and flavoring agents. One may dilute or increase the volume of the therapeutic with an inert material. These diluents could include carbohydrates, especially mannitol, ^-lactose, anhydrous lactose, cellulose, sucrose, modified dextrans and starch. Certain inorganic salts may be also be used as fillers including calcium triphosphate, magnesium carbonate and sodium chloride. Some commercially available diluents are Fast-Flo, Emdex, STA-Rx 1500, Emcompress and Avicell. Disintegrants may be included in the formulation of the therapeutic into a solid dosage form. Materials used as disintegrates include but are not limited to starch, including the commercial disintegrant based on starch, Explotab. Sodium starch glycolate, Amberlite, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethyl cellulose, natural sponge and bentonite may all be used. Another form of the disintegrants are the insoluble cationic exchange resins. Powdered gums may be used as disintegrants and as binders and these can include powdered gums such as agar, Karaya or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants. Binders may be used to hold the therapeutic agent together to form a hard tablet and include materials from natural products such as acacia, tragacanth, starch and gelatin. Others include methyl cellulose (MC), ethyl cellulose (EC) and carboxymethyl cellulose (CMC). Polyvinyl pyrrolidone (PVP) and hydroxypropylmethyl cellulose (HPMC) could both be used in alcoholic solutions to granulate the therapeutic. An anti-frictional agent may be included in the formulation of the therapeutic to prevent sticking during the formulation process. Lubricants may be used as a layer between the therapeutic and the die wall, and these can include but are not limited to; stearic acid including its magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils and waxes. Soluble lubricants may also be used such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol of various molecular weights, Carbowax 4000 and 6000. Glidants that might improve the flow properties of the drug during formulation and to aid rearrangement during compression might be added. The glidants may include starch, talc, pyrogenic silica and hydrated silicoaluminate. To aid dissolution of the therapeutic into the aqueous environment a surfactant might be added as a wetting agent. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate and dioctyl sodium sulfonate. Cationic detergents which can be used and can include benzalkonium chloride and benzethonium chloride. Potential non-ionic detergents that could be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50 and 60, glycerol monostearate, polysorbate 40, 60, 65 and 80, sucrose fatty acid ester, methyl cellulose and carboxymethyl cellulose. These surfactants could be present in the formulation of the compound of the invention or derivative either alone or as a mixture in different ratios. Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Microspheres formulated for oral administration may also be used. Such microspheres have been well defined in the art. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. For topical administration, the compound may be formulated as solutions, gels, ointments, creams, suspensions, etc. as are well-known in the art. Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral or pulmonary administration. For administration by inhalation, compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch. Also contemplated herein is pulmonary delivery of the compounds disclosed herein (or salts thereof). The compound is delivered to the lungs of a mammal while inhaling and traverses across the lung epithelial lining to the blood stream. Other reports of inhaled molecules include Adjei et al., Pharm Res 7:565-569 (1990); Adjei et al., Int J Pharmaceutics 63:135-144 (1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13(suppl. 5):143-146 (1989) (endothelin-1); Hubbard et al., Annal Int Med 3:206-212 (1989) ( ^1- antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (a-1-proteinase); Oswein et al., 1990, "Aerosolization of Proteins", Proceedings of Symposium on Respiratory Drug Delivery II, Keystone, Colorado, March, (recombinant human growth hormone); Debs et al., 1988, J Immunol 140:3482-3488 (interferon-gamma and tumor necrosis factor alpha) and Platz et al., U.S. Pat. No.5,284,656 (granulocyte colony stimulating factor; incorporated by reference). A method and composition for pulmonary delivery of drugs for systemic effect is described in U.S. Pat. No.5,451,569 (incorporated by reference), issued Sep.19, 1995 to Wong et al. Contemplated for use in the practice of this invention are a wide range of mechanical devices designed for pulmonary delivery of therapeutic products, including but not limited to nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those skilled in the art. Some specific examples of commercially available devices suitable for the practice of this invention are the Ultravent nebulizer, manufactured by Mallinckrodt, Inc., St. Louis, Mo.; the Acorn II nebulizer, manufactured by Marquest Medical Products, Englewood, Colo.; the Ventolin metered dose inhaler, manufactured by Glaxo Inc., Research Triangle Park, North Carolina; and the Spinhaler powder inhaler, manufactured by Fisons Corp., Bedford, Mass. All such devices require the use of formulations suitable for the dispensing of the compounds of the invention. Typically, each formulation is specific to the type of device employed and may involve the use of an appropriate propellant material, in addition to the usual diluents, adjuvants and/or carriers useful in therapy. Also, the use of liposomes, microcapsules or microspheres, inclusion complexes, or other types of carriers is contemplated. Chemically modified compound of the invention may also be prepared in different formulations depending on the type of chemical modification or the type of device employed. Formulations suitable for use with a nebulizer, either jet or ultrasonic, will typically comprise a compound of the invention (or derivative) dissolved in water at a concentration of about 0.1 to 25 mg of biologically active compound of the invention per mL of solution. The formulation may also include a buffer and a simple sugar (e.g., for inhibitor stabilization and regulation of osmotic pressure). The nebulizer formulation may also contain a surfactant, to reduce or prevent surface induced aggregation of the compound of the invention caused by atomization of the solution in forming the aerosol. Formulations for use with a metered-dose inhaler device will generally comprise a finely divided powder containing the compound of the invention (or derivative) suspended in a propellant with the aid of a surfactant. The propellant may be any conventional material employed for this purpose, such as a chlorofluorocarbon, a hydrochlorofluorocarbon, a hydrofluorocarbon, or a hydrocarbon, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or combinations thereof. Suitable surfactants include sorbitan trioleate and soya lecithin. Oleic acid may also be useful as a surfactant. Formulations for dispensing from a powder inhaler device will comprise a finely divided dry powder containing compound of the invention (or derivative) and may also include a bulking agent, such as lactose, sorbitol, sucrose, or mannitol in amounts which facilitate dispersal of the powder from the device, e.g., 50 to 90% by weight of the formulation. The compound of the invention (or derivative) should advantageously be prepared in particulate form with an average particle size of less than 10 micrometers ( ^m), most preferably 0.5 to 5 ^m, for most effective delivery to the deep lung. Nasal delivery of a pharmaceutical composition of the present invention is also contemplated. Nasal delivery allows the passage of a pharmaceutical composition of the present invention to the blood stream directly after administering the therapeutic product to the nose, without the necessity for deposition of the product in the lung. Formulations for nasal delivery include those with dextran or cyclodextran. For nasal administration, a useful device is a small, hard bottle to which a metered dose sprayer is attached. In one embodiment, the metered dose is delivered by drawing the pharmaceutical composition of the present invention solution into a chamber of defined volume, which chamber has an aperture dimensioned to aerosolize and aerosol formulation by forming a spray when a liquid in the chamber is compressed. The chamber is compressed to administer the pharmaceutical composition of the present invention. In a specific embodiment, the chamber is a piston arrangement. Such devices are commercially available. Alternatively, a plastic squeeze bottle with an aperture or opening dimensioned to aerosolize an aerosol formulation by forming a spray when squeezed is used. The opening is usually found in the top of the bottle, and the top is generally tapered to partially fit in the nasal passages for efficient administration of the aerosol formulation. Preferably, the nasal inhaler will provide a metered amount of the aerosol formulation, for administration of a measured dose of the drug. The compounds, when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Alternatively, the active compounds may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. The compounds may also be formulated in rectal or vaginal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. In addition to the formulations described above, a compound may also be formulated as a depot preparation. Such long acting formulations may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. The pharmaceutical compositions also may comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Suitable liquid or solid pharmaceutical preparation forms are, for example, aqueous or saline solutions for inhalation, microencapsulated, encochleated, coated onto microscopic gold particles, contained in liposomes, nebulized, aerosols, pellets for implantation into the skin, or dried onto a sharp object to be scratched into the skin. The pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops or preparations with protracted release of active compounds, in whose preparation excipients and additives and/or auxiliaries such as disintegrants, binders, coating agents, swelling agents, lubricants, flavorings, sweeteners or solubilizers are customarily used as described above. The pharmaceutical compositions are suitable for use in a variety of drug delivery systems. For a brief review of methods for drug delivery, see Langer R, Science 249:1527-33 (1990). The compound of the invention and optionally other therapeutics may be administered per se (neat) or in the form of a pharmaceutically acceptable salt or cocrystal. When used in medicine the salts or cocrystals should be pharmaceutically acceptable, but non- pharmaceutically acceptable salts or cocrystals may conveniently be used to prepare pharmaceutically acceptable salts or cocrystals thereof. Such salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulphuric, nitric, phosphoric, maleic, acetic, salicylic, p-toluene sulphonic, tartaric, citric, methane sulphonic, formic, malonic, succinic, naphthalene-2-sulphonic, and benzene sulphonic. Also, such salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts of the carboxylic acid group. Suitable buffering agents include: acetic acid and a salt (1-2% w/v); citric acid and a salt (1-3% w/v); boric acid and a salt (0.5-2.5% w/v); and phosphoric acid and a salt (0.8-2% w/v). Suitable preservatives include benzalkonium chloride (0.003-0.03% w/v); chlorobutanol (0.3-0.9% w/v); parabens (0.01-0.25% w/v) and thimerosal (0.004-0.02% w/v). Pharmaceutical compositions of the invention contain an effective amount of a compound as described herein and optionally therapeutic agents included in a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” means one or more compatible solid or liquid filler, diluents or encapsulating substances which are suitable for administration to a human or other vertebrate animal. The term “carrier” denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The components of the pharmaceutical compositions also are capable of being commingled with the compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency. The therapeutic agent(s), including specifically but not limited to a compound of the invention, may be provided in particles. Particles as used herein means nanoparticles or microparticles (or in some instances larger particles) which can consist in whole or in part of the compound of the invention or the other therapeutic agent(s) as described herein. The particles may contain the therapeutic agent(s) in a core surrounded by a coating, including, but not limited to, an enteric coating. The therapeutic agent(s) also may be dispersed throughout the particles. The therapeutic agent(s) also may be adsorbed into the particles. The particles may be of any order release kinetics, including zero-order release, first-order release, second-order release, delayed release, sustained release, immediate release, and any combination thereof, etc. The particle may include, in addition to the therapeutic agent(s), any of those materials routinely used in the art of pharmacy and medicine, including, but not limited to, erodible, nonerodible, biodegradable, or nonbiodegradable material or combinations thereof. The particles may be microcapsules which contain the compound of the invention in a solution or in a semi-solid state. The particles may be of virtually any shape. Both non-biodegradable and biodegradable polymeric materials can be used in the manufacture of particles for delivering the therapeutic agent(s). Such polymers may be natural or synthetic polymers. The polymer is selected based on the period of time over which release is desired. Bioadhesive polymers of particular interest include bioerodible hydrogels described in Sawhney H S et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein. These include polyhyaluronic acids, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginate, chitosan, poly(methyl methacrylates), poly(ethyl methacrylates), poly(butylmethacrylate), poly(isobutyl methacrylate), poly(hexylmethacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), and poly(octadecyl acrylate). The therapeutic agent(s) may be contained in controlled release systems. The term “controlled release” is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation are controlled. This refers to immediate as well as non-immediate release formulations, with non-immediate release formulations including but not limited to sustained release and delayed release formulations. The term “sustained release” (also referred to as “extended release”) is used in its conventional sense to refer to a drug formulation that provides for gradual release of a drug over an extended period of time, and that preferably, although not necessarily, results in substantially constant blood levels of a drug over an extended time period. The term “delayed release” is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug there from. “Delayed release” may or may not involve gradual release of drug over an extended period of time, and thus may or may not be “sustained release.” Use of a long-term sustained release implant may be particularly suitable for treatment of chronic conditions. “Long-term” release, as used herein, means that the implant is constructed and arranged to deliver therapeutic levels of the active ingredient for at least 7 days, and preferably 30-60 days. Long-term sustained release implants are well-known to those of ordinary skill in the art and include some of the release systems described above. It will be understood by one of ordinary skill in the relevant arts that other suitable modifications and adaptations to the compositions and methods described herein are readily apparent from the description of the invention contained herein in view of information known to the ordinarily skilled artisan, and may be made without departing from the scope of the invention or any embodiment thereof. Having now described the present invention in detail, the same will be more clearly understood by reference to the following examples, which are included herewith for purposes of illustration only and are not intended to be limiting of the invention. EXAMPLES The invention is further described in the following examples, which do not limit the scope of the invention described in the claims. Example 1: SLC34A1 Transport Assay SLC34A1 transport activity was measured through the use of a radiometric phosphate transport assay. A stably expressing cell line was made by transfecting human SLC34A1 into Flp-In T-REx 293 cells (Invitrogen). The Flp-In SLC34A1 cell lines were grown in DMEM + Glutamax-I (1X), Gibco #A41920-01 supplemented with 10% FBS (Gibco #16140-071), 1x Penicillin/ Streptomycin, 0.250 mg/mL Hygromycin B (Thermo #10687010), 0.01 mg/mL Blasticidin S HCl (Gibco #A11139-03), at 37°C, 5% CO₂. Two days prior to a transport assay, cells were split and plated at a density of 30k cells/well (96-well, 100 µL total volume) or 18k cells/well (384-well, 40 µL total volume) in Poly-D-lysine coated Isoplate-96 TC or Viewplate-384 TC plates (Perkin Elmer, # 6005070 or #6007480). Plating media was DMEM + Glutamax-I (1X), Gibco #A41920-01 supplemented with 10% FBS (Gibco #16140-071), 1x Penicillin/ Streptomycin. Cells were replaced in the incubator, and one day prior to transport were induced with 1 µg/mL tetracycline. Cell media was removed by manually removing the media and washing robotically. The wash manually removed, followed by robotic addition of 20 µL of Live Cell Imaging Solution with compound (Final DMSO 0.5%). The cells were incubated at room temperature for 20 minutes prior to robotic addition of 10 µL of radioactive phosphate solution (240 µM sodium phosphate in Live Cell Imaging Solution, pH 7.4, 33 µCi/mL ³³P as phosphate). Cells were incubated at room temperature, then robotically washed once with Live Cell Imaging Solution. The cells were lysed by robotic addition 30 µL of Ultima Gold XR Scintillation Fluid (Perkin Elmer), sealed, and scanned on a scintillation counter for radioactive signal. Relative phosphate uptake through SLC34A1 was determined by normalizing the measured radioactive signal using the signal from the compound free 0.5% DMSO (negative control) and 10 µM positive control. The positive control is disclosed in Filipski, K.J. et al. ACS Med. Chem. Lett.2018, 9, 440−445, and has the structure:

380 nM (Filipski et al.); 278 nM (as measured in assay herein). Example 2: Synthesis of Exemplary Compounds Synthesis of the azaindole core (Core Synthesis Procedure 1)

Step 1: Synthesis of 2 To a suspension of potassium tert-butoxide (70.1 g, 624.76 mmol) in anhydrous toluene (700 mL) was added a solution of methyl trifluoroacetate (80.0 g, 624.756 mmol) in acetonitrile (25.02 g, 624.756 mmol) dropwise at room temperature. After addition, the resulting mixture was stirred at 80 ^oC for 6 hrs. The mixture was then cooled to room temperature and filtered to give crude 2 (80.1 g, 73.1% yield) as a yellow solid which was used for the next step without any further purification.¹H NMR (400 MHz, D₂O) δ 4.55 (s, 1H). Step 2: Synthesis of 3 To a suspension of 2 (80.0 g, 456.75 mmol) in acetonitrile (800 mL) was added tosyl chloride (223.6 g, 1172.83 mmol) portion wise at room temperature, and the resulting mixture was stirred at room temperature overnight. The mixture was then concentrated under vacuum and the residue was diluted with water (800 mL) and extracted with EtOAc (400 mL) twice. The combined organic layers were washed with brine (300 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was then purified by flash column chromatography on silica gel (eluted with PE/EtOAc= 100: 0 to 10: 1) to give compound 3 (80.0 g, 60.1 % yield) as a yellow oil.¹H NMR (400 MHz, CDCl₃) Major: δ 7.96 (d, J = 8.4 Hz, 2H), 7.44 (t, J = 5.9 Hz, 2H), 6.02 (s, 1H), 2.50 (s, 3H). Minor: δ 7.84 (d, J = 8.4 Hz, 2H), 7.44 (t, J = 5.9 Hz, 2H), 6.14 (s, 1H), 2.51 (s, 3H). Step 3: Synthesis of 6 To a solution of compound 4 (25.0 g, 304.47 mmol) in MeOH (500 mL) was added 5 (53.34 g, 304.47 mmol) at room temperature, and the reaction mixture was stirred at room temperature overnight. The mixture was then concentrated under vacuum to remove most of the solvent and the residue was diluted with EtOAc (400 mL) and washed with water (200 mL x 2) and brine (300 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was then purified by flash column chromatography on silica gel (eluted with PE/EtOAc= 100: 0 to 10: 1) to give 6 (50.0 g, 68.3 % yield) as a white solid.¹H NMR (400 MHz, CDCl₃) δ 5.31 (d, J = 5.7 Hz, 1H), 4.49 (d, J = 6.3 Hz, 1H), 4.34 – 4.26 (m, 4H), 3.86 (s, 1H), 2.19 (s, 3H), 1.31 (t, J = 7.1 Hz, 6H). Step 4: Synthesis of 7 To a solution of 6 (50.0 g, 208.11 mmol) in EtOH (300 mL) a solution of sodium ethoxide in ethanol (21% w/w, 15.58 g, 228.92 mmol) was added drop-wise at room temperature under N2 atmosphere. The mixture was then stirred at room temperature for 16 hrs. Most of the solvent was removed under vacuum and the residue was diluted with ice-water (500 mL) and extracted with EtOAc (100 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluted with PE/EtOAc= 100: 0 to 2: 1) to give 7 (27.0 g, 77.1 % yield) as a off-white solid. LC/MS (ESI) m/z: 169 (M+H)⁺.¹H NMR (400 MHz, DMSO-d6) δ 10.22 (s, 1H), 5.29 (d, J = 2.4 Hz, 1H), 4.93 (s, 2H), 4.14 (q, J = 7.1 Hz, 2H), 2.06 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H). Step 5: Synthesis of 8 To a mixture of 7 (27.0 g, 160.52 mmol) and DIEA (62.24 g, 481.57 mmol) in DCM (300 mL) was added 3 (74.8 g, 256.84 mmol) at room temperature. The resulting mixture was then stirred at room temperature for 8 hrs. The mixture was then washed with water (300 mL) and brine (300 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude product was purified by flash column chromatography on silica gel (eluted with PE/EtOAc= 100: 0 to 5: 1) to give 8 (27.0 g, 58.5 % yield) as a brown solid. LC/MS (ESI) m/z: 288 (M+H)⁺. Step 6: Synthesis of 9 To a solution of 8 (26.0 g, 90.52 mmol) in acetonitrile (200 mL) was added DBU (13.78 g, 90.52 mmol) at room temperature and the resulting mixture was refluxed overnight. The mixture was then cooled to room temperature and concentrated under vacuum. The residue was then purified by flash column chromatography on silica gel (eluted with DCM/MeOH=100:0 to 10:1) to give 9 (14.0 g, 64.1% yield) as brown solid. LC/MS (ESI) m/z: 242 (M+H)⁺. Step 7: Synthesis of 10 To a solution of 9 (14.0 g, 58.05 mmol) in acetonitrile (70 mL) was added POCl₃ (26.7 g, 174.151 mmol) drop-wise at 0 ^oC, and the resulting mixture was refluxed for 3 hrs. The mixture was then cooled down to room temperature and concentrated under vacuum. The residue was diluted with EtOAc (200 mL) and washed with saturated NaHCO₃ solution (200 mL) and brine (200 mL). The organic layer was then dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluted with PE/EtOAc=100:0 to 3:1) to give 10 (14.0 g, 92.8 % yield) as a brown solid. LC/MS (ESI) m/z: 260 (M+H)⁺.¹H NMR (400 MHz, DMSO-d6) δ 12.89 (s, 1H), 6.77 (d, J = 0.7 Hz, 1H), 2.58 (d, J = 0.6 Hz, 3H). Step 8: Synthesis of 11 To a solution of 10 (10.0 g, 38.52 mmol) in DMF (50 mL) was added NCS (5.4 g, 40.44 mmol) portion-wise at room temperature, and the resulting mixture was stirred at 50 ^oC for 2 hrs. The mixture was then cooled down to room temperature, diluted with water (300 mL) and extracted with EtOAc (100 mL) twice. The combined organic layers were washed with brine (200 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluted with PE/EtOAc=100:0 to 3:1) to give 11 (10.0 g, 88.2 % yield) as a brown solid. LC/MS (ESI) m/z: 294 (M+H)⁺.¹H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H), 2.57 (s, 3H). General procedure for the SnAr (General Procedure 1):

Step 1: Synthesis of 13 To a mixture of 11 (1.0 eq.) and the corresponding amine 12 (2.0 eq.) in acetonitrile was added DIPEA (3.0 eq.) and the resulting mixture was heated to 80 ^oC overnight. The mixture was then cooled down to room temperature and concentrated under vacuum. The residue was diluted with water and extracted with EtOAc twice. The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified via prep- HPLC to give 13. Synthesis of 1A/1B

A mixture of 11 (200 mg, 0.681 mmol), trans-4-Piperidinol-3-methyl-hydrochloride (1:1)(206 mg, 1.36 mmol) and DIEA (355 uL, 2.04 mmol) in MeCN (5 mL) was stirred at 80 ^oC for 2 hrs. The mixture was then cooled to room temperature and concentrated undee vacuum. The residue was diluted with water (40 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel (eluted with PE/EtOAc=100:0 to 3:1) to give 1A/1B (231 mg, 91.2 % yield) as a yellow solid and a mixture of enantiomers. The mixture was then purified by chiral column and both enantiomers were isolated. General procedure for ester hydrolysis (General Procedure 2)

To a solution of compound 14 (1.0 eq.) in MeOH/H₂O (3:1, V/V) was added LiOH-H₂O (2.0 eq.), and the resulting mixture was stirred at room temperature for 2 hrs. The reaction mixture was adjusted to pH=3 with aq. HCl (1M) and extracted with EtOAc twice. The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluted with PE/EtOAc) to give compound 15. Synthesis of 2B

To a solution of 2A (230 mg, 0.571 mmol) in MeOH/H2O (12 mL, 3:1) was added LiOH- H₂O (48 mg, 1.142 mmol), and the resulting mixture was stirred at room temperature for 2 hrs. The reaction mixture was adjusted to pH=3 with aqueous HCl (1M), extracted with EtOAc (50 mL x 3). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluted with DCM/MeOH=100:1 to 10:1) to give 2B (180 mg, 81.1% yield) as a white solid. LC/MS (ESI) m/z: 387 (M+H)⁺.1H NMR (400 MHz, MeOD) δ 3.91 (dt, J = 12.5, 3.2 Hz, 2H), 3.58 – 3.46 (m, 2H), 2.63 (tt, J = 10.7, 4.1 Hz, 1H), 2.53 (s, 3H), 2.18 – 2.08 (m, 2H), 2.05 – 1.97 (m, 2H). General procedure for amide coupling (General Procedure 3)

To a mixture of acid 16 (1.0 eq.) and appropriate amine (1.5 eq.) in DCM were added HATU (1.5 eq.) and DIEA (3.0 eq.) and the reaction mixture was stirred at room temperature for 12 hrs. The reaction mixture was then quenched with ice water and extracted with DCM twice. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified via prep-HPLC to give 17. Synthesis of 3B

To a mixture of 3A (50 mg, 0.131 mmol) and dimethylamine hydrochloride (16 mg, 0.159mmol) in DCM (5 mL) were added HATU (74 mg, 0.159 mmol) and DIEA (51 mg, 0.393mmol) at 0 °C and the reaction mixture was stirred at room temperature for 12 hrs. The reaction mixture was then quenched with ice-water (20 mL) and extracted with DCM (10 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified via pre-HPLC to give 3B (20 mg, 37.3% yield) as a white solid. LC/MS (ESI) m/z: 415.9 (M+H)⁺.1H NMR (400 MHz, MeOD) δ 4.67 (dd, J = 7.1, 3.1 Hz, 1H), 3.87 (dddd, J = 29.9, 14.8, 9.2, 2.5 Hz, 5H), 3.63 (td, J = 11.0, 5.0 Hz, 1H), 3.21 (s, 3H), 3.01 (s, 3H), 2.55 (s, 3H). General procedure for Boc-deprotection (General Procedure 4)

Compound 18 (1.0 eq.) was dissolved in a mixture of TFA/DCM (1:4, V/V) at 0^oC and the resulting mixture was stirred at room temperature for 2 hrs. The reaction mixture was then concentrated under vacuum to afford the crude product which was purified by prep-HPLC to give the amine 19. Synthesis of 4B

4A (30 mg, 0.061 mmol) was dissolved in a mixture of DCM (3 mL) and TFA (1 mL) at 0^oC and the resulting mixture was stirred at room temperature for 2 hrs. The reaction mixture was then concentrated under vacuum, and the residue was purified by prep-HPLC to give 4B (15.3 mg, 63.9 % yield) as a white solid. LC/MS (ESI) m/z: 398 (M+H)⁺.1H NMR (400 MHz, CD₃OD) δ 3.72 (q, J = 12.5 Hz, 3H), 3.43 – 3.34 (m, 3H), 2.57 (s, 3H), 2.07 (ddd, J = 16.0, 12.3, 6.1 Hz, 5H), 2.02 – 1.91 (m, 3H). General procedure for acetylation (General Procedure 5)

To a mixture of 20 (1.0 eq.) and TEA (3.0 eq.) in DCM was added dropwise Ac₂O (1.0 eq.) at 0 ^oC and the resulting mixture was stirred at room temperature for 12 hrs. The reaction mixture was then concentrated under vacuum, and the residue purified via prep-HPLC to give 21. Synthesis of 4C

To a mixture of 4B (10 mg, 0.025 mmol) and TEA (8 mg, 0.075mmol) in DCM (3mL) was added dropwise Ac2O (3 mg, 0.025mmol) at 0 ^oC and the resulting mixture was stirred at room temperature for 12hrs. The reaction mixture was then concentrated under vacuum, and the residue was purified via prep-HPLC to give 4C (8 mg, 72.2% yield) as a white solid. LC/MS (ESI) m/z: 440 (M+H)⁺.¹H NMR (400 MHz, CD₃OD) δ 4.50 (d, J = 10.2 Hz, 1H), 3.83 (d, J = 12.9 Hz, 1H), 3.60 (ddd, J = 15.3, 10.5, 5.8 Hz, 2H), 3.37 – 3.33 (m, 2H), 3.07 (td, J = 13.3, 4.6 Hz, 1H), 2.53 (s, 3H), 2.40 – 2.30 (m, 1H), 2.25 – 2.11 (m, 1H), 2.09 (s, 3H), 2.01 – 1.91 (m, 1H), 1.90 – 1.78 (m, 3H), 1.63 (d, J = 14.1 Hz, 1H). The compounds in the table below were prepared from the appropriate starting materials described previously or commercially available using the above procedures. Table 1A

Step 1: Synthesis of 72A To a mixture of 11 (200 mg, 0.683 mmol) in THF (20 mL) was added NaH (41 mg, 1.025 mmol, 60 % of in mineral oil) at 0 ^oC under N2 atmosphere. After stirring for 30 mins at 0 ^oC, CH₃I (97 mg, 0.683 mmol) was added drop-wise and the resulting mixture was stirred at room temperature for 2 hours under nitrogen atmosphere. The mixture was then quenched with ice water (20 mL) and extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluted with PE: EtOAc=100:0 to 3:1) to give 72AB (42 mg, 20.1% yield) as a white solid. Step 2: Synthesis of 72B A mixture of 72A (42 mg, 0.137 mmol), piperidin-4-ol (28 mg, 0.274 mmol) and DIEA (53 mg, 0.411 mmol) in MeCN (10 mL) was stirred at 80 ^oC for 2 hrs. The mixture was then cooled to room temperature and concentrated under vacuum. The residue was diluted with water (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified via prep-HPLC to give 72B (18 mg, 35.2 % yield) as white solid.LC/MS (ESI) m/z: 373 (M+H)⁺.¹H NMR (400 MHz, DMSO) δ 4.84 (d, J = 3.9 Hz, 1H), 4.09 (s, 3H), 3.73 (s, 1H), 3.51 (s, 2H), 3.40 - 3.32 (m, 2H), 2.52 (s, 3H), 1.98 – 1.87 (m, 2H), 1.71 – 1.60 (m, 2H). Synthesis of 73B

Step 1: Synthesis of 73A To a mixture of 11 (24 mg, 0.204 mmol) and (S)-morpholin-2-ylmethanol (50 mg, 0.170 mmol) in CH3CN (8 mL) was added DIEA (44 mg, 0.340 mmol), and the resulting mixture was stirred at 80 °C for 2 hrs. The reaction mixture was then cooled down to room temperature and concentrated under vacuum. The residue was purified via prep-HPLC to give 73A (30 mg, 39.2 % yield) as a white solid. Step 2: Synthesis of 73B To a solution of 73A (25 mg, 0.067 mmol) in DCM (5 mL) were added TEA (21 mg, 0.200 mmol) and acetyl chloride (9 mg, 0.080 mmol) at 0 °C and the resulting mixture was stirred at 25 °C for 12 hrs. The mixture was then concentrated under vacuum and the residue was purified via prep-HPLC to give 73B (10 mg, 36.0 % yield) as a white solid. LC-MS: m/z 417 (M+H).¹H NMR (400 MHz, MeOD) δ 4.24 (dd, J = 11.6, 5.7 Hz, 1H), 4.16 – 3.99 (m, 3H), 3.96 – 3.82 (m, 2H), 3.76 – 3.62 (m, 2H), 3.42 (dd, J = 12.3, 10.1 Hz, 1H), 2.54 (s, 3H), 2.08 (s, 3H). Synthesis of 74B

Step 1: Synthesis of 11-F To a solution of 10 (50 mg, 0.193 mmol) in MeCN (5 mL) was added Selectflour (137 mg, 0.385 mmol), and the resulting mixture was stirred at room temperature for 16 hrs. The mixture was then concentrated under vacuum, and the residue was purified by prep-TLC (DCM: EA=10:1) to afford 11-F (20.0 mg, 42.8 % yield, 60.2% purity) as a white solid. LC/MS (ESI) m/z: 278 (M+H) ⁺. Step 2: Synthesis of 74B To a solution of 11-F (20 mg, 0.042 mmol, 60.2 % purity) in MeCN (5 mL) were added TEA (13 mg, 0.126 mmol) and (S)-morpholin-2-ylmethanol (8 mg, 0.063 mmol). The resulting mixture was stirred at 80 ^oC for 12 hrs. The mixture was then cooled down to room temperature and concentrated under vacuum. The crude product was purified by Prep-TLC (PE: EA=2:1) to afford compound 74B (5.9 mg, 19.3 % yield) as a white solid. LC/MS (ESI) m/z: 359 (M+H)⁺.¹H NMR (400 MHz, DMSO) δ 11.40 (s, 1H), 4.86 (s, 1H), 4.01 (d, J = 12.3 Hz, 1H), 3.83 – 3.63 (m, 4H), 3.60 – 3.44 (m, 3H), 3.39 – 3.35 (m, 1H), 2.48 (d, J = 1.3 Hz, 3H). Synthesis of 75C

Step 1: Synthesis of 75A To a mixture of 10 (170 mg, 0.578 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5- tetramethyl-1,3,2-dioxaborolane (122 mg, 0.578 mmol) and K2CO3 (160 mg, 1.156 mmol) in 1,4-dioxane/H2O (13 mL, 10:3) was added Pd(dppf)Cl2 (21 mg, 0.029 mmol) at room temperature under N₂ atmosphere. The resulting mixture was then stirred at 85 ^o C under N₂ atmosphere for 12 hrs. The mixture was then cooled down to room temperature, diluted with EtOAc (20 mL) and filtered. The filtrate was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by flash column chromatography (eluted with PE/EtOAc= 100: 0 to 3: 1) to give 75A (110 mg, 55.6 % yield) as a white solid. LC/MS (ESI) m/z: 308 (M+H)⁺. Step 2: Synthesis of 75B A mixture of 75A (80 mg, 0.234 mmol) and PtO₂ (25 mg) in methanol (10 mL) was stirred at room temperature under H2 atmosphere overnight. The mixture was then filtered and concentrated under vacuum to give crude product 75B (70 mg, 96.6 % yield) as a white solid which was used for next step without any further purification. LC/MS (ESI) m/z: 310 (M+H)⁺. Step 3: Synthesis of 75C To a solution of 75B (30 mg, 0.097 mmol) in DMF (5 mL) was added NCS (19 mg, 0.146 mmol) portion wise at 0 ^oC, and the resulting mixture was stirred at room temperature overnight. The mixture was then diluted with saturated NH₄Cl solution (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude residue was purified by flash column chromatography (eluted with PE/EtOAc= 100: 0 to 5: 1) to give 75C (6 mg, 18.0 % yield) as a white solid. LC/MS (ESI) m/z: 344 (M+H) ⁺.¹H NMR (400 MHz, DMSO-d6) δ 12.63 (s, 1H), 4.09 - 4.05 (m, 2H), 3.72 – 3.60 (m, 1H), 3.52 (t, J = 11.0 Hz, 2H), 2.57 (s, 3H), 2.45 – 2.29 (m, 2H), 1.71 (d, J = 10.7 Hz, 2H). Synthesis of 76E

Step 1: Synthesis of 76A To a mixture of 10 (200 mg, 0.772 mmol) and 1 (250 mg, 0.927mmol) in 1,4-dioxane/H2O (48 mL, 7:1) were added Pd(dppf)Cl₂ (58 mg, 0.080mmol) and Na₂CO₃(250 mg, 2.320 mmol) under nitrogen atmosphere, and the mixture was stirred at 100 ^oC for 12 hours. The mixture was then cooled down to room temperature, diluted with EtOAc (50 mL) and filtered. The filtrate was washed with brine (30 mL), dried over anhydrous Na₂SO₄ and concentrated under vacuum. The residue was purified by column chromatography on silica gel (eluted with PE/EtOAc=100:0 to 10:1) to give 76A (200 mg, 71.4% yield) as a gray solid. LC/MS (ESI) m/z: 364 (M+H)⁺. Step 2: Synthesis of 76B To a solution of 76A (160 mg, 0.402 mmol) in DCM (12 mL) was added drop-wise TFA (3 mL) at 0^oC, and the resulting mixture was stirred for 12 hours at room temperature. The mixture was then concentrated under vacuum to give crude 76B (120 mg, 84.3 % yield) as a white solid which was used for next step without any further purification.LC/MS (ESI) m/z: 320 (M+H)⁺. Step 3: Synthesis of 76C To a solution of 76B (120 mg, 0.376 mmol) in methanol (5 mL) was added NaBH₄ (13 mg, 0.376 mmol) at 0^oC, and the resulting mixture was stirred at room temperature for 1 hour. The mixture was then quenched with ice-water (20 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by flash column chromatography (eluted with PE/EtOAc= 100: 0 to 10: 1) to give 76C (100 mg, 82.8 % yield) as a white solid. LC/MS (ESI) m/z: 322 (M+H) ⁺. Step 4: Synthesis of 76D A mixture of 76C (50 mg, 0.156 mmol) and PtO2 (8 mg) in methanol (12 mL) was stirred at room temperature under H2 atmosphere overnight. The mixture was then filtered and concentrated under vacuum to give 76D (50 mg, 99.3 % yield) as a white solid which was used for next step without any further purification. LC/MS (ESI) m/z: 324 (M+H)⁺. Step 5: Synthesis of 76E To a solution of 76D (50 mg, 0.155 mmol) in DMF (6 mL) was added a solution of NCS (31 mg, 0.232 mmol) in DMF (2 mL) at 0 ^oC drop-wise, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was then diluted with water (20 mL) and extracted with EtOAc (15 mL x 2). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under vacuum. The crude residue was purified by flash column chromatography (eluted with DCM/MeOH= 100:0 to 5:1) to give 76E (1.4 mg, 2.5 % yield) as a white solid. LC/MS (ESI) m/z: 358 (M+H) ⁺.¹H NMR (400 MHz, CD3OD) δ 4.20 – 4.12 (m, 1H), 3.48 - 3.42 (m, 1H), 2.60 (s, 3H), 2.48 – 2.29 (m, 2H), 2.03 - 1.99 (m, 2H), 1.83 - 1.76 (m, 2H), 1.75 - 1.66 (m, 2H). Example 3. Additional Experimentals General procedure for debenzylation (General Procedure 6)

  Pd/C (10% w/w) was added to a solution of the corresponding amine (1.0 eq.) in i-PrOH (0.02M). The resulting mixture was stirred under H2 atmosphere at room temperature overnight. The mixture was then diluted with DCM, filtered and the filtrate was concentrated under reduced pressure to give the desired amine. Synthesis of 77C

Step 1 – Synthesis of 77B Pd/C (8 mg, 10% w/w) was added to a solution of 77A (75mg, 0.23mmol - prepared following the general procedure for amide coupling) in i-PrOH (10 mL) and the resulting mixture was stirred under H₂ atmosphere at room temperature overnight. The mixture was then diluted with DCM (20 mL), filtered and the filtrate was concentrated under reduced pressure to give JN-17072-2 (40 mg, 73.17 % yield) as a yellow oil, which was used for the next step without any further purification. Step 2 – Synthesis of 77C 77C was prepared using the general procedure for the SnAr. Azaindole 11 (20 mg, 0.068 mmol) was added to a mixture of 77B (40 mg, 0.10 mmol) and DIEA (39 mg, 0.30 mmol) in MeCN (5 mL), and the resulting mixture was stirred at 80 °C overnight under nitrogen atmosphere. After cooling the reaction mixture was concentrated and the residue was purified by pre-HPLC to afford 77C (13.1 mg, 38.46 % yield) as a white solid. LC/MS (ESI) m/z: 500 (M+H)⁺.¹H NMR (400 MHz, CD₃OD) δ 7.61 (s, 1H), 3.95 (d, J = 11.8 Hz, 1H), 3.83 (d, J = 12.3 Hz, 1H), 3.61-3.48 (m, 1H), 3.48-3.40 (m, 1H), 3.36 (d, J = 4.6 Hz, 4H), 3.27-3.05 (m, 3H), 2.52 (s, 3H), 2.01-1.88 (m, 1H), 1.85-1.69 (m, 1H), 1.69-1.46 (m, 2H), 1.16 (s, 6H), 1.07 (d, J = 4.4 Hz, 3H). General procedure for urea synthesis (General Procedure 7)

Step 1 Triphosgene (0.5 eq.) was added at - 50 °C under nitrogen atmosphere to a solution of the corresponding amine (1.0 eq.) in toluene (0.03 M), and the resulting mixture was stirred at 110 °C for 3 hours. After cooling to room temperature, the mixture was then concentrated under reduced pressure to give the crude corresponding isocyanate, which was used for the next step without any further purification. Step 2 A solution of the corresponding isocyanate (1 eq.) in anhydrous DCM (0.05M) was added dropwise at 0 °C to a mixture of the appropriate amine (2 eq.) and DIEA (4 eq.) in anhydrous DCM (0.1 M), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was then quenched with saturated aq. NaHCO3 solution and extracted with DCM twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated to dryness. The crude product was then purified by prep-HPLC.

78A was prepared using the general procedure for SnAr followed by the Boc deprotection also described above. Step 1 – Synthesis of 78B Triphosgene (17 mg, 0.056 mmol) was added at - 50 °C under nitrogen atmosphere to a solution of 78A (40 mg, 0.11 mmol) in toluene (3 mL), and the resulting mixture was stirred at 110 °C for 3 hours. After cooling to room temperature, the mixture was then concentrated under reduced pressure to give crude 78B (40 mg, 93.10 % yield) as a colorless oil, which was used in the next step without any further purification. Step 2 – Synthesis of 78C DIEA (54 mg, 0.42 mmol) was added to a mixture of methylamine hydrochloride (14 mg, 0.21 mmol) in anhydrous DCM (2 mL) and the mixture was stirred at 0 °C for 10 min. Then a solution of 78B (40 mg, 0.104 mmol) in anhydrous DCM (2 mL) was added dropwise at 0 °C to the above mixture, and the resulting mixture was stirred at room temperature for 2 hours. The mixture was then quenched with saturated aq. NaHCO₃ solution (10 mL) and extracted with DCM (10 mL) twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to dryness. The crude product was purified by prep- HPLC to give 78C (17 mg, 39.41 % yield) as a white solid. LC/MS (ESI) m/z: 415 (M+H)⁺. ¹H NMR (400 MHz, DMSO-d₆) 11.70 (s, 1H), 6.06 (d, J = 7.7 Hz, 1H), 5.61 (d, J = 4.7 Hz, 1H), 3.83 (d, J = 12.3 Hz, 2H), 3.67 (d, J = 7.3 Hz, 1H), 3.50 (t, J = 10.9 Hz, 2H), 2.56 (d, J = 4.6 Hz, 3H), 2.51 (s, 3H), 1.95 (d, J = 10.4 Hz, 2H), 1.62-1.54(m, 2H). General procedure for sulfonamide synthesis (General Procedure 8)

DIEA (22 mg, 0.17 mmol) and the appropriate sulfonyl chloride (1.2 eq.) were added to a solution of the corresponding amine (2 eq.) in DCM (0.03 M), and the resulting mixture was stirred at 0 °C for 1 hour. The mixture was then diluted with water (5 mL) and extracted with DCM (10 mL) twice. The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄ and concentrated to dryness. The crude product was purified by prep. HPLC Synthesis of 79B

DIEA (22 mg, 0.17 mmol) and 79A (12.94 mg, 0.101 mmol) were added to a solution of ethanesulfonyl chloride (30 mg, 0.084 mmol) in DCM (3 mL), and the resulting mixture was stirred at 0 °C for 1 hour. The mixture was then diluted with water (5 mL) and extracted with DCM (10 mL) twice. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and concentrated to dryness. The crude product was then purified by prep. HPLC to afford 79B (6.0 mg, 15.90 % yield) as a white solid. LC/MS (ESI) m/z: 450 (M+H)⁺.¹H NMR (400 MHz, DMSO-d₆) δ 11.71 (s, 1H), 7.31 (d, J = 7.5 Hz, 1H), 3.86 (d, J = 12.5 Hz, 2H), 3.55 – 3.47 (m, 2H), 3.46 – 3.38 (m, 1H), 3.12 - 3.02 (m, 2H), 2.48 (s, 3H), 2.04 – 1.94 (m, 2H), 1.77-1.69 (m, 2H), 1.23 (t, J = 7.3 Hz, 3H). Synthesis of 11-Br (Core Synthesis Procedure 2)

Step 1 – Synthesis of 11-Br NBS (206 mg, 1.16 mmol) was added to a solution of 10 (300 mg, 1.16 mmol) in MeCN (10 mL), and the resulting mixture was stirred at 50 °C for 1 hour. The mixture was then concentrated under reduced pressure to dryness, and the residue was dissolved in EtOAc (20 mL) and washed with NaHCO₃ (20 mL) and brine (20 mL). The organic layer was then dried over anhydrous Na2SO4 and concentrated to dryness. The crude product was purified by column chromatography on silica gel (eluting with PE: EtOAc = 100:0 to 1:1) to afford 11- Br (305 mg, 78.1 % yield) as brown solid. LC/MS (ESI) m/z: 338/340 (M+H)⁺. Step 2 - Synthesis of 80A DIEA (86 mg, 0.67 mmol) was added to a mixture of (3S,4S)-3-methylpiperidin-4-ol (16 mg, 0.13 mmol) and 11-Br (30 mg, 0.089 mmol) in MeCN (10 mL), and the resulting mixture was stirred at 80 °C overnight. The mixture was then filtered and the filtrate was concentrated to dryness. The residue was purified by pre-HPLC to give 80A (23 mg, 62.14% yield) as a white solid. LC/MS (ESI) m/z: 417 (M+H)⁺.¹H NMR (400 MHz, DMSO-d₆) δ 11.77 (s, 1H), 4.83 (d, J = 5.5 Hz, 1H), 3.89-3.72 (m, 2H), 3.51-3.44 (m, 1H), 3.28-3.21 (m, 1H), 3.13-3.08 (m, 1H), 2.50 (s, 3H), 2.20-1.98 (m, 1H), 1.79-1.58 (m, 2H), 0.99 (d, J = 6.6 Hz, 3H). Synthesis of 81D and 81E 81D and 81E were synthesized using the general procedure described above for amide coupling (General Procedure 3), Boc-deprotection (General Procedure 4) and SnAr (General Procedure 1), with the core prepared by Core Synthesis Procedure 1.

Step 1 HATU (164 mg, 0.43 mmol) and DIEA (112 mg, 0.86 mmol) were added to a solution of JN- 81A (70 mg, 0.29 mmol) in DMF (2 mL), followed by 1-(methoxymethyl)cyclopropan-1- amine (44 mg, 0.43 mmol), and the resulting mixture was stirred at room temperature for 18 hours. The mixture was then diluted with water (5 mL) and extracted with DCM (10 mL*3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure to dryness. The crude product was purified by column chromatography on silica gel (eluting with DCM: MeOH = 100:0 to 95:5) to afford 81B (70 mg, 74.54 % yield) as a yellow oil. LC/MS (ESI) m/z: 327 (M+H)⁺. Step 2 TFA (1 mL) was added dropwise at 0 °C to a solution of 81B (70 mg, 0.22 mmol) in DCM (5 mL), and the resulting mixture was stirred at room temperature for 2 hours. The mixture was then concentrated under reduced pressure to give crude 81C (38 mg, 78.23 % yield) as a yellow oil, which was used in the next step without any further purification. Step 3 Azaindole 11 (35 mg, 0.12 mmol) was added to a mixture of 81C (38 mg, 0.18 mmol) and DIEA (69 mg, 0.54 mmol) in MeCN (2 mL), and the resulting mixture was stirred at 80 °C under nitrogen atmosphere for 12 hours. The mixture was then concentrated under reduced pressure to dryness, and the crude product was purified by pre-HPLC to afford the enantiomeric mixture (48 mg, 83.19 % yield) as a white solid. The mixture was then further purified via SFC (Waters Thar 80 preparative SFC; ChiralCel OD, 250×4.6 mm 5µm; OD_MeOH_DEA_40) to obtain 81E (21.6 mg, 45.12% yield) as a white solid and 81D (22.3 mg, 46.45% yield) as a white solid. LC/MS (ESI) m/z: 484 (M+H)⁺.¹H NMR (400 MHz, CD3OD) δ 8.43 (s, 1H), 4.37 - 4.33 (m, 1H), 4.24 - 4.20(m, 1H), 4.05 (d, J = 9.2 Hz, 1H), 3.89 (d, J = 9.2 Hz, 1H), 3.49 (d, J =10.4 Hz, 1H), 3.38 (d, J = 10.4 Hz,1H), 3.35 (s, 3H), 2.77-2.74 (m, 1H), 2.48 (s, 3H), 1.28 (s, 3H), 1.16 (s, 3H), 0.78 (d, J =5.6 Hz, 4H). Synthesis of 11-F (Core Synthesis Procedure 3)

To a solution of 10 (50 mg, 0.193 mmol) in MeCN (5 mL) was added Selectflour (137 mg, 0.385 mmol), and the resulting mixture was stirred at room temperature for 16 hrs. The mixture was then concentrated under vacuum, and the residue was purified by prep-TLC (DCM: EA=10:1) to afford 11-F (20.0 mg, 42.8 % yield, 60.2% purity) as a white solid. LC/MS (ESI) m/z: 278 (M+H) ⁺. Synthesis of 11-HM (Core Synthesis Procedure 4)

Step 1 NaH (136 mg, 3.40 mmol) was added at 0 ^oC under nitrogen to a solution of 11 (500 mg, 1.70 mmol) in anhydrous THF (8 mL), and the resulting mixture was stirred at 0 ^oC for 30 minutes. Then SEMCl (340 mg, 2.04 mmol) was slowly added and the reaction mixture was stirred at 0 ^oC for 30 minutes. After completion, the reaction mixture was quenched with water (30 mL) and extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na₂SO₄, filtered and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (eluted with PE/EtOAc= 100: 0 to 10: 1) to afford XX-1 (470 mg, 65% yield) as a gray solid. LC/MS (ESI) m/z: 424 (M+H)⁺. Step 2 AIBN (165 mg, 1.00 mmol) was added at 0 ^oC to a solution of XX-1 (470 mg, 1.11 mmol) in CCl₄ (8 mL), followed by the addition of NBS (296 mg, 1.37 mmol) at 0 ^oC. The resulting mixture was heated to 80 ^oC and stirred for 6 hours under N2. The mixture was then filtered and the filtrate was concentrated to give XX-2 (520.mg, contained some de-SEM adduct) as a yellow solid which was used in the next step without any further purification. LC/MS (ESI) m/z: 502,504 (M+H)⁺. Step 3 Cu₂O (635 mg, 4.44 mmol) was added at room temperature to a solution of XX-2 (520 mg, 1.03 mmol) in DMSO (15 mL) and H2O (3 mL), and the reaction mixture was stirred overnight at room temperature. The mixture was then diluted with water (10 mL) and extracted with EtOAc (20 mL). The organic layer was then washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash column chromatography on silica gel (eluted with DCM/MeOH= 100: 0 to 10: 1) to give 11-HM (85 mg, 26% yield) as a yellow solid. LC/MS (ESI) m/z: 310 (M+H)⁺. Synthesis of 11-CN (Core Synthesis Procedure 5)

Step 1 HMTA (271.0 mg, 1.93 mmol) was added to a solution of 10 (500.0 mg, 1.93 mmol) in AcOH (10 mL) and H2O (5 mL), and the resulting mixture was stirred at 80 ^oC overnight under N₂ atmosphere. The mixture was then concentrated under reduced pressure to afford YY-1 (512.0 mg, 92% yield) as a yellow solid, which was used in the next step without any further purification. LC/MS (ESI) m/z: 288 (M+H)⁺. Step 2 NH2OH^.HCl (29.0 mg, 0.42 mmol) and TEA (0.29 mL, 2.08 mmol) were added to a solution of YY-1 (100.0 mg, 0.35 mmol) in THF (10 mL) and DMF (2 mL), and the resulting mixture was stirred at 80 ^oC overnight under N₂ atmosphere. The mixture was then concentrated under reduced pressure to give YY-2 (126 mg, crude) as a yellow solid, which was used in the next step without any further purification. LC/MS (ESI) m/z: 303 (M+H)⁺. Step 3 A solution of YY-2 (126.0 mg) in Ac2O (10 mL) was stirred at 130 ^oC for 3hours. The reaction mixture was then poured into ice-water (30 mL) and the resulting suspension was filtered and the filter cake was washed with H₂O (5 mL x 5). The filter cake was then dried under vacuum to give 11-CN (56.8 mg, 57% yield in two steps) as a yellow solid. LC/MS (ESI) m/z: 285 (M+H)⁺. Example 4. Additional Exemplary Compounds The compounds exemplified in the following table were prepared using one or more of General Procedures 1-8, starting from a core prepared by one of Core Synthesis Procedures 1-5.

238 239 239

277 278 278

278 278 279

INCORPORATION BY REFERENCE All of the U.S. patents and U.S. patent application publications cited herein are hereby incorporated by reference. EQUIVALENTS Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims

We claim: 1. A compound having the structure of Formula (I):

wherein X₁ is absent or is selected from –O–, –SO₂–, –C(O)–, –N(X₂)–, and –C(X₃)₂–; X₂ is selected from –H, alkyl, and –SO₂–X₂''; X2'' is alkyl; each X₃ is independently selected from –H and alkyl; R₁ is selected from an optionally substituted aminoalkyl, optionally substituted alkylaminoalkyl, optionally substituted alkoxyalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and R2 is selected from –H, halogen (e.g., chloro), nitrile, and alkyl; R2' is selected from an alkyl, hydroxyalkyl, alkenyl, alkynyl, cycloalkyl, and aryl; R₂'' is selected from H, alkyl, and acyl; provided that when X₁ is –O– or –N(X₂)– and R₁ is a nitrogen-containing heterocyclyl, then the –O– or –N(X2)– is not directly bonded to a nitrogen on the heterocyclyl; provided that when X₁ is absent, R₂ is –Cl, R₂' is –CH₃, and R₂'' is –H, then R₁ is not

or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein X₁ is absent or is selected from –O–, –SO₂–, –C(O)–, –N(X₂)–, and –C(X₃)₂–; X₂ is selected from –H, alkyl, and –SO₂–X₂''; X2'' is alkyl; each X₃ is independently selected from –H and alkyl; R₁ is selected from an optionally substituted aminoalkyl, optionally substituted alkylaminoalkyl, optionally substituted alkoxyalkyl, optionally substituted cycloalkyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and R2 is selected from –H, halogen (e.g., chloro), and alkyl; R2' is selected from an alkyl, alkenyl, alkynyl, cycloalkyl, and aryl; R₂'' is selected from H, alkyl, and acyl; provided that when X₁ is –O– or –N(X₂)– and R₁ is a nitrogen-containing heterocyclyl, then the –O– or –N(X2)– is not directly bonded to a nitrogen on the heterocyclyl; provided that when X₁ is absent, R₂ is –Cl, R₂' is –CH₃, and R₂'' is –H, then R₁ is not

or a pharmaceutically acceptable salt thereof. 3. The compound of claim 1 or 2, wherein X1 is absent, or is selected from –SO2–, – C(O)–, and –C(X3)2–. 4. The compound of claim 3, wherein X1 is absent. 5. The compound of claim 3 or 4, wherein R₁ is an unsubstituted heterocyclyl. 6. The compound of claim 5, wherein R1 is selected from an unsubstituted azetidinyl, unsubstituted pyrrolidinyl, unsubstituted piperazinyl, unsubstituted piperazinonyl, unsubstituted morpholinyl, unsubstituted dioxothiomorpholinyl, unsubstituted tetrahydrofuranyl, and unsubstituted tetrahydropyranyl.

7. The compound of claim 6, wherein R1 is selected from

8. The compound of claim 3 or 4, wherein R₁ is a substituted heterocyclyl. 9. The compound of claim 8, wherein R1 is –NR3R4; and R₃ and R₄ combine to form a substituted azetidinyl, substituted pyrrolidinyl, substituted piperazinyl, substituted piperazinonyl, substituted morpholinyl, or substituted dioxothiomorpholinyl. 10. The compound of claim 9, wherein

Ra, Rb, Ri and Rj are independently selected from -H, halogen, -CN, -CF3, and alkyl; Rc, Rd, Re, Rf, Rg and Rh are independently selected from -H, halogen, -CN, -CF3, - OH, -CO₂H, -NH₂, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -OR₅, -C(O)NR₅R₆, -NR₅C(O)R₆, C(O)R₇, - NR5C(O)NR5R6, -SO2R7, -NHSO2R7, -SO2NR5R6, alkyl-C(O)NR5R6, alkyl-NR5C(O)R6, alkyl-C(O)R₇, alkyl-NR₅C(O)NR₅R_6, alkyl-SO₂R₇, alkyl-SO₂NR₅R₆, and -NHC(O)NR₇, or R_c taken together with R_d and the carbon atom to which they are bonded form an unsubstituted or substituted C3-C6 cycloalkyl or C4-C6 heterocyclyl, or Re taken together with Rf and the carbon atom to which they are bonded form an unsubstituted or substituted C₃-C₆ cycloalkyl or C₄-C₆ heterocyclyl, or Rc taken together with Re and the carbon atoms to which they are bonded form an unsubstituted or substituted C3-C6 cycloalkyl, or R_d taken together with R_f and the carbon atoms to which they are bonded form an unsubstituted or substituted C₃-C₆ cycloalkyl, or Rc taken together with Ri form a methylene bridge, or Rd taken together with Rj form a methylene bridge, or R_c taken together with R_g form a methylene bridge, or R_d taken together with R_h form a methylene bridge; each occurrence of R₅ and R₆ is independently selected from -H, -CF3, alkyl, aminoalkyl, hydroxyalkyl, methoxyalkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl, or provided that in the case of -C(O)NR₅R₆, -NR₅C(O)NR₅R_6, alkyl-C(O)NR₅R₆, and alkyl-NR5C(O)NR5R6 the R5 taken together with R6 and the nitrogen atom to which they are bonded may form an unsubstituted or substituted C4-C6 heterocyclyl; and each occurrence of R₇ is selected from alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl; provided that at least one of R_a, R_b, R_c, R_d, R_e, R_f, R_g, R_h, R_i, and R_j is not -H. 11. The compound of claim

Ra, Rb, Ri and Rj are independently selected from -H, halogen, -CN, -CF3, and alkyl; Rc, Rd, Re, Rf, Rg and Rh are independently selected from -H, halogen, -CN, -CF3, - OH, -CO₂H, -NH₂, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -C(O)NR₅R₆, -NR₅C(O)R₆, C(O)R₇, - NR5C(O)NR5R6, -SO2R7, -SO2NR5R6, alkyl-C(O)NR5R6, alkyl-NR5C(O)R6, alkyl-C(O)R7, alkyl-NR5C(O)NR5R6, alkyl-SO2R7, and alkyl-SO2NR5R6, or R_c taken together with R_d and the carbon atom to which they are bonded form an unsubstituted or substituted C3-C6 cycloalkyl or C4-C6 heterocyclyl, or Re taken together with Rf and the carbon atom to which they are bonded form an unsubstituted or substituted C3-C6 cycloalkyl or C₄-C₆ heterocyclyl; each occurrence of R5 and R6 is independently selected from -H, alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl, or provided that in the case of -C(O)NR5R6, -NR5C(O)NR5R6, alkyl-C(O)NR₅R₆, and alkyl-NR₅C(O)NR₅R₆ the R₅ taken together with R₆ and the nitrogen atom to which they are bonded may form an unsubstituted or substituted C₄-C₆ heterocyclyl; and each occurrence of R₇ is selected from alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl; provided that at least one of R_a, R_b, R_c, R_d, R_e, R_f, R_g, R_h, R_i, and R_j is not -H.

12. The compound of claim 10 or 11, wherein R_a, R_b, R_i and R_j are independently selected from -H, halogen, -CN, -CF₃, and alkyl; and Rc, Rd, Re, Rf, Rg and Rh are independently selected from -H, halogen, -CN, -CF3, -OH, - CO₂H, -NH₂, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, -C(O)NR5R6, -NR5C(O)R6, C(O)R7, alkyl-C(O)NR5R6, alkyl- NR5C(O)R6, and alkyl-C(O)R7. 13. The compound of claim 10 or 11, wherein Ra, Rb, Ri and Rj are each –H; and R_c, R_d, R_e, R_f, R_g and R_h are independently selected from -H, halogen, -OH, -CO₂H, - alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkyl, -C(O)NR₅R₆, -NR₅C(O)R₆, C(O)R7, alkyl-C(O)NR5R6, and alkyl-NR5C(O)R6. 14. The compound of claim 13, wherein Ra, Rb, Ri and Rj are each –H; and Rc, Rd, Re, Rf, Rg and Rh are independently selected from -H, -F, -OH, -CH2OH, CH₂OCH₃, -CH₂NH₂, -CO₂H, -CH₃, -CH(CH₃)₂, -CH₂CH(CH₃)₂, -C(O)NH₂, - C(O)N(H)(CH3), -C(O)N(CH3)2, alkyl-C(O)N(H)(CH3), -CH2-C(O)N(CH3)2, - N(H)C(O)CH3, -N(CH3)C(O)CH3, -CH2-N(H)C(O)CH3, -CH2-N(CH3)C(O)CH3, -CH(CH2)2, and

15. The compound of claim 10, wherein R_a, R_b, R_i and R_j are each –H; and Rc, Rd, Re, Rf, Rg and Rh are independently selected from -H, -F, -OH, -CH3, -CF3, - OCH3, -OCF3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2OCH3,-CH2CH2CH3, -CH2F, - NHSO₂CH₃, -NHSO₂CH₂CH₃, -NHC(O)NHCH₃, -NHC(O)CH₃, -C(O)NH₂, -C(O)NHCH₃, - C(O)NHCH₂CH₃, -C(O)NHCH(CH₃)₂, -C(O)NHCH₂CH₂OCH₃, -CH₂NHC(O)CH₃, - CH2NHC(O)CH2CH3, -CH2NHC(O)CH2NH2, -CH2NHC(O)C(CH3)2CH3, - CH₂NHC(O)C(CH₃)₂NH₂, -CH₂NHC(O)C(CH₃)₂CH₂OH, -CH₂NHC(O)C(CH₃)₂CH₂OCH₃, - CH₂NHC(O)C(CH₃)₂OCH₃, -CH₂C(O)NH₂, -CH₂C(O)NHCH₃, and -CH₂C(O)N(CH₃)₂.

16. The compound of claim 10, wherein R_a, R_b, R_i and R_j are each –H; and R_c, R_d, R_e, R_f, R_g and R_h are independently selected from -H, -F, -OH, -CH₃, -CF₃, -OCH₃, - OCF3, -CH2CH3, -CH2OH, -CH2CH2OH, -CH2OCH3,-CH2CH2CH3, -CH2F, -O-cyclopropyl, -C(O)NH-cyclopropyl, -C(O)NH-oxatenyl, -C(O)NH-tetrahydofuranyl, -C(O)NH- tetrahydopyranyl, -CH2NHC(O)-cyclopropyl,

. 17. The compound of any one of claims 10-16, wherein R₁ is:

. 18. The compound of claim 17, wherein R1 is selected from:

. 19. The compound of claim 18, where R1 is selected from:

20. The compound of claim 18, where R1 is selected from:

N , ^{H2N O} _{, , , , , ,} , , , , , , , O N O N N N , _H ^N OH , _H OH , , , , , ^OH _, N N N N HN F F F ^O , OH , OH , OH , _{, , , ,} N HN , , , ^{MeO O} _{, ,}

21. The compound of claim 17, wherein R1 is selected from:

. 22. The compound of claim 21, wherein

23. The compound of any one of claims 10-16, wherein R₁ is selected from:

24. The compound of claim 23, wherein R1 is selected from:

25. The compound of any one of claims 10-16, wherein R1 is selected from:

26. The compound of claim 25, wherein R₁ is selected from:

27. The compound of claim 25, wherein R₁ is selected from:

28. The compound of claim 10 or 11, wherein R_a, R_b, R_e, R_f, R_g, R_h, R_i, and R_j are independently selected from -H, halogen, -CN, - CF3, and alkyl; and Rc taken together with Rd and the carbon atom to which they are bonded form an unsubstituted or substituted C₃-C₆ cycloalkyl or C₄-C₆ heterocyclyl.

29. The compound of claim 28, wherein Rc taken together with Rd and the carbon atom to which they are bonded form an unsubstituted or substituted azetidinyl, pyrrolidinyl, piperazinyl, oxatenyl, tetrahydrofuranyl, tetrahydropyranyl, or sulfolanyl. 30. The compound of claim 29, wherein each substituent is independently selected from halogen, -OH, -CN, -CF₃, alkyl, and acetyl. 31. The compound of claim 10 or 11, wherein R_a, R_b, R_c, R_d, R_g, R_h, R_i, and R_j are independently selected from -H, halogen, -CN, - CF₃, and alkyl; and Re taken together with Rf and the carbon atom to which they are bonded form an unsubstituted or substituted C₃-C₆ cycloalkyl or C₄-C₆ heterocyclyl. 32. The compound of claim 31, wherein Re taken together with Rf and the carbon atom to which they are bonded form an unsubstituted or substituted azetidinyl, pyrrolidinyl, piperazinyl, oxatenyl, tetrahydrofuranyl, tetrahydropyranyl, and sulfolanyl. 33. The compound of claim 32, wherein each substituent is independently selected from halogen, -OH, -CN, -CF₃, alkyl, and acetyl. 34. The compound of claim 28 or 31, wherein R1 is selected from

,

35. The compound of claim 10, wherein R_a, R_b, R_g, R_h, R_i, and R_j are each -H; one of Re and Rf is -H and the other of Re and Rf is -OH; Rc taken together with Rd and the carbon atom to which they are bonded form an unsubstituted or substituted C₃-C₆ cycloalkyl or C₄-C₆ heterocyclyl. 36. The compound of claim 10, wherein R_a, R_b, R_d, R_g, R_h, R_i, and R_j are each -H; R_f is -OH; and Rc taken together with Re and the carbon atoms to which they are bonded form an unsubstituted or substituted C3-C6 cycloalkyl. 37. The compound of claim 10, wherein Ra, Rb, Rc, Rg, Rh, Ri, and Rj are each -H; R_e is -OH; and Rd taken together with Rf and the carbon atoms to which they are bonded form an unsubstituted or substituted C3-C6 cycloalkyl. 38. The compound of claim 10, wherein Ra, Rb, Rd, Rg, Rh, and Rj are each -H; one of Re and Rf is -H and the other of Re and Rf is -OH; and R_c taken together with R_i form a methylene bridge. 39. The compound of claim 10, wherein R_a, R_b, R_c, R_g, R_h, and R_i are each -H; one of Re and Rf is -H and the other of Re and Rf is -OH; and Rd taken together with Rj form a methylene bridge.

40. The compound of claim 10, wherein R_a, R_b, R_c, R_g, R_h, and R_i are each -H; one of Re and Rf is -H and the other of Re and Rf is -OH; and Rj taken together with Rd form a methylene bridge. 41. The compound of claim 10, wherein Ra, Rb, Rd, Rf, Rh, and Ri are each -H; one of R_e and R_f is -H and the other of R_e and R_f is -OH; and R_c taken together with R_g form a methylene bridge. 42. The compound of claim 10, wherein R_a, R_b, R_c, R_g, R_h, and R_i are each -H; one of Re and Rf is -H and the other of Re and Rf is -OH; and Rd taken together with Rh form a methylene bridge.

43. The compound of any one of claims 35-42, wherein R₁ is selected from .

44. The compound of claim 9, wherein

R_a, R_b, R_i and R_j are independently selected from -H, halogen, -CN, -CF₃, and alkyl; Rc, Rd, Rg and Rh are independently selected from -H, halogen, -CN, -CF3, -CO2H, - alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -C(O)NR₅R₆, -NR₅C(O)R₆, C(O)R₇, -NR₅C(O)NR₅R₆, -SO₂R₇, - SO2N R5R6, alkyl-C(O)NR5R6, alkyl-NR5C(O)R6, alkyl-C(O)R7, alkyl-NR5C(O)NR5R6, alkyl-SO2R7, and alkyl-SO2N R5R6, or Rc taken together with Rd and the carbon atom to which they are bonded form an unsubstituted or substituted C₃-C₆ cycloalkyl or C₄-C₆ heterocyclyl; each occurrence of R₅ and R₆ is independently selected from -H, alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl, or provided that in the case of -C(O)NR5R6, -NR5C(O)NR5R6, alkyl-C(O)NR5R6, and alkyl-NR5C(O)NR5R6 the R5 taken together with R6 and the nitrogen atom to which they are bonded may form an unsubstituted or substituted C₄-C₆ heterocyclyl; and each occurrence of R7 is selected from alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl; provided that at least one of R_a, R_b, R_c, R_d, R_g, R_h, R_i, and R_j is not -H. 45. The compound of claim 44, wherein R_a, R_b, R_i and R_j are independently selected from -H, halogen, -CN, -CF₃, and alkyl; Rc, Rd, Rg and Rh are independently selected from -H, halogen, -CN, -CF3, -CO2H, - alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, -C(O)NR₅R₆, -NR₅C(O)R₆, C(O)R₇, alkyl-C(O)NR₅R₆, alkyl-NR₅C(O)R₆, and alkyl-C(O)R7. 46. The compound of claim 44 or 45, wherein Ra, Rb, Ri and Rj are each –H; and Rc, Rd, Rg and Rh are independently selected from -H, halogen, -CO2H, - alkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, cycloalkyl, -C(O)NR₅R₆, -NR₅C(O)R₆, C(O)R₇, alkyl-C(O)NR₅R₆, and alkyl-NR₅C(O)R₆. 47. The compound of claim 46, wherein R_a, R_b, R_i and R_j are each –H; and Rc, Rd, Rg and Rh are independently selected from -H, -F, -CH2OH, -CH2OCH3, - CH2NH2, -CO2H, -CH3, -CH(CH3)2, -CH2CH(CH3)2, -C(O)NH2, -C(O)N(H)(CH3), - C(O)N(CH₃)₂, alkyl-C(O)N(H)(CH₃), -CH₂-C(O)N(CH₃)₂, -N(H)C(O)CH₃, - N(CH3)C(O)CH3, -CH2-N(H)C(O)CH3, -CH2-N(CH3)C(O)CH3, -CH(CH2)2, and

48. The compound of any one of claims 44-47, wherein

49. The compound of claim 48, wherein R1 is selected from:

50. The compound of claim 49, wherein R1 is selected from:

51. The compound of claim 44, wherein Ra, Rb, Rg, Rh, Ri, and Rj are independently selected from -H, halogen, -CN, -CF3, and alkyl; and R_c taken together with R_d and the carbon atom to which they are bonded form an unsubstituted or substituted C₃-C₆ cycloalkyl or C₄-C₆ heterocyclyl. 52. The compound of claim 51, wherein R_c taken together with R_d and the carbon atom to which they are bonded form an unsubstituted or substituted azetidinyl, pyrrolidinyl, piperazinyl, oxatenyl, tetrahydrofuranyl, tetrahydropyranyl, or sulfolanyl.

53. The compound of claim 52, wherein each substituent is independently selected from halogen, -OH, -CN, -CF₃, alkyl, and acetyl. 54. The compound of claim 51, wherein R₁ is selected from:

55. The compound of claim 9, wherein R₁ is

Ra, Rb, Ri and Rj are independently selected from -H, halogen, -CN, -CF3, and alkyl; Rc, Rd, Rg and Rh are independently selected from -H, halogen, -CN, -CF3, -CO2H, - alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -C(O)NR₅R₆, -NR₅C(O)R₆, C(O)R₇, -NR₅C(O)NR₅R₆, -SO₂R₇, - SO2NR5R6, alkyl-C(O)NR5R6, alkyl-NR5C(O)R6, alkyl-C(O)R7, alkyl-NR5C(O)NR5R6, alkyl- SO₂R₇, and alkyl-SO₂NR₅R₆; R_k is selected from –H, alkyl, and cycloalkyl; each occurrence of R5 and R6 is independently selected from -H, alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl, or provided that in the case of -C(O)NR5R6, -NR5C(O)NR5R6, alkyl-C(O)NR₅R₆, and alkyl-NR₅C(O)NR₅R₆ the R₅ taken together with R₆ and the nitrogen atom to which they are bonded may form an unsubstituted or substituted C4-C6 heterocyclyl; and each occurrence of R₇ is selected from alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl; provided that at least one of Ra, Rb, Rc, Rd, Rg, Rh, Ri, Rj, and Rk is not -H. 56. The compound of claim 55, wherein Ra, Rb, Rc, Rd, Rg, Rh, Ri, and Rj are each -H; and Rk is selected from alkyl and cycloalkyl.

57. The compound of claim 56, wherein R₁ is selected from:

. 58. The compound of claim 9, wherein

R_k is selected from alkyl and cycloalkyl. 59. The compound of claim 58, wherein R1 is:

. 60. The compound of claim 9, wherein

Ra, Rb, Ri, and Rj are independently selected from -H, halogen, -CN, -CF3, and alkyl; R_c, R_d, R_g, and R_h are independently selected from -H, halogen, -CN, -CF₃, -OH, - CO₂H, -NH₂, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -OR5, -C(O)NR5R6, -NR5C(O)R6, C(O)R7, - NR5C(O)NR5R6, -SO2R7, -NHSO2R7, -SO2NR5R6, alkyl-C(O)NR5R6, alkyl-NR5C(O)R6, alkyl-C(O)R₇, alkyl-NR₅C(O)NR₅R_6, alkyl-SO₂R₇, alkyl-SO₂NR₅R₆, and -NHC(O)NR₇, or Rc taken together with Rd and the carbon atom to which they are bonded form an unsubstituted or substituted C3-C6 cycloalkyl or C4-C6 heterocyclyl, or R_c taken together with R_g or R_d taken together with R_h, and the carbon atoms to which they are bonded form an unsubstituted or substituted C₃-C₆ cycloalkyl or C₄-C₆ heterocyclyl; each occurrence of R5 and R6 is independently selected from -H, -CF3, alkyl, aminoalkyl, hydroxyalkyl, methoxyalkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl, or provided that in the case of -C(O)NR5R6, -NR5C(O)NR5R6, alkyl-C(O)NR5R6, and alkyl-NR5C(O)NR5R6 the R5 taken together with R6 and the nitrogen atom to which they are bonded may form an unsubstituted or substituted C₄-C₆ heterocyclyl; and each occurrence of R7 is selected from alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl; provided that at least one of R_a, R_b, R_c, R_d, R_g, R_h, R_i, and R_j is not -H. 61. The compound of claim 9, wherein

R_a, R_b, R_i, and R_j are independently selected from -H, halogen, -CN, -CF₃, and alkyl; R_c, R_d, R_g, and R_h are independently selected from -H, halogen, -CN, -CF₃, -OH, - CO2H, -NH2, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -C(O)NR5R6, -NR5C(O)R6, C(O)R7, - NR₅C(O)NR₅R₆, -SO₂R₇, -SO₂NR₅R₆, alkyl-C(O)NR₅R₆, alkyl-NR₅C(O)R₆, alkyl-C(O)R₇, alkyl-NR5C(O)NR5R6, alkyl-SO2R7, and alkyl-SO2NR5R6, or Rc taken together with Rd and the carbon atom to which they are bonded form an unsubstituted or substituted C₃-C₆ cycloalkyl or C₄-C₆ heterocyclyl; each occurrence of R5 and R6 is independently selected from -H, alkyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl, or provided that in the case of -C(O)NR₅R₆, -NR₅C(O)NR₅R_6, alkyl-C(O)NR₅R₆, and alkyl-NR₅C(O)NR₅R₆ the R₅ taken together with R₆ and the nitrogen atom to which they are bonded may form an unsubstituted or substituted C4-C6 heterocyclyl; and each occurrence of R7 is selected from alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl; provided that at least one of Ra, Rb, Rc, Rd, Rg, Rh, Ri, and Rj is not -H. 62. The compound of claim 60 or 61, wherein Ra, Rb, Ri and Rj are independently selected from -H, halogen, -CN, -CF3, and alkyl; and Rc, Rd, Rg and Rh are independently selected from -H, halogen, -CN, -CF3, -OH, - CO₂H, -NH₂, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, -C(O)NR₅R₆, -NR₅C(O)R₆, C(O)R₇, alkyl-C(O)NR₅R₆, alkyl- NR5C(O)R6, and alkyl-C(O)R7. 63. The compound of any one of claims 60-62, wherein Rc, Rd, Rg and Rh are independently selected from –H, alkyl, hydroxyalkyl, aminoalkyl, and alkoxyalkyl. 64. The compound of claim 60 or 61, wherein R1 has the structure:

. 65. The compound of claim 64, wherein R1 is selected from:

. 66. The compound of claim 64, wherein R1 is selected from:

67. The compound of claim 65 or 66, wherein R₁ is selected from:

68. The compound of claim 60 or 61, wherein Ra, Rb, Rg, Rh, Ri, and Rj are each -H; and Rc taken together with Rd and the carbon atom to which they are bonded form an unsubstituted or substituted C₃-C₆ cycloalkyl or C₄-C₆ heterocyclyl. 69. The compound of claim 68, wherein Rc taken together with Rd and the carbon atom to which they are bonded form an unsubstituted or substituted azetidinyl, pyrrolidinyl, piperazinyl, oxatenyl, tetrahydrofuranyl, tetrahydropyranyl, or sulfolanyl. 70. The compound of claim 69, wherein each substituent is independently selected from halogen, -OH, -CN, -CF₃, alkyl, and acetyl. 71. The compound of claim 65 or 69, wherein R₁ is selected from:

,

72. The compound of claim 60, wherein R_d and R_h are each -H; and R_c taken together with R_g and the carbon atom to which they are bonded form a substituted C3-C6 cycloalkyl. 73. The compound of claim 60, wherein Rc and Rg are each -H; and R_d taken together with R_h and the carbon atom to which they are bonded form a substituted C₃-C₆ cycloalkyl. 74. The compound of claim 72 or 73, wherein substituted C3-C6 cycloalkyl is substituted with halo or hydroxyl.

75. The compound of claim 72 or 73, wherein R1 is selected from:

R_a, R_b, R_e and R_f are independently selected from -H, halogen, -CN, -CF₃, and alkyl; R_c and R_d are independently selected from -H, halogen, -CN, -CF₃, -OH, -CO₂H, - NH2, alkyl, haloalkyl, hydroxyalkyl, methoxyalkyl, aminoalkyl, alkylaminoalkyl, alkoxyalkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl, -C(O)NR₅R₆, -NR₅C(O)R₆, C(O)R₇, - NR₅C(O)NR₅R₆, -SO₂R₇, -SO₂NR₅R₆, alkyl-C(O)NR₅R₆, alkyl-NR₅C(O)R₆, alkyl-C(O)R₇, alkyl-NR5C(O)NR5R6, alkyl-SO2R7, and alkyl-SO2NR5R6, or Rc taken together with Rd and the carbon atom to which they are bonded form an unsubstituted or substituted C₃-C₆ cycloalkyl or C₄-C₆ heterocyclyl; each occurrence of R5 and R6 is independently selected from -H, alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl, or provided that in the case of -C(O)NR5R6, -NR5C(O)NR5R6, alkyl-C(O)NR₅R₆, and alkyl-NR₅C(O)NR₅R₆ the R₅ taken together with R₆ and the nitrogen atom to which they are bonded may form an unsubstituted or substituted C₄-C₆ heterocyclyl; and each occurrence of R₇ is selected from alkyl, heteroalkyl, haloalkyl, aryl, and heteroaryl, provided that one of Ra, Rb, Rc, Rd, Re and Rf is not –H. 77. The compound of claim 76, wherein Ra, Rb, Re, and Rf are each –H; and Rc and Rd are independently selected from –H, alkyl, hydroxyalkyl, aminoalkyl, and alkoxyalkyl. 78. The compound of claim 76, wherein Ra, Rb, Re, and Rf are each -H; and R_c taken together with R_d and the carbon atom to which they are bonded form an unsubstituted or substituted C3-C6 cycloalkyl or C4-C6 heterocyclyl. 79. The compound of claim 78, wherein R_c taken together with R_d and the carbon atom to which they are bonded form an unsubstituted or substituted azetidinyl, pyrrolidinyl, piperazinyl, oxatenyl, tetrahydrofuranyl, tetrahydropyranyl, or sulfolanyl. 80. The compound of claim 79, wherein each substituent is independently selected from halogen, -OH, -CN, -CF3, alkyl, and acetyl. 81. The compound of claim 76, wherein R1 is selected from:

. 82. The compound of claim 76, wherein R1 is selected from:

83. The compound of any one of claims 1-4, wherein R1 is an unsubstituted heteroaryl. 84. The compound of claim 83, wherein R₁ is selected from unsubstituted oxazolyl, unsubstitutedpyrazolyl, and unsubstituted triazolyl. 85. The compound of claim 84, wherein R₁ is selected from

86. The compound of claim 1 or 2, wherein X1 is selected from –O–, –SO2–, –C(O)–, – N(X₂)–, and –C(X₃)₂–. 87. The compound of claim 1 or 2, wherein X1 is absent. 88. The compound of claim 86 or 87, wherein R1 is an unsubstituted cycloalkyl. 89. The compound of claim 88, wherein R₁ is

. 90. The compound of claim 86 or 87, wherein R1 is a substituted cycloalkyl. 91. The compound of claim 90, wherein each substituent is independently selected from halogen, -OH, -CN, -CF3, and alkyl. 92. The compound of claim 91, wherein

93. The compound of claim 91, wherein R₁ is selected from

94. The compound of claim 86, wherein X1 is –N(X2)–, wherein X2 is –H or –CH3. 95. The compound of claim 86 or 94, wherein R₁ is selected from an optionally substituted alkylaminoalkyl, alkoxyalkyl, and cycloalkyl. 96. The compound of claim 95, wherein each substituent is independently selected from halogen, -OH, -CN, -CF3, and alkyl. 97. The compound of claim 95, wherein R₁ is selected from –NH-(alkyl)-N(CH₃)₂, – N(CH₃)-(alkyl)-N(CH₃)₂, –NH-(alkyl)-OCH₃, and –N(CH₃)-(alkyl)-OCH₃. 98. The compound of claim 95, wherein

99. The compound of any one of claims 1-98, wherein R2 is selected from –CH3, –Cl, and –F. 100. The compound of any one of claims 1-98, wherein R2 is selected from –Br and -CN. 101. The compound of any one of claims 1-100, wherein R₂' is –CH₃. 102. The compound of any one of claims 1-100, wherein R2' is –CH2-OH. 103. The compound of any one of claims 1-102, wherein R₂'' is –H, –CH₃, or –C(O)CH₃. 104. The compound of any one of claims 1-102, wherein R2'' is –H. 105. The compound of claim 1 having the structure of any one of the compounds recited in Table 1. 106. The compound of claim 1 having the structure of any one of the compounds recited in Table 2.

107. A pharmaceutical composition, comprising a compound of any one of claims 1-106; and a pharmaceutical acceptable excipient. 108. A method of treating or preventing chronic kidney disease, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-106. 109. The method of claim 108, wherein the chronic kidney disease is selected from Alport syndrome, C3-glomerulopathy, tubulointerstitial nephritis, diabetic nephropathy, idiopathic nephrosclerosis, hemolytic uremic syndrome, focal segmental glomerulosclerosis, ApoL1 nephropathy, hypertensive nephrosclerosis, IgA nephropathy, membraneous nephropathy, and acute phosphate nephropathy. 110. A method of treating or preventing media calcification, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-106. 111. A method of treating or preventing vascular calcification, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-106. 112. The method of claim 110 or 111, wherein the media or vascular calcification is associated with chronic kidney disease in the subject. 113. The method of claim 110 or 111, wherein the media or vascular calcification is associated with heart disease in the subject. 114. The method of claim 113, wherein the heart disease is associated with elevated FGF- 23 levels in the subject. 115. The method of claim 110 or 111, wherein the media or vascular calcification is associated with Moenckeberg's medial sclerosis, atherosclerosis, intima calcification, postmenopausal osteoporosis, type II diabetes, aging, hypophosphaturia, hyperparathyroidism, Vitamin D disorders, Vitamin K deficiency, Kawasaki disease, arterial calcification due to lack of CD73 (ACDC), generalized arterial calcification of infancy (GACI), idiopathic basal ganglia calcification (IBGC), pseudoxanthoma elasticum (PXE), morbus fahr ferrocalcinosis, Singleton-Merten syndrome, P-thalassemia, calciphylaxis, heterotrophic ossification, pre-term placental calcification, uterine calcification, calcified uterine fibroma, idiopathic basal ganglia calcification (FIBGC), morbus fahr ferrocalcinosis, idiopathic basal ganglia calcification, aortic valve calcification, cerebral calcification tumor calcinosis, or tumor lysis syndrome. 116. A method of treating or preventing acromegaly, rhabdomyolysis, hemolysis, hyperphosphatemia, familial hyperphosphatemia, hypoparathyroidism, pseudohypoparathyroidism, secondary hyperparathyroidism, osteodystrophy, CKD-mineral and bone disorder, diabetic ketoacidosis, metabolic acidosis, respiratory acidosis, fulminant hepatitis, hepatic osteodystrophy, hyperthermia, malignant hyperthermia, sarcoidosis, arterial hypertension, peripheral artery disease, rheumatoid arthritis, calcium-phosphate-mediated inflammasomopathies, pulmonary alveolar microlithiasis, or heart disease, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-106. 117. A method of treating or preventing a disease or disorder asscociated with elevated FGF-23 levels, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-106. 118. The method of claim 117, wherein the disease or disorder is heart disease.