GRK2 INHIBITORS AND USES THEREOF RELATED APPLICATIONS [001] This application claims priority under 35 U.S.C. § 119(e) to United States Provisional Patent Applications, U.S.S.N.63/248,867, filed September 27, 2021; U.S.S.N.63/250,105, filed September 29, 2021; and U.S.S.N.63/279,881, filed November 16, 2021, the entire contents of each of which is incorporated herein by reference. BACKGROUND [002] G protein-coupled receptor kinases (GRKs) participate in the processes of regulation of multiple G protein-coupled receptors (GPCRs) of great physiological and pharmacological relevance. These proteins form a family of seven members that phosphorylate agonist-activated receptors on serine/threonine residues, promoting internalization, recycling and/or degradation processes of GPCRs. [003] GRK2, which is the most ubiquitous and best characterized isoform of the family of GRKs, has been found to regulate the activity of different GPCRs involved in diseases such as cancer, along with cytosolic proteins involved in proliferative and survival signaling pathways, as well as non-GPCR membrane proteins with oncogenic potential. GRK2 protein levels and activity have also been reported to be enhanced in patients and/or in preclinical models of other diseases such as heart failure, cardiac hypertrophy, and hypertension. [004] Accordingly, there is a need to develop new compounds that decrease the level and/or activity of G protein-coupled receptor kinases (GRKs), including compounds that inhibit GRK (e.g., GRK2) kinase activity. SUMMARY [005] Provided herein are G protein-coupled receptors kinase inhibitors (e.g., GRK2 inhibitors, GRK3 inhibitors), including compounds of any of the formulae herein, pharmaceutical compositions and kits comprising the same, and methods of using the same (e.g., for the treatment and/or prevention of diseases, e.g., cancer, in a subject). Also provided herein are methods of preparing the compounds and pharmaceutical compositions described herein. [006] In one aspect, provided herein are compounds of Formula (I): and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof, wherein X ¹ , X ³ , X ⁴ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , a, b, c, n, and m are as defined herein. [007] In certain embodiments, for example, a compound of Formula (I) is selected from the compounds recited in Table 1 (infra), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof. [008] The compounds provided herein are inhibitors of GRK family member proteins (e.g., GRK2, GRK3) and are therefore useful for treating and/or preventing diseases (e.g., cancer) in a subject. In certain embodiments, the compounds provided herein are GRK2 inhibitors. In certain embodiments, the compounds provided herein are GRK3 inhibitors. In certain embodiments, the compounds provided herein are selective GRK2 inhibitors, i.e., selective for GRK2 over other kinases (e.g., over other GRK family member proteins). In certain embodiments, the compounds provided herein are selective GRK3 inhibitors, i.e., selective for GRK3 over other kinases (e.g., over other GRK family member proteins). [009] In another aspect, provided herein are pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, and one or more pharmaceutically acceptable carriers or excipients. In certain embodiments, a pharmaceutical composition provided herein comprises a therapeutically and/or prophylactically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof. The pharmaceutical compositions described herein are useful for treating and/or preventing diseases (e.g., cancer) in a subject. The pharmaceutical compositions provided herein may further comprise one or more additional therapeutic agents (e.g., anti-cancer agents). [010] In other aspects, provided herein are methods and uses of the compounds and pharmaceutical compositions provided herein, including the following: (a) Methods of treating and/or preventing a proliferative disease (e.g., cancer) in a subject comprising administering to the subject a therapeutically and/or prophylactically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co- crystal, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the proliferative disease is cancer. In certain embodiments, the cancer is related to the activity of a GRK family member protein (e.g., GRK2, GRK3) in a subject or cell. In certain embodiments, the cancer is pancreatic cancer or colon cancer. (b) Methods of inhibiting tumor growth in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the tumor is a pancreatic or colon tumor. (c) Methods of treating and/or preventing a cardiovascular disease in a subject comprising administering to the subject a therapeutically and/or prophylactically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the cardiovascular disease is heart failure, cardiac hypertrophy, or hypertension. In certain embodiments, the cardiovascular disease is related to the activity of a GRK family member protein (e.g., GRK2, GRK3) in a subject or cell. (d) Methods of treating opioid addiction in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof. (e) Methods of treating and/or preventing a GRK2- or GRK3-related disease in a subject comprising administering to the subject a therapeutically and/or prophylactically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co- crystal, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the GRK2-related disease is related to increased activity of GRK2 in a subject. In certain embodiments, the GRK3-related disease is related to increased activity of GRK3 in a subject. (f) Methods of inhibiting GRK2 or GRK3 activity in vivo or in vitro comprising contacting a GRK2 or GRK3 protein with a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof. In certain embodiments, the inhibiting occurs in vivo (i.e., in a subject). In certain embodiments, the inhibiting occurs in vitro (e.g., in a cell line, enzymatic assay, or biological sample). In certain embodiments, the inhibition is selective GRK2 inhibition. In certain embodiments, the inhibition is selective GRK3 inhibition. [011] In another aspect, provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof, and pharmaceutical compositions thereof, for use in any of the methods provided herein. [012] In yet another aspect, provided herein are uses of compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof, and pharmaceutical compositions thereof, for the preparation of medicaments (e.g., for treating and/or preventing a disease, e.g., cancer, in a subject). [013] In another aspect, provided herein are kits comprising a compound of (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof. The kits described herein may include a single dose or multiple doses of the compound or pharmaceutical composition thereof. The kits described herein are useful in any method or use provided herein, and optionally further comprise instructions for using the kit (e.g., instructions for using the compound or composition included in the kit). [014] Also provided herein are methods of preparing compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof, and pharmaceutical compositions thereof. Synthetic intermediates useful in the preparation of the compounds are also provided herein and are considered to be part of the invention. [015] The details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the invention will be apparent from the Definitions, Examples, Figures, and Claims. DEFINITIONS Chemical Definitions [016] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 ^th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Michael B. Smith, March’s Advanced Organic Chemistry, 7 ^th Edition, John Wiley & Sons, Inc., New York, 2013; Richard C. Larock, Comprehensive Organic Transformations, John Wiley & Sons, Inc., New York, 2018; and Carruthers, Some Modern Methods of Organic Synthesis, 3 ^rd Edition, Cambridge University Press, Cambridge, 1987. [017] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw–Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The present disclosure additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. [018] Unless otherwise provided, formulae and structures depicted herein include compounds that do not include isotopically enriched atoms, and also include compounds that include isotopically enriched atoms (“isotopically labeled derivatives”). For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of ¹⁹ F with ¹⁸ F, or the replacement of a carbon by a ¹³ C- or ¹⁴ C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays. The term “isotopes” refers to variants of a particular chemical element such that, while all isotopes of a given element share the same number of protons in each atom of the element, those isotopes differ in the number of neutrons. [019] When a range of values (“range”) is listed, it encompasses each value and sub-range within the range. A range is inclusive of the values at the two ends of the range unless otherwise provided. For example “C _1-6 alkyl” encompasses, C ₁ , C ₂ , C ₃ , C ₄ , C ₅ , C ₆ , C _1–6 , C _1–5 , C _1–4 , C _1–3 , C _1–2 , C _2–6 , C _2–5 , C _2–4 , C _2–3 , C _3–6 , C _3–5 , C _3–4 , C _4–6 , C _4–5 , and C _5–6 alkyl. [020] Use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive. [021] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups. [022] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C _1–20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C _1–12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C _1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C _1–9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C _1–8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C _1–7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C _1–6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C _1–5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C _1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C _1–2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C ₁ alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C _2-6 alkyl”). Examples of C _1–6 alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2- butanyl, tert-amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n- heptyl (C7), n-octyl (C8), n-dodecyl (C12), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1–12 alkyl (such as unsubstituted C1–6 alkyl, e.g., −CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu or s-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1–12 alkyl (such as substituted C1–6 alkyl, e.g., –CH2F, –CHF2, –CF3, – CH2CH2F, –CH2CHF2, –CH2CF3, or benzyl (Bn)). [023] The term “haloalkyl” is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some embodiments, the haloalkyl moiety has 1 to 20 carbon atoms (“C1–20 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 10 carbon atoms (“C1–10 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 9 carbon atoms (“C1–9 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C _1–8 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 7 carbon atoms (“C _1–7 haloalkyl”).In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C _1–6 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 5 carbon atoms (“C _1–5 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C _1–4 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C _1–3 haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C _1–2 haloalkyl”). In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with fluoro to provide a “perfluoroalkyl” group. In some embodiments, all of the haloalkyl hydrogen atoms are independently replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include –CHF ₂ , −CH ₂ F, −CF ₃ , −CH ₂ CF ₃ , −CF ₂ CF ₃ , −CF ₂ CF ₂ CF ₃ , −CCl ₃ , −CFCl ₂ , −CF ₂ Cl, and the like. [024] The term “heteroalkyl” refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–20 heteroalkyl”). In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 12 carbon atoms and 1 or more heteroatoms within the parent chain (“C _1–12 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 11 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–11 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–10 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–9 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–8 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–7 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“C1–6 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C1–5 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C1–4 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“C1–3 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“C1–2 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“C1 heteroalkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“C2-6 heteroalkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. [025] The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 20 carbon atoms (“C _2-20 alkenyl”). In some embodiments, an alkenyl group has 2 to 12 carbon atoms (“C _2–12 alkenyl”). In some embodiments, an alkenyl group has 2 to 11 carbon atoms (“C _2–11 alkenyl”). In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C _2–10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C _2–9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C _2–8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C _2–7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C _2–6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C _2–5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C _2–4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C _2–3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atom (“C ₂ alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1- butenyl). Examples of C2–4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1- butenyl (C ₄ ), 2-butenyl (C ₄ ), butadienyl (C ₄ ), and the like. Examples of C _2–6 alkenyl groups include the aforementioned C _2-4 alkenyl groups as well as pentenyl (C ₅ ), pentadienyl (C ₅ ), hexenyl (C ₆ ), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., −CH=CHCH3 or ) may be in the (E)- or (Z)-configuration. [026] The term “heteroalkenyl” refers to an alkenyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 20 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C _2–20 heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 12 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2–12 heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 11 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2–11 heteroalkenyl”). In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2–10 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“C2–9 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2–8 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2–7 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“C2–6 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“C2–5 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“C _2–4 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“C2–3 heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“C ₂ heteroalkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“C _2–6 heteroalkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. [027] The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C2-20 alkynyl”). In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C2-10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. [028] The term “heteroalkynyl” refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (e.g., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 20 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C _2–20 heteroalkynyl”). In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C _2–10 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C _2–9 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C _2–8 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C _2–7 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“C _2–6 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“C _2–5 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms within the parent chain (“C _2–4 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“C _2–3 heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“C ₂ heteroalkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“C _1–6 heteroalkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. [029] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 14 ring carbon atoms (“C3-14 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 13 ring carbon atoms (“C3-13 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 12 ring carbon atoms (“C3-12 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 11 ring carbon atoms (“C3-11 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 carbocyclyl groups include the aforementioned C _3-6 carbocyclyl groups as well as cycloheptyl (C ₇ ), cycloheptenyl (C ₇ ), cycloheptadienyl (C ₇ ), cycloheptatrienyl (C ₇ ), cyclooctyl (C ₈ ), cyclooctenyl (C ₈ ), bicyclo[2.2.1]heptanyl (C ₇ ), bicyclo[2.2.2]octanyl (C ₈ ), and the like. Exemplary C _3-10 carbocyclyl groups include the aforementioned C _3-8 carbocyclyl groups as well as cyclononyl (C ₉ ), cyclononenyl (C ₉ ), cyclodecyl (C ₁₀ ), cyclodecenyl (C ₁₀ ), octahydro-1H-indenyl (C ₉ ), decahydronaphthalenyl (C ₁₀ ), spiro[4.5]decanyl (C ₁₀ ), and the like. Exemplary C _3-8 carbocyclyl groups include the aforementioned C _3-10 carbocyclyl groups as well as cycloundecyl (C ₁₁ ), spiro[5.5]undecanyl (C ₁₁ ), cyclododecyl (C ₁₂ ), cyclododecenyl (C ₁₂ ), cyclotridecane (C ₁₃ ), cyclotetradecane (C ₁₄ ), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. [030] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the carbocyclyl includes 0, 1, or 2 C=C double bonds in the carbocyclic ring system, as valency permits. [031] The term “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non- aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3–14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl is substituted or unsubstituted, 3- to 8-membered, monocyclic heterocyclyl, wherein 1, 2, or 3 atoms in the heterocyclic ring system are independently oxygen, nitrogen, or sulfur, as valency permits. [032] In some embodiments, a heterocyclyl group is a 5–10 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–8 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–6 membered non-aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. [033] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6- membered heterocyclyl groups containing 3 heteroatoms include triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include azepanyl, oxepanyl and thiepanyl. Exemplary 8- membered heterocyclyl groups containing 1 heteroatom include azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8- naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H- furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3- dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo- [2,3-b]pyridinyl, 4,5,6,7-tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like. [034] The term “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C _6-14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C ₆ aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C ₁₀ aryl”; e.g., naphthyl such as 1–naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C ₁₄ aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. [035] The term “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 pi electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, e.g., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In certain embodiments, the heteroaryl is substituted or unsubstituted, 5- or 6-membered, monocyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. In certain embodiments, the heteroaryl is substituted or unsubstituted, 9- or 10-membered, bicyclic heteroaryl, wherein 1, 2, 3, or 4 atoms in the heteroaryl ring system are independently oxygen, nitrogen, or sulfur. [036] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. [037] Exemplary 5-membered heteroaryl groups containing 1 heteroatom include pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include tetrazolyl. Exemplary 6- membered heteroaryl groups containing 1 heteroatom include pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl. [038] “Carbocyclylalkyl” is a subset of “alkyl” and refers to an alkyl group substituted by a carbocyclyl group, wherein the point of attachment is on the alkyl group (e.g., “optionally substituted C _3-8 carbocyclyl C _1-6 alkyl” is a C _1-6 alkyl group substituted by a C _3-8 carbocyclyl group, wherein the point of attachment is on the alkyl group, and both the alkyl and carbocyclyl groups are optionally further substituted). [039] “Arylalkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl group (e.g., “optionally substituted C _6-10 aryl C _1-6 alkyl” is a C _1-6 alkyl group substituted by a C _6-10 aryl group, wherein the point of attachment is on the alkyl group, and both the alkyl and aryl groups are optionally further substituted). [040] “Heterocyclylalkyl” is a subset of “alkyl” and refers to an alkyl group substituted by a heterocyclyl group, wherein the point of attachment is on the alkyl group (e.g., “optionally substituted 3-8 membered heterocyclyl C _1-6 alkyl” is a C _1-6 alkyl group substituted by a 3-8 membered heterocyclyl group, wherein the point of attachment is on the alkyl group, and both the alkyl and heterocyclyl groups are optionally further substituted). [041] “Heteroarylalkyl” is a subset of “alkyl” and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl group (e.g., “optionally substituted C5-10 heteroaryl C1-6 alkyl” is a C1-6 alkyl group substituted by a C5-10 heteroaryl group, wherein the point of attachment is on the alkyl group, and both the alkyl and heteroaryl groups are optionally further substituted). [042] The term “acyl” refers to a group having the general formula −C(=O)R ^aa , −C(=O)OR ^aa , N(R ^bb )2, and −C(=S)S(R ^aa ), wherein R ^aa and R ^bb are as defined herein. Exemplary acyl groups include aldehydes (−CHO), carboxylic acids (−CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. [043] The term “halo” or “halogen” refers to fluorine (fluoro, −F), chlorine (chloro, −Cl), bromine (bromo, −Br), or iodine (iodo, −I). [044] The term “silyl” refers to the group –Si(R ^aa )3, wherein R ^aa is as defined herein. [045] The term “unsaturated bond” refers to a double or triple bond. The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond. The term “saturated” or “fully saturated” refers to a moiety that does not contain a double or triple bond, e.g., the moiety only contains single bonds. [046] Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl. [047] A group is optionally substituted unless expressly provided otherwise. The term “optionally substituted” refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. “Optionally substituted” refers to a group which is substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds and includes any of the substituents described herein that results in the formation of a stable compound. The present disclosure contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this disclosure, heteroatoms such as nitrogen, oxygen, and sulfur may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The embodiments described herein are not limited in any manner by the exemplary substituents described herein. [048] Exemplary substituents (e.g., carbon atom substituents) include halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −OR ^aa , −ON(R ^bb )2, −N(R ^bb )2, −N(R ^bb )3 ⁺ X ⁻ , −N(OR ^cc )R ^bb , −SH, −SR ^aa , −SSR ^cc , −C(=O)R ^aa , −CO2H, −CHO, −C(OR ^cc )2, −CO2R ^aa , −OC(=O)R ^aa , −OCO2R ^aa , −C(=O)N(R ^bb )2, −OC(=O)N(R ^bb )2, −NR ^bb C(=O)R ^aa , −NR ^bb CO2R ^aa , −NR ^bb C(=O)N(R ^bb )2, −C(=NR ^bb )R ^aa , −P(OR ^cc ) ₃ ⁺ X ⁻ , −P(R ^cc ) ₄ , −P(OR ^cc ) ₄ , −OP(R ^cc ) ₂ , −OP(R ^cc ) ₃ ⁺ X ⁻ , −OP(OR ^cc ) ₂ , −OP(OR ^cc ) ₃ ⁺ X ⁻ , −OP(R ^cc ) ₄ , −OP(OR ^cc ) ₄ , −B(R ^aa ) ₂ , −B(OR ^cc ) ₂ , −BR ^aa (OR ^cc ), C _1–20 alkyl, C _1–20 perhaloalkyl, C _2–20 alkenyl, C _2–20 alkynyl, C _1–20 heteroalkyl, C _2–20 heteroalkenyl, C _2–20 heteroalkynyl, C _3-10 carbocyclyl, 3- 14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups; wherein X ⁻ is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(R ^bb ) ₂ , =NNR ^bb C(=O)R ^aa , =NNR ^bb C(=O)OR ^aa , =NNR ^bb S(=O) ₂ R ^aa , =NR ^bb , or =NOR ^cc ; wherein: each instance of R ^aa is, independently, selected from C _1–20 alkyl, C _1–20 perhaloalkyl, C _2–20 alkenyl, C _2–20 alkynyl, C _1–20 heteroalkyl, C _2–20 heteroalkenyl, C _2–20 heteroalkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl, or two R ^aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each of the alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups; each instance of R ^bb is, independently, selected from hydrogen, −OH, −OR ^aa , −N(R ^cc )2, −CN, −C(=O)R ^aa , −C(=O)N(R ^cc )2, −CO2R ^aa , −SO2R ^aa , −C(=NR ^cc )OR ^aa , −C(=NR ^cc )N(R ^cc )2, −SO2N(R ^cc )2, −SO2R ^cc , −SO2OR ^cc , −SOR ^aa , −C(=S)N(R ^cc )2, −C(=O)SR ^cc , −C(=S)SR ^cc , −P(=O)(R ^aa )2, −P(=O)(OR ^cc )2, −P(=O)(N(R ^cc )2)2, C1–20 alkyl, C1–20 perhaloalkyl, C2–20 alkenyl, C2–20 alkynyl, C1–20 heteroalkyl, C2–20 heteroalkenyl, C2–20 heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two R ^bb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups; each instance of R ^cc is, independently, selected from hydrogen, C1–20 alkyl, C1–20 perhaloalkyl, C2–20 alkenyl, C2–20 alkynyl, C1–20 heteroalkyl, C2–20 heteroalkenyl, C2–20 heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two R ^cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups; each instance of R ^dd is, independently, selected from halogen, −CN, −NO2, −N3, −P(=O)(OR ^ee ) ₂ , −P(=O)(R ^ee ) ₂ , −OP(=O)(R ^ee ) ₂ , −OP(=O)(OR ^ee ) ₂ , C _1–10 alkyl, C _1–10 perhaloalkyl, C _2–10 alkenyl, C _2–10 alkynyl, C _1–10 heteroalkyl, C _2–10 heteroalkenyl, C _2–10 heteroalkynyl, C _3-10 carbocyclyl, 3-10 membered heterocyclyl, C _6-10 aryl, and 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups, or two geminal R ^dd substituents are joined to form =O or =S; wherein X ⁻ is a counterion; each instance of R ^ee is, independently, selected from C _1–10 alkyl, C _1–10 perhaloalkyl, C _2–10 alkenyl, C _2–10 alkynyl, C _1–10 heteroalkyl, C _2–10 heteroalkenyl, C _2–10 heteroalkynyl, C _3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups; each instance of R ^ff is, independently, selected from hydrogen, C1–10 alkyl, C1–10 perhaloalkyl, C2–10 alkenyl, C2–10 alkynyl, C1–10 heteroalkyl, C2–10 heteroalkenyl, C2–10 heteroalkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, and 5-10 membered heteroaryl, or two R ^ff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^gg groups; each instance of R ^gg is, independently, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −OC1–6 alkyl, −ON(C1–6 alkyl)2, −N(C1–6 alkyl)2, −N(C1–6 alkyl)3 ⁺ X ⁻ , −NH(C1–6 alkyl)2 ⁺ X ⁻ , −NH2(C1–6 alkyl) ⁺ X ⁻ , −NH3 ⁺ X ⁻ , −N(OC1–6 alkyl)(C1–6 alkyl), −N(OH)(C1–6 alkyl), −NH(OH), −SH, −SC1–6 alkyl, −SS(C1–6 alkyl), −C(=O)(C1–6 alkyl), −CO2H, −CO2(C1–6 alkyl), −OC(=O)(C1–6 alkyl), −OCO2(C1–6 alkyl), −C(=O)NH2, −C(=O)N(C1–6 alkyl)2, −OC(=O)NH(C1–6 alkyl), −NHC(=O)( C1–6 alkyl), −N(C1–6 alkyl)C(=O)( C 6 alkyl), −NHCO2(C1–6 alkyl), −NHC(=O)N(C1–6 alkyl)2, −NHC(=O)NH(C1–6 alkyl), −NHC(=O)NH2, −C(=NH)O(C1–6 alkyl), −OC(=NH)(C1–6 alkyl), −OC(=NH)OC1–6 alkyl, −C(=NH)N(C1–6 alkyl)2, −C(=NH)NH(C1–6 alkyl), −C(=NH)NH2, −OC(=NH)N(C1–6 alkyl)2, −OC(NH)NH(C1– 6 alkyl), −OC(NH)NH2, −NHC(NH)N(C1–6 alkyl)2, −NHC(=NH)NH2, −NHSO2(C1–6 alkyl), −SO2N(C1–6 alkyl)2, −SO2NH(C1–6 alkyl), −SO2NH2, −SO2C1–6 alkyl, −SO2OC1–6 alkyl, −OSO ₂ C _1–6 alkyl, −SOC _1–6 alkyl, −Si(C _1–6 alkyl) ₃ , −OSi(C _1–6 alkyl) ₃ −C(=S)N(C _1–6 alkyl) ₂ , C(=S)NH(C _1–6 alkyl), C(=S)NH ₂ , −C(=O)S(C _1–6 alkyl), −C(=S)SC _1–6 alkyl, −SC(=S)SC _1–6 alkyl, −P(=O)(OC _1–6 alkyl) ₂ , −P(=O)(C _1–6 alkyl) ₂ , −OP(=O)(C _1–6 alkyl) ₂ , −OP(=O)(OC _1–6 alkyl) ₂ , C _1–10 alkyl, C _1–10 perhaloalkyl, C _2–10 alkenyl, C _2–10 alkynyl, C _1–10 heteroalkyl, C _2–10 heteroalkenyl, C _2–10 heteroalkynyl, C _3-10 carbocyclyl, C _6-10 aryl, 3-10 membered heterocyclyl, or 5-10 membered heteroaryl; or two geminal R ^gg substituents can be joined to form =O or =S; and each X ⁻ is a counterion. [049] In certain embodiments, the molecular weight of a substituent (e.g., carbon atom substituent) is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g/mol. [050] In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and/or silicon atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and/or nitrogen atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and/or iodine atoms. In certain embodiments, a substituent consists of carbon, hydrogen, fluorine, and/or chlorine atoms. [051] In certain embodiments, exemplary substituents (e.g., carbon atom substituents) include halogen, −CN, −NO ₂ , −N ₃ , −SO ₂ H, −SO ₃ H, −OH, −OR ^aa , −N(R ^bb ) ₂ , −N(R ^bb ) ₃ ⁺ X ⁻ , −SH, −SR ^aa , −C(=O)R ^aa , −CO ₂ H, −CHO, −CO ₂ R ^aa , −OC(=O)R ^aa , −OCO ₂ R ^aa , −C(=O)N(R ^bb ) ₂ , −OC(=O)N(R ^bb ) ₂ , −NR ^bb C(=O)R ^aa , −NR ^bb CO2R ^aa , −NR ^bb C(=O)N(R ^bb )2, −NR ^bb SO2R ^aa , −SO2N(R ^bb )2, −SO2R ^aa , −SO2OR ^aa , −OSO2R ^aa , −S(=O)R ^aa , −OS(=O)R ^aa , −Si(R ^aa )3, −OSi(R ^aa )3, −P(=O)(R ^aa )2, −P(=O)(OR ^cc )2, −OP(=O)(R ^aa )2, −OP(=O)(OR ^cc )2, −P(=O)(N(R ^bb )2)2, −OP(=O)(N(R ^bb )2)2, −NR ^bb P(=O)(R ^aa )2, −NR ^bb P(=O)(OR ^cc )2, −NR ^bb P(=O)(N(R ^bb )2)2, −B(R ^aa )2, −B(OR ^cc )2, −BR ^aa (OR ^cc ), C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3- 10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl; wherein X ⁻ is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(R ^bb )2, =NNR ^bb C(=O)R ^aa , =NNR ^bb C(=O)OR ^aa , =NNR ^bb S(=O)2R ^aa , =NR ^bb , or =NOR ^cc ; each instance of R ^aa is, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3- 14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two R ^aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; each instance of R ^bb is, independently, selected from hydrogen, −OH, −OR ^aa , −N(R ^cc )2, −CN, −C(=O)R ^aa , −C(=O)N(R ^cc )2, −CO2R ^aa , −SO2R ^aa , −C(=NR ^cc )OR ^aa , −C(=NR ^cc )N(R ^cc )2, −SO2N(R ^cc )2, −SO2R ^cc , −SO2OR ^cc , −SOR ^aa , −P(=O)(R ^aa )2, −P(=O)(OR ^cc )2, −P(=O)(N(R ^cc )2)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10alkynyl, C3- 10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two R ^bb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; and each instance of R ^cc is, independently, selected from hydrogen, C _1-10 alkyl, C _1-10 perhaloalkyl, C _2-10 alkenyl, C _2-10 alkynyl, heteroC _1-10 alkyl, heteroC _2-10 alkenyl, heteroC _2-10 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl, or two R ^cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring. [052] In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C _1-6 alkyl, −OR ^aa , −SR ^aa , −N(R ^bb ) ₂ , –CN, –NO ₂ , −C(=O)R ^aa , −CO ₂ R ^aa , −C(=O)N(R ^bb ) ₂ , −OC(=O)R ^aa , −OCO ₂ R ^aa , −OC(=O)N(R ^bb ) ₂ , −NR ^bb C(=O)R ^aa , −NR ^bb CO ₂ R ^aa , or −NR ^bb C(=O)N(R ^bb ) ₂ . In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C _1–10 alkyl, −OR ^aa , −SR ^aa , −N(R ^bb ) ₂ , –CN, –NO ₂ , −C(=O)R ^aa , −CO ₂ R ^aa , −C(=O)N(R ^bb ) ₂ , −OC(=O)R ^aa , −OCO ₂ R ^aa , −OC(=O)N(R ^bb ) ₂ , −NR ^bb C(=O)R ^aa , −NR ^bb CO ₂ R ^aa , or −NR ^bb C(=O)N(R ^bb ) ₂ , wherein R ^aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C _1–6 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each R ^bb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C _1–6 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −OR ^aa , −SR ^aa , −N(R ^bb )2, –CN, or –NO2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C1–6 alkyl, −OR ^aa , −SR ^aa , −N(R ^bb )2, –CN, –SCN, or –NO2, wherein R ^aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–6 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each R ^bb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). [053] In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −C(=O)R ^aa , −CO2R ^aa , −C(=O)N(R ^bb )2, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −C(=O)R ^aa , −CO2R ^aa , −C(=O)N(R ^bb )2, or a nitrogen protecting group, wherein R ^aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each R ^bb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, or a nitrogen protecting group. In certain embodiments, each nitrogen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C _1-6 alkyl or a nitrogen protecting group. [054] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include −OH, −OR ^aa , −N(R ^cc ) ₂ , −C(=O)R ^aa , −C(=O)N(R ^cc ) ₂ , −CO ₂ R ^aa , −SO ₂ R ^aa , −C(=NR ^cc )R ^aa , −C(=NR ^cc )OR ^aa , −C(=NR ^cc )N(R ^cc ) ₂ , −SO ₂ N(R ^cc ) ₂ , −SO ₂ R ^cc , −SO ₂ OR ^cc , −SOR ^aa , −C(=S)N(R ^cc ) ₂ , −C(=O)SR ^cc , −C(=S)SR ^cc , C _1–10 alkyl (e.g., aralkyl, heteroaralkyl), C _1–20 alkenyl, C _1–20 alkynyl, hetero C _1–20 alkyl, hetero C _1–20 alkenyl, hetero C _1–20 alkynyl, C _3-10 carbocyclyl, 3-14 membered heterocyclyl, C _6-14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R ^dd groups, and wherein R ^aa , R ^bb , R ^cc and R ^dd are as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 ^rd edition, John Wiley & Sons, 1999, incorporated herein by reference. [055] For example, in certain embodiments, at least one nitrogen protecting group is an amide group (e.g., a moiety that includes the nitrogen atom to which the nitrogen protecting groups (e.g., −C(=O)R ^aa ) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N- benzoylphenylalanyl derivatives, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o- nitrophenoxyacetamide, acetoacetamide, (N’-dithiobenzyloxyacylamino)acetamide, 3-(p- hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o- nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3- methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivatives, o-nitrobenzamide, and o-(benzoyloxymethyl)benzamide. [056] In certain embodiments, at least one nitrogen protecting group is a carbamate group (e.g., a moiety that includes the nitrogen atom to which the nitrogen protecting groups (e.g., −C(=O)OR ^aa ) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2- sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9- (10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4- methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1–(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1- dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and 4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1- adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p- methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4- methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5- benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m- nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6- nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N- dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p’-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1- (3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1- phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p- (phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate. [057] In certain embodiments, at least one nitrogen protecting group is a sulfonamide group (e.g., a moiety that includes the nitrogen atom to which the nitrogen protecting groups (e.g., −S(=O)2R ^aa ) is directly attached). In certain such embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl-4- methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4- methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4- methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4- methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), ^-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4- (4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide. [058] In certain embodiments, each nitrogen protecting group, together with the nitrogen atom to which the nitrogen protecting group is attached, is independently selected from the group consisting of phenothiazinyl-(10)-acyl derivatives, N’-p-toluenesulfonylaminoacyl derivatives, N’- phenylaminothioacyl derivatives, N-benzoylphenylalanyl derivatives, N-acetylmethionine derivatives, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5- substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5- triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2- (trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo- 3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4- methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4- methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9- fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N’-oxide, N-1,1- dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N- diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N-(N’,N’- dimethylaminomethylene)amine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5- chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N- cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivatives, N- diphenylborinic acid derivatives, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o- nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2- nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys). In some embodiments, two instances of a nitrogen protecting group together with the nitrogen atoms to which the nitrogen protecting groups are attached are N,N’-isopropylidenediamine. [059] In certain embodiments, a nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p- methoxyphenyl (PMP), 2,2,2-trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds). In certain embodiments, at least one nitrogen protecting group is Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts. [060] In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −C(=O)R ^aa , −CO2R ^aa , −C(=O)N(R ^bb )2, or an oxygen protecting group. In certain embodiments, each oxygen atom substituents is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C _1-6 alkyl, −C(=O)R ^aa , −CO ₂ R ^aa , −C(=O)N(R ^bb ) ₂ , or an oxygen protecting group, wherein R ^aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C _1-6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each R ^bb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C _1-6 alkyl, or a nitrogen protecting group. In certain embodiments, each oxygen atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C _1-6 alkyl or an oxygen protecting group. [061] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include −R ^aa , −N(R ^bb ) ₂ , −C(=O)SR ^aa , −C(=O)R ^aa , −CO ₂ R ^aa , −C(=O)N(R ^bb ) ₂ , −C(=NR ^bb )R ^aa , −C(=NR ^bb )OR ^aa , −C(=NR ^bb )N(R ^bb ) ₂ , −S(=O)R ^aa , −SO ₂ R ^aa , −Si(R ^aa ) ₃ , −P(R ^cc ) ₂ , −P(R ^cc ) ₃ ⁺ X ⁻ , −P(OR ^cc ) ₂ , −P(OR ^cc ) ₃ ⁺ X ⁻ , −P(=O)(R ^aa ) ₂ , −P(=O)(OR ^cc ) ₂ , and −P(=O)(N(R ^bb ) ₂ ) ₂ , wherein X ⁻ , R ^aa , R ^bb , and R ^cc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 ^rd edition, John Wiley & Sons, 1999, incorporated herein by reference. [062] In certain embodiments, each oxygen protecting group, together with the oxygen atom to which the oxygen protecting group is attached, is selected from the group consisting of methoxy, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p- methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2- trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4- methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8- trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1- methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4- dinitrophenyl, benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl, o-nitrobenzyl, p- nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3- methyl-2-picolyl N-oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, ^-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p- methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4’- bromophenacyloxyphenyl)diphenylmethyl, 4,4^,4^-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4^,4^-tris(levulinoyloxyphenyl)methyl, 4,4^,4^-tris(benzoyloxyphenyl)methyl, 4,4'-Dimethoxy-3"'- [N-(imidazolylmethyl) ]trityl Ether (IDTr-OR), 4,4'-Dimethoxy-3"'-[N- (imidazolylethyl)carbamoyl]trityl Ether (IETr-OR), 1,1-bis(4-methoxyphenyl)-1^-pyrenylmethyl, 9- anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t- butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4- (ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4- methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2- (triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t- butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S- benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4- azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy)ethyl carbonate (MTMEC-OR), 4-(methylthiomethoxy)butyrate, 2- (methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3- tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, ^-naphthoate, nitrate, alkyl N,N,N’,N’-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). [063] In certain embodiments, an oxygen protecting group is silyl. In certain embodiments, an oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2- trimethylsilylethyl carbonate, methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methyoxy-2-propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p- methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p- methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).In certain embodiments, at least one oxygen protecting group is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl. [064] In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −C(=O)R ^aa , −CO2R ^aa , −C(=O)N(R ^bb )2, or a sulfur protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C _1-6 alkyl, −C(=O)R ^aa , −CO ₂ R ^aa , −C(=O)N(R ^bb ) ₂ , or a sulfur protecting group, wherein R ^aa is hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C _1-6 alkyl, or an oxygen protecting group when attached to an oxygen atom; and each R ^bb is independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C _1-6 alkyl, or a nitrogen protecting group. In certain embodiments, each sulfur atom substituent is independently substituted (e.g., substituted with one or more halogen) or unsubstituted C _1-6 alkyl or a sulfur protecting group. [065] In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). In some embodiments, each sulfur protecting group is selected from the group consisting of −R ^aa , −N(R ^bb ) ₂ , −C(=O)SR ^aa , −C(=O)R ^aa , −CO ₂ R ^aa , −C(=O)N(R ^bb ) ₂ , −C(=NR ^bb )R ^aa , −C(=NR ^bb )OR ^aa , −C(=NR ^bb )N(R ^bb ) ₂ , −S(=O)R ^aa , −SO ₂ R ^aa , −Si(R ^aa ) ₃ , −P(R ^cc ) ₂ , −P(R ^cc ) ₃ ⁺ X ⁻ , −P(OR ^cc ) ₂ , −P(OR ^cc ) ₃ ⁺ X ⁻ , −P(=O)(R ^aa ) ₂ , −P(=O)(OR ^cc ) ₂ , and −P(=O)(N(R ^bb ) ₂ ) ₂ , wherein R ^aa , R ^bb , and R ^cc are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 ^rd edition, John Wiley & Sons, 1999, incorporated herein by reference. [066] In certain embodiments, a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl. [067] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (e.g., including one formal negative charge). An anionic counterion may also be multivalent (e.g., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F ^– , Cl ^– , Br ^– , I ^– ), NO3 ^– , ClO4 ^– , OH ^– , H2PO4 ^– , HCO3 ⁻ , HSO4 ^– , sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p–toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5– sulfonate, ethan–1–sulfonic acid–2–sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4 ⁻ , PF4 ^– , PF6 ^– , AsF6 ^– , SbF6 ^– , B[3,5-(CF3)2C6H3]4] ^– , B(C6F5)4 ⁻ , BPh4 ^– , Al(OC(CF3)3)4 ^– , and carborane anions (e.g., CB11H12 ^– or (HCB11Me5Br6) ^– ). Exemplary counterions which may be multivalent include CO3 ²⁻ , HPO4 ²⁻ , PO4 ³⁻ , B4O7 ²⁻ , SO4 ²⁻ , S2O3 ²⁻ , carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes. [068] These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The embdiments provided herein are not limited in any manner by the above exemplary listing of substituents. Other Definitions [069] The following definitions are more general terms used throughout the present application. [070] As used herein, the term “salt” refers to any and all salts and encompasses pharmaceutically acceptable salts. Salts include ionic compounds that result from the neutralization reaction of an acid and a base. A salt is composed of one or more cations (positively charged ions) and one or more anions (negative ions) so that the salt is electrically neutral (without a net charge). Salts of the compounds of the present disclosure include those derived from inorganic and organic acids and bases. Examples of acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2–hydroxy–ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2–naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3–phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, hippurate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1–4 alkyl) ₄ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further salts include ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. [071] The term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N ⁺ (C _1-4 alkyl) ₄ ⁻ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. [072] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. [073] “Stereoisomers” that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture.” [074] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations. [075] The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates. [076] The term “hydrate” refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R⋅x H2O, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R⋅0.5 H ₂ O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R⋅2 H ₂ O) and hexahydrates (R⋅6 H ₂ O)). [077] The term “polymorph” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions. [078] The term “crystalline” or “crystalline form” refers to a solid form substantially exhibiting three- dimensional order. In certain embodiments, a crystalline form of a solid is a solid form that is substantially not amorphous. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of a crystalline form includes one or more sharply defined peaks. [079] The term “amorphous” or “amorphous form” refers to a form of a solid (“solid form”), the form substantially lacking three-dimensional order. In certain embodiments, an amorphous form of a solid is a solid form that is substantially not crystalline. In certain embodiments, the X-ray powder diffraction (XRPD) pattern of an amorphous form includes a wide scattering band with a peak at 2^ of, e.g., between 20 and 70°, inclusive, using CuK^ radiation. In certain embodiments, the XRPD pattern of an amorphous form further includes one or more peaks attributed to crystalline structures. In certain embodiments, the maximum intensity of any one of the one or more peaks attributed to crystalline structures observed at a 2^ of between 20 and 70°, inclusive, is not more than 300-fold, not more than 100-fold, not more than 30-fold, not more than 10-fold, or not more than 3-fold of the maximum intensity of the wide scattering band. In certain embodiments, the XRPD pattern of an amorphous form includes no peaks attributed to crystalline structures. [080] The term “co-crystal” refers to a crystalline structure comprising at least two different components (e.g., a compound disclosed herein and an acid), wherein each of the components is independently an atom, ion, or molecule. In certain embodiments, none of the components is a solvent. In certain embodiments, at least one of the components is a solvent. A co-crystal of a compound disclosed herein and an acid is different from a salt formed from a compound disclosed herein and the acid. In the salt, a compound disclosed herein is complexed with the acid in a way that proton transfer (e.g., a complete proton transfer) from the acid to a compound disclosed herein easily occurs at room temperature. In the co-crystal, however, a compound disclosed herein is complexed with the acid in a way that proton transfer from the acid to a compound disclosed herein does not easily occur at room temperature. In certain embodiments, in the co-crystal, there is no proton transfer from the acid to a compound disclosed herein. In certain embodiments, in the co-crystal, there is partial proton transfer from the acid to a compound disclosed herein. Co-crystals may be useful to improve the properties (e.g., solubility, stability, and ease of formulation) of a compound disclosed herein. [081] The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N- alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid derivative forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are particular prodrugs. In some cases it is desirable to prepare double ester-type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Aliphatic or aromatic (e.g., alkyl, alkenyl, alkynyl, aryl, or arylalkyl) esters of the compounds described herein may be preferred. [082] Throughout the present disclosure, references to “the compound” and “a compound” provided herein are intended to encompass the compound or group of compounds, and also pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof as described herein. [083] The terms “composition” and “formulation” are used interchangeably. [084] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non- human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The term “patient” refers to a human subject in need of treatment of a disease. [085] The term “biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample. [086] The term “administer,” “administering,” or “administration” refers to implanting, absorbing, ingesting, injecting, inhaling, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject. [087] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. [088] The term “prevent,” “preventing,” or “prevention” refers to a prophylactic treatment of a subject who is not and was not with a disease but is at risk of developing the disease or who was with a disease, is not with the disease, but is at risk of regression of the disease. In certain embodiments, the subject is at a higher risk of developing the disease or at a higher risk of regression of the disease than an average healthy member of a population. [089] The terms “condition,” “disease,” and “disorder” are used interchangeably. [090] An “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, severity of side effects, disease, or disorder, the identity, pharmacokinetics, and pharmacodynamics of the particular compound, the condition being treated, the mode, route, and desired or required frequency of administration, the species, age and health or general condition of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain embodiments, an effective amount is a prophylactic treatment. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses. [091] A “therapeutically effective amount” of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting GRK2 activity in a subject. In certain embodiments, a therapeutically effective amount is an amount sufficient for inhibiting GRK3 activity in a subject. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a proliferative disease (e.g., cancer) in a subject. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a cardiovascular disease in a subject. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a GRK2-related disease in a subject. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating a GRK3-related disease in a subject. [092] A “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount sufficient for inhibiting GRK2 activity in a subject. In certain embodiments, a prophylactically effective amount is an amount sufficient for inhibiting GRK3 activity in a subject. In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a proliferative disease (e.g., cancer) in a subject. In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a cardiovascular disease in a subject. In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a GRK2-related disease in a subject. In certain embodiments, a prophylactically effective amount is an amount sufficient for preventing a GRK3- related disease in a subject. [093] “G protein-coupled receptor kinases” (GPCRKs, GRKs) are a family of protein kinases within the AGC (protein kinase A, protein kinase G, protein kinase C) group of kinases. GRKs use ATP to add phosphate to serine and threonine residues in specific locations of target proteins. In particular, GRKs phosphorylate intracellular domains of G protein-coupled receptors (GPCRs). GRKs function in tandem with arrestin proteins to regulate the sensitivity of GPCRs for stimulating downstream heterotrimeric G protein and G protein-independent signaling pathways. Identified members of the GRK protein family include GRK1-7 (i.e., GRK1, GRK2, GRK3, GRK4, GRK5, GRK6, GRK7). [094] As used herein, the term “GRK2” refers to G-protein-coupled receptor kinase 2 and belongs to the G-protein-coupled receptor kinase subfamily of the Ser/Thr protein kinases. Human GRK2 is encoded by the ADRBK1 gene, the nucleic acid sequence of which is set forth in SEQ ID NO: 1, below: ATGGCGGACCTGGAGGCGGTGCTGGCCGACGTGAGCTACCTGATGGCCATGGAGAAGAGC AAGGCCACGC CGGCCGCGCGCGCCAGCAAGAAGATCCTGCTGCCCGAGCCCAGCATCCGCAGTGTCATGC AGAAGTACCT GGAGGACCGGGGCGAGGTGACCTTTGAGAAGATCTTTTCCCAGAAGCTGGGGTACCTGCT CTTCCGAGAC TTCTGCCTGAACCACCTGGAGGAGGCCAGGCCCTTGGTGGAATTCTATGAGGAGATCAAG AAGTACGAGA AGCTGGAGACGGAGGAGGAGCGTGTGGCCCGCAGCCGGGAGATCTTCGACTCATACATCA TGAAGGAGCT GCTGGCCTGCTCGCATCCCTTCTCGAAGAGTGCCACTGAGCATGTCCAAGGCCACCTGGG GAAGAAGCAG GTGCCTCCGGATCTCTTCCAGCCATACATCGAAGAGATTTGTCAAAACCTCCGAGGGGAC GTGTTCCAGA AATTCATTGAGAGCGATAAGTTCACACGGTTTTGCCAGTGGAAGAATGTGGAGCTCAACA TCCACCTGAC CATGAATGACTTCAGCGTGCATCGCATCATTGGGCGCGGGGGCTTTGGCGAGGTCTATGG GTGCCGGAAG GCTGACACAGGCAAGATGTACGCCATGAAGTGCCTGGACAAAAAGCGCATCAAGATGAAG CAGGGGGAGA CCCTGGCCCTGAACGAGCGCATCATGCTCTCGCTCGTCAGCACTGGGGACTGCCCATTCA TTGTCTGCAT GTCATACGCGTTCCACACGCCAGACAAGCTCAGCTTCATCCTGGACCTCATGAACGGTGG GGACCTGCAC TACCACCTCTCCCAGCACGGGGTCTTCTCAGAGGCTGACATGCGCTTCTATGCGGCCGAG ATCATCCTGG GCCTGGAGCACATGCACAACCGCTTCGTGGTCTACCGGGACCTGAAGCCAGCCAACATCC TTCTGGACGA GCATGGCCACGTGCGGATCTCGGACCTGGGCCTGGCCTGTGACTTCTCCAAGAAGAAGCC CCATGCCAGC GTGGGCACCCACGGGTACATGGCTCCGGAGGTCCTGCAGAAGGGCGTGGCCTACGACAGC AGTGCCGACT GGTTCTCTCTGGGGTGCATGCTCTTCAAGTTGCTGCGGGGGCACAGCCCCTTCCGGCAGC ACAAGACCAA AGACAAGCATGAGATCGACCGCATGACGCTGACGATGGCCGTGGAGCTGCCCGACTCCTT CTCCCCTGAA CTACGCTCCCTGCTGGAGGGGTTGCTGCAGAGGGATGTCAACCGGAGATTGGGCTGCCTG GGCCGAGGGG CTCAGGAGGTGAAAGAGAGCCCCTTTTTCCGCTCCCTGGACTGGCAGATGGTCTTCTTGC AGAAGTACCC TCCCCCGCTGATCCCCCCACGAGGGGAGGTGAACGCGGCCGACGCCTTCGACATTGGCTC CTTCGATGAG GAGGACACAAAAGGAATCAAGTTACTGGACAGTGATCAGGAGCTCTACCGCAACTTCCCC CTCACCATCT CGGAGCGGTGGCAGCAGGAGGTGGCAGAGACTGTCTTCGACACCATCAACGCTGAGACAG ACCGGCTGGA GGCTCGCAAGAAAGCCAAGAACAAGCAGCTGGGCCATGAGGAAGACTACGCCCTGGGCAA GGACTGCATC ATGCATGGCTACATGTCCAAGATGGGCAACCCCTTCCTGACCCAGTGGCAGCGGCGGTAC TTCTACCTGT TCCCCAACCGCCTCGAGTGGCGGGGCGAGGGCGAGGCCCCGCAGAGCCTGCTGACCATGG AGGAGATCCA GTCGGTGGAGGAGACGCAGATCAAGGAGCGCAAGTGCCTGCTCCTCAAGATCCGCGGTGG GAAACAGTTC ATTTTGCAGTGCGATAGCGACCCTGAGCTGGTGCAGTGGAAGAAGGAGCTGCGCGACGCC TACCGCGAGG CCCAGCAGCTGGTGCAGCGGGTGCCCAAGATGAAGAACAAGCCGCGCTCGCCCGTGGTGG AGCTGAGCAA GGTGCCGCTGGTCCAGCGCGGCAGTGCCAACGGCCTCTGA (SEQ ID NO: 1) [095] The term “GRK2” also refers to natural variants of the wild-type GRK2 protein, such as proteins having at least 85% identity (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity, or more) to the amino acid sequence of wild-type human GRK2, which is set forth in SEQ ID NO: 2, below: MADLEAVLADVSYLMAMEKSKATPAARASKKILLPEPSIRSVMQKYLEDRGEVTFEKIFS QKLGYLLFRD FCLNHLEEARPLVEFYEEIKKYEKLETEEERVARSREIFDSYIMKELLACSHPFSKSATE HVQGHLGKKQ VPPDLFQPYIEEICQNLRGDVFQKFIESDKFTRFCQWKNVELNIHLTMNDFSVHRIIGRG GFGEVYGCRK ADTGKMYAMKCLDKKRIKMKQGETLALNERIMLSLVSTGDCPFIVCMSYAFHTPDKLSFI LDLMNGGDLH YHLSQHGVFSEADMRFYAAEIILGLEHMHNRFVVYRDLKPANILLDEHGHVRISDLGLAC DFSKKKPHAS VGTHGYMAPEVLQKGVAYDSSADWFSLGCMLFKLLRGHSPFRQHKTKDKHEIDRMTLTMA VELPDSFSPE LRSLLEGLLQRDVNRRLGCLGRGAQEVKESPFFRSLDWQMVFLQKYPPPLIPPRGEVNAA DAFDIGSFDE EDTKGIKLLDSDQELYRNFPLTISERWQQEVAETVFDTINAETDRLEARKKAKNKQLGHE EDYALGKDCI MHGYMSKMGNPFLTQWQRRYFYLFPNRLEWRGEGEAPQSLLTMEEIQSVEETQIKERKCL LLKIRGGKQF ILQCDSDPELVQWKKELRDAYREAQQLVQRVPKMKNKPRSPVVELSKVPLVQRGSANGL (SEQ ID NO: 2) [096] As used herein, the term “GRK2-related disease” refers to a diseases or condition that is associated with cells that express or overexpress GRK2 (e.g., cancer cells that express or overexpress GRK2 compared to a reference). In certain embodiments, a GRK2-related disease is a disease or condition associated with aberrant (e.g., increased) activity of GRK2 in a subject. GRK2-related disorders can be identified by assessing a cell or a biopsy of a tissue sample for GRK2 expression and comparing it to GRK2 expression in a reference cell or tissue sample. [097] As used herein, the term “GRK3” refers to G-protein-coupled receptor kinase 3 and belongs to the G-protein-coupled receptor kinase subfamily of the Ser/Thr protein kinases. Human GRK3 is encoded by the ADRBK2 gene. The term “GRK3” also refers to natural variants of the wild-type GRK3 protein, such as proteins having at least 85% identity (e.g., 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.9% identity, or more) to the amino acid sequence of wild-type human GRK3, which is set forth in SEQ ID NO: 3, below: MADLEAVLADVSYLMAMEKSKATPAARASKRIVLPEPSIRSVMQKYLAERNEITFDKIFN QKIGFLLFKDFCLNEINEAVPQVKFYEEIKEYEKLDNEEDRLCRSRQIYDAYIMKELLSC SHPFSKQAVEHVQSHLSKKQVTSTLFQPYIEEICESLRGDIFQKFMESDKFTRFCQWKNV ELNIHLTMNEFSVHRIIGRGGFGEVYGCRKADTGKMYAMKCLDKKRIKMKQGETLALNER IMLSLVSTGDCPFIVCMTYAFHTPDKLCFILDLMNGGDLHYHLSQHGVFSEKEMRFYATE IILGLEHMHNRFVVYRDLKPANILLDEHGHARISDLGLACDFSKKKPHASVGTHGYMAPE VLQKGTAYDSSADWFSLGCMLFKLLRGHSPFRQHKTKDKHEIDRMTLTVNVELPDTFSPE LKSLLEGLLQRDVSKRLGCHGGGSQEVKEHSFFKGVDWQHVYLQKYPPPLIPPRGEVNAA DAFDIGSFDEEDTKGIKLLDCDQELYKNFPLVISERWQQEVTETVYEAVNADTDKIEARK RAKNKQLGHEEDYALGKDCIMHGYMLKLGNPFLTQWQRRYFYLFPNRLEWRGEGESRQNL LTMEQILSVEETQIKDKKCILFRIKGGKQFVLQCESDPEFVQWKKELNETFKEAQRLLRR APKFLNKPRSGTVELPKPSLCHRNSNGL (SEQ ID NO: 3) [098] As used herein, the term “GRK3-related disease” refers to a diseases or condition that is associated with cells that express or overexpress GRK3 (e.g., cancer cells that express or overexpress GRK3 compared to a reference). In certain embodiments, a GRK3-related disease is a disease or condition associated with aberrant (e.g., increased) activity of GRK3 in a subject. GRK3-related disorders can be identified by assessing a cell or a biopsy of a tissue sample for GRK3 expression and comparing it to GRK3 expression in a reference cell or tissue sample. [099] As used herein the term “inhibit,” “inhibition,” or “inhibiting” in the context of enzymes, for example, in the context of a kinase (e.g., GRK2, GRK3), refers to a reduction in the activity of the enzyme or a downstream effect. In some embodiments, the term refers to a reduction of the level of enzyme activity (e.g., GRK2 activity, GRK3 activity) to a level that is statistically significantly lower than an initial level, which may, for example, be a baseline or control level of enzyme activity. In some embodiments, the term refers to a reduction of the level of enzyme activity (e.g., GRK2 activity, GRK3 activity) to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of enzyme activity. [100] A compound described herein is a “selective” inhibitor if it inhibits one or more enzymes to a greater extent than over other enzymes. [101] In certain embodiments, the compounds provided herein are selective GRK2 inhibitors, i.e., that selectively inhibit GRK2 activity over other proteins (e.g., over other protein kinases, e.g., over other GRK family member proteins). In certain embodiments, the selectivity is at least 2-fold, at least 3- fold, at least 5-fold, at least 10-fold, at least 30-fold, at least 50-fold, at least 100-fold, at least 300- fold, at least 500-fold, at least 1,000-fold, at least 3,000-fold, at least 5,000-fold, at least 10,000-fold, at least 30,000-fold, at least 50,000-fold, or at least 100,000-fold. In certain embodiments, the selectivity is not more than 100,000-fold, not more than 10,000-fold, not more than 1,000-fold, not more than 100-fold, not more than 10-fold, or not more than 2-fold. Combinations of the above- referenced ranges (e.g., at least 2-fold and not more than 10,000-fold) are also within the scope of the disclosure. [102] In certain embodiments, the compounds provided herein are selective GRK3 inhibitors, i.e., that selectively inhibit GRK3 activity over other proteins (e.g., over other protein kinases, e.g., over other GRK family member proteins). In certain embodiments, the selectivity is at least 2-fold, at least 3- fold, at least 5-fold, at least 10-fold, at least 30-fold, at least 50-fold, at least 100-fold, at least 300- fold, at least 500-fold, at least 1,000-fold, at least 3,000-fold, at least 5,000-fold, at least 10,000-fold, at least 30,000-fold, at least 50,000-fold, or at least 100,000-fold. In certain embodiments, the selectivity is not more than 100,000-fold, not more than 10,000-fold, not more than 1,000-fold, not more than 100-fold, not more than 10-fold, or not more than 2-fold. Combinations of the above- referenced ranges (e.g., at least 2-fold and not more than 10,000-fold) are also within the scope of the disclosure. [103] For example, the selectivity of a compound described herein in inhibiting the activity of GRK2 or GRK3 over a different protein (e.g., a different GRK family member protein) may be measured by the quotient of the IC50 value of the compound in inhibiting the activity of the different protein over the IC50 value of the compound in inhibiting the activity of GRK2 or GRK3. The selectivity of a compound described herein for GRK2 or GRK3 over a different protein (e.g., a different GRK family member protein) may also be measured by the quotient of the Kd value of an adduct of the compound and the different protein over the Kd value of an adduct of the compound and GRK2 or GRK3. [104] By a “reference” is meant any useful reference used to compare protein or mRNA levels. The reference can be any sample, standard, standard curve, or level that is used for comparison purposes. The reference can be a normal reference sample or a reference standard or level. A “reference sample” can be, for example, a control, e.g., a predetermined negative control value such as a “normal control” or a prior sample taken from the same subject; a sample from a normal healthy subject, such as a normal cell or normal tissue; a sample (e.g., a cell or tissue) from a subject not having a disease; a sample from a subject that is diagnosed with a disease, but not yet treated with a compound described herein; a sample from a subject that has been treated by a compound described herein; or a sample of a purified protein (e.g., any described herein) at a known normal concentration. By “reference standard or level” is meant a value or number derived from a reference sample. A “normal control value” is a pre-determined value indicative of non-disease state, e.g., a value expected in a healthy control subject. Typically, a normal control value is expressed as a range (“between X and Y”), a high threshold (“no higher than X”), or a low threshold (“no lower than X”). A subject having a measured value within the normal control value for a particular biomarker is typically referred to as “within normal limits” for that biomarker. A normal reference standard or level can be a value or number derived from a normal subject not having a disease or disorder (e.g., cancer); a subject that has been treated with a compound described herein. In preferred embodiments, the reference sample, standard, or level is matched to the sample subject sample by at least one of the following criteria: age, weight, sex, disease stage, and overall health. A standard curve of levels of a purified protein, e.g., any described herein, within the normal reference range can also be used as a reference. BRIEF DESCRIPTION OF THE DRAWINGS [105] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and together with the description, provide non-limiting examples of the invention. [106] FIGS.1A-1B. GRK2 inhibitor Compound 1 (“Cmpd 1”) inhibits PAXF1657 pancreatic tumor growth in NOD-^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ !^^"#^$^"^^ !^^%^^ (FIG.1A). Treatment was well tolerated as indicated by percent bodyweight (%BW) change (FIG.1B). [107] FIGS.2A-2C. GRK2 inhibitor Compound 1 (“Cmpd 1”) inhibits MC38 colon tumor growth in C57BL/6 mice. Tumor growth inhibition (TGI)%: 3 mpk: 39%; 6 mpk: 27%; anti-PD1: 47% (32% against RIgG2a) (FIG.2A). Compound 1/Vehicle administered IP BID; anti-PD1/RIgG2a administered IP 3x/week. Treatment was well tolerated as indicated by percent bodyweight (%BW) change (FIG.2B). GRK2 inhibitor Compound 1 does not inhibit tumor growth of colon MC38 murine cancer in immunodeficient NSG mice, demonstrating immune-dependent anti-tumor activity of the GRK2 inhibitor in vivo (FIG.2C). [108] FIG.3. GRK2 inhibitor Compound 1 (“Cmpd 1”) improves anti-tumor activity of anti-PD1 antibody in combination therapy (colon MC38 murine tumor model in C57BL/6 mice). %TGI (Day 24): anti-PD1: 34%; anti-PD1 + Compound 1: 54%. [109] FIG.4. Comparison demonstrating that Compound 1 (“Cmpd 1”) in combination with anti-PD1 has immune-dependent anti-tumor activity and synergistic efficacy in the MC38 colorectal (CRC) tumor model. Synergistic efficay of the combination is seen in colorectal cancer (CRC) MC38 murine tumor model in C57BL/6 mice, but neither GRK2 inhibitor Compound 1 nor aPD1 inhibit tumor growth in immunodeficient NSG mice. [110] FIG.5. GRK2 inhibitors (including Compound 1) induce myeloid pro-inflammatory genes in human PBMCs. [111] FIG.6. Further data showing that GRK2 inhibitors (Compound 1, Compounds A-C) induce expression of pro-inflammatory genes in human PBMCs. [112] FIG.7. GRK2 inhibitors (Compound 1, Compounds A-C) induce subtle increase of IL-2 secretion in T-cells compared to DMSO. [113] FIG.8. GRK2 inhibitors (Compound 1, Compounds A-C) induce expression of pro- inflammatory genes in human pancreatic cancer cell line PAXF1657. [114] FIG.9. GRK2 inhibitor Compound 1 induces expression of pro-inflammatory genes in human pancreatic xenograft PAXF1657 in vivo. [115] FIG.10. GRK2 inhibitor Compound 1 delays progression of PAXF1657 through G2/M cell cycle phase following G2 cell cycle arrest with CDK1 inhibitor RO-3306. [116] FIG.11. Structures of certain GRK2 inhibitors referenced herein (Compound 1, Compounds A- C). DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS [117] Provided herein are G protein-coupled receptor kinase (e.g., GRK2, GRK3) inhibitors, including compounds of any of the formulae herein (e.g., Formula (I)), pharmaceutical compositions and kits comprising the same, and methods of using the same (e.g., for the treatment and/or prevention of diseases, e.g., cancer, in a subject). In certain embodiments, the compounds are selective GRK2 inhibitors. In certain embodiments, the compounds are selective GRK3 inhibitors. Also provided herein are methods of preparing the compounds and pharmaceutical compositions described herein. Compounds [118] In certain embodiments, provided herein are compounds of Formula (I): (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof, wherein: X ¹ is CH, CR ⁹ , or N; X ³ is –NR ¹ – or –O–; X ⁴ is –NR ⁸ –, –O–, –S–, –S(=O)–, or –S(=O) ₂ –; R ¹ is hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C _1-6 acyl, or a nitrogen protecting group; R ² and R ⁴ are each independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 acyl, or a nitrogen protecting group; each instance of R ³ is independently halogen, –CN, –OR ^O , –N(R ^N ) ₂ , –SR ^S , optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, or optionally substituted C _1-6 acyl; each instance R ⁶ and R ⁹ is independently halogen, –CN, –OR ^O , –N(R ^N ) ₂ , optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, or optionally substituted C _1-6 acyl; optionally wherein R ¹ and R ⁹ are joined together with the intervening atoms to form optionally substituted 5-8 membered heterocyclyl; R ⁵ is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-8 carbocyclyl C1-6 alkyl, optionally substituted 3-8 membered heterocyclyl C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted 5-10 membered heteroaryl C1-6 alkyl, optionally substituted C1-6 acyl, or a nitrogen protecting group; optionally wherein R ⁴ and R ⁵ are joined together with the intervening atoms to form optionally substituted 3-8 membered heterocyclyl; each instance of R ⁷ is independently halogen, optionally substituted C1-6 alkyl, –CN, –OR ^O , –N(R ^N )2, or –SR ^S , or two R ⁷ on the same carbon atom are taken together to form =O, or two R ⁷ on the same carbon atom are joined together with the intervening atoms to form optionally substituted C3-8 carbocyclyl or optionally substituted 3-8 membered heterocyclyl; R ⁸ is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-8 carbocyclyl C1-6 alkyl, optionally substituted 3-8 membered heterocyclyl C _1-6 alkyl, optionally substituted C _6-10 aryl C _1-6 alkyl, optionally substituted 5-10 membered heteroaryl C _1-6 alkyl, optionally substituted C _1-6 acyl, or a nitrogen protecting group; each instance of R ^O is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C _1-6 acyl, or an oxygen protecting group; each instance of R ^N is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C _1-6 acyl, or a nitrogen protecting group, or two R ^N bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted 3-8 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl; each instance of R ^S is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C1-6 acyl, or a sulfur protecting group; a and b are each independently 0, 1, or 2; c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as valency permits; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, or 4. [119] In certain embodiments, provided herein are compounds of Formula (I): (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof, wherein: X ¹ is CH, CR ⁹ , or N; X ³ is –NR ¹ – or –O–; X ⁴ is –NR ⁸ – or –O–; R ¹ is hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C _1-6 acyl, or a nitrogen protecting group; R ² and R ⁴ are each independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or a nitrogen protecting group; each instance of R ³ is independently halogen, –CN, –OR ^O , –N(R ^N )2, –SR ^S , optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, or optionally substituted C1-6 acyl; each instance R ⁶ and R ⁹ is independently halogen, –CN, –OR ^O , –N(R ^N ) ₂ , optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, or optionally substituted C1-6 acyl; optionally wherein R ¹ and R ⁹ are joined together with the intervening atoms to form optionally substituted 5-8 membered heterocyclyl; R ⁵ is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-8 carbocyclyl C1-6 alkyl, optionally substituted 3-8 membered heterocyclyl C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted 5-10 membered heteroaryl C1-6 alkyl, optionally substituted C1-6 acyl, or a nitrogen protecting group; optionally wherein R ⁴ and R ⁵ are joined together with the intervening atoms to form optionally substituted 3-8 membered heterocyclyl; each instance of R ⁷ is independently halogen, optionally substituted C1-6 alkyl, –CN, –OR ^O , –N(R ^N )2, or –SR ^S , or two R ⁷ on the same carbon atom are taken together to form =O, or two R ⁷ on the same carbon atom are joined together with the intervening atoms to form optionally substituted C3-8 carbocyclyl or optionally substituted 3-8 membered heterocyclyl; R ⁸ is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-8 carbocyclyl C1-6 alkyl, optionally substituted 3-8 membered heterocyclyl C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted 5-10 membered heteroaryl C1-6 alkyl, optionally substituted C1-6 acyl, or a nitrogen protecting group; each instance of R ^O is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C _1-6 acyl, or an oxygen protecting group; each instance of R ^N is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C _1-6 acyl, or a nitrogen protecting group, or two R ^N bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted 3-8 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl; each instance of R ^S is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C _1-6 acyl, or a sulfur protecting group; a and b are each independently 1 or 2; c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as valency permits; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, or 4. [120] In certain embodiments, a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof. [121] In certain embodiments, a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof. [122] In certain embodiments, a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof. [123] In certain embodiments, a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof. [124] In certain embodiments, a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof. [125] In certain embodiments, a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof. [126] In certain embodiments, a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof. [127] In certain embodiments, a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof. [128] In certain embodiments, a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof. [129] In certain embodiments, a compound of Formula (I) is selected from the compounds recited in Table 1 (infra), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof. In certain embodiments, a compound of Formula (I) is selected from the compounds recited in Table 1 (infra), and pharmaceutically acceptable salts thereof. In certain embodiments, a compound of Formula (I) is selected from the compounds recited in Table 1 (infra). [130] For example, in certain embodiments, a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof. [131] For example, in certain embodiments, a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof. [132] For example, in certain embodiments, a compound of Formula (I) is selected from the group consisting of: , and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof. [133] In the various aspects and embodiments disclosed herein, express reference to a compound of Formula (I) is understood to alternatively refer to a compound of any disclosed subgenus or species thereof, for example, to a compound of Table 1 (infra). [134] The following definitions and embodiments apply to all generic formulae comprising the relevant groups (e.g., Formula (I) or any subgeneric structure thereof) provided herein. [135] As defined herein, X ¹ is CH, CR ⁹ , or N. In certain embodiments, X ¹ is CH. In certain embodiments, X ¹ is CR ⁹ . In certain embodiments, X ¹ is N. [136] As defined herein, R ⁹ is halogen, –CN, –OR ^O , –N(R ^N )2, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, or optionally substituted C1-6 acyl. In certain embodiments, R ⁹ is halogen, –CN, –OR ^O , –N(R ^N )2, optionally substituted C1-6 alkyl, or optionally substituted C1-6 acyl. In certain embodiments, R ⁹ is halogen. In certain embodiments, R ⁹ is –F. In certain embodiments, R ⁹ is –OR ^O (e.g., –OC1-6 alkyl). In certain embodiments, R ⁹ is –OMe. [137] As defined herein, X ³ is –NR ¹ – or –O–. In certain embodiments, X ³ is –NR ¹ –. In certain embodiments, X ³ is –NH–. In certain embodiments, X ³ is –O–. [138] As defined herein, R ¹ is hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C _1-6 acyl, or a nitrogen protecting group. In certain embodiments, R ¹ is hydrogen or optionally substituted C _1-6 alkyl. In certain embodiments, R ¹ is hydrogen. In certain embodiments, R ¹ is optionally substituted C _1-6 alkyl. In certain embodiments, R ¹ is unsubstituted C _1-6 alkyl. In certain embodiments, R ¹ is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert- butyl, and . In certain embodiments, R ¹ is methyl. [139] In certain embodiments, R ¹ and R ⁹ are joined together with the intervening atoms to form optionally substituted 5-8 membered heterocyclyl. In certain embodiments, R ¹ and R ⁹ are joined together with the intervening atoms to form optionally substituted 7-membered heterocyclyl. [140] In certain embodiments, X ⁴ is –NR ⁸ –, –O–, –S–, –S(=O)–, or –S(=O) ₂ –. In certain embodiments, X ⁴ is –NR ⁸ – or –O–. In certain embodiments, X ⁴ is –NR ⁸ –. In certain embodiments, X ⁴ is –NH–. In certain embodiments, X ⁴ is –O–. In certain embodiments, X ⁴ is –S–. In certain embodiments, X ⁴ is –S(=O)–, In certain embodiments, X ⁴ is –S(=O) ₂ –. [141] As defined herein, R ⁸ is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-8 carbocyclyl C1- 6 alkyl, optionally substituted 3-8 membered heterocyclyl C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted 5-10 membered heteroaryl C1-6 alkyl, optionally substituted C1-6 acyl, or a nitrogen protecting group. In certain embodiments, R ⁸ is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 acyl, or a nitrogen protecting group. In certain embodiments, R ⁸ is hydrogen or optionally substituted C1-6 alkyl. In certain embodiments, R ⁸ is hydrogen. In certain embodiments, R ⁸ is optionally substituted C1-6 alkyl. In certain embodiments, R ⁸ is unsubstituted C1-6 alkyl. In certain embodiments, R ⁸ is selected from the group consisting of hydrogen, methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, , , [142] As defined herein, R ² is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 acyl, or a nitrogen protecting group. In certain embodiments, R ² is hydrogen. In certain embodiments, R ² is optionally substituted C _1-6 alkyl. In certain embodiments, R ² is unsubstituted C _1-6 alkyl (e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl). In certain embodiments, R ² is optionally substituted C _1-6 acyl. In certain embodiments, R ² is a nitrogen protecting group. [143] As defined herein, R ⁴ is hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or a nitrogen protecting group. In certain embodiments, R ⁴ is hydrogen. In certain embodiments, R ⁴ is optionally substituted C _1-6 alkyl. In certain embodiments, R ⁴ is unsubstituted C _1-6 alkyl (e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl). In certain embodiments, R ⁴ is optionally substituted C _1-6 acyl. In certain embodiments, R ⁴ is a nitrogen protecting group. [144] As defined herein, each instance of R ³ is independently halogen, –CN, –OR ^O , –N(R ^N ) ₂ , –SR ^S , optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, or optionally substituted C1-6 acyl. In certain embodiments, each instance of R ³ is independently halogen or optionally substituted C _1-6 alkyl. In certain embodiments, at least one instance of R ³ is halogen. In certain embodiments, at least one instance of R ³ is –F. In certain embodiments, at least one instance of R ³ is optionally substituted C1-6 alkyl. In certain embodiments, at least one instance of R ³ is unsubstituted C1-6 alkyl (e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl). [145] As defined herein, n is 0, 1, 2, 3, or 4. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. [146] As defined herein, each instance of R ⁶ is independently halogen, –CN, –OR ^O , –N(R ^N )2, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, or optionally substituted C1-6 acyl. In certain embodiments, each instance of R ⁶ is independently halogen, –CN, –OR ^O , –N(R ^N )2, optionally substituted C1-6 alkyl, or optionally substituted C1-6 acyl. In certain embodiments, each instance of R ⁶ is independently halogen, –OR ^O , or optionally substituted C1-6 alkyl. In certain embodiments, each instance of R ⁶ is independently halogen or optionally substituted C1-6 alkyl. In certain embodiments, at least one instance of R ⁶ is halogen. In certain embodiments, at least one instance of R ⁶ is –OR ^O (e.g., –OC1-6 alkyl). In certain embodiments, at least one instance of R ⁶ is optionally substituted C1-6 alkyl. In certain embodiments, at least one instance of R ⁶ is unsubstituted C1-6 alkyl (e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl). [147] As defined herein, m is 0, 1, 2, or 3. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. [148] As defined herein, R ⁵ is hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C _3-8 carbocyclyl C _{1- 6} alkyl, optionally substituted 3-8 membered heterocyclyl C _1-6 alkyl, optionally substituted C _6-10 aryl C _1-6 alkyl, optionally substituted 5-10 membered heteroaryl C _1-6 alkyl, optionally substituted C _1-6 acyl, or a nitrogen protecting group. In certain embodiments, R ⁵ is hydrogen. In certain embodiments, R ⁵ is optionally substituted C _1-6 alkyl. In certain embodiments, R ⁵ is optionally substituted C _1-6 heteroalkyl. In certain embodiments, R ⁵ is optionally substituted C _2-6 alkenyl. In certain embodiments, R ⁵ is optionally substituted C _2-6 alkynyl. In certain embodiments, R ⁵ is optionally substituted C _3-8 carbocyclyl. In certain embodiments, R ⁵ is optionally substituted 3-8 membered heterocyclyl. In certain embodiments, R ⁵ is optionally substituted C _6-10 aryl. In certain embodiments, R ⁵ is optionally substituted 5-10 membered heteroaryl. In certain embodiments, R ⁵ is optionally substituted C _3-8 carbocyclyl C _1-6 alkyl. In certain embodiments, R ⁵ is optionally substituted 3-8 membered heterocyclyl C1-6 alkyl. In certain embodiments, R ⁵ is optionally substituted C6-10 aryl C1-6 alkyl. In certain embodiments, R ⁵ is optionally substituted 5-10 membered heteroaryl C _1-6 alkyl. In certain embodiments, R ⁵ is optionally substituted C _1-6 acyl. In certain embodiments, R ⁵ is a nitrogen protecting group. [149] In certain embodiments, R ⁴ and R ⁵ are joined together with the intervening atoms to form optionally substituted 3-8 membered heterocyclyl. In certain embodiments, R ⁴ and R ⁵ are joined together with the intervening atoms to form optionally substituted 3-8 membered heterocyclyl comprising 1 or 2 heteroatoms independently selected from O, N, and S. In certain embodiments, R ⁴ and R ⁵ are joined together with the intervening atoms to form optionally substituted 5- or 6-membered heterocyclyl comprising 1 or 2 heteroatoms independently selected from O, N, and S. In certain embodiments, R ⁴ and R ⁵ are joined together with the intervening atoms to form optionally substituted 5- or 6-membered heterocyclyl comprising 1 or 2 heteroatoms independently selected from O and N. [150] In certain embodiments, R ⁵ is of the formula: , wherein: G ¹ is CH, CR ¹⁵ , or N; G ² , G ³ , G ⁴ , and G ⁵ are each independently CH, CR ¹⁶ , or N; each instance of R ¹⁵ and R ¹⁶ is independently halogen, –OR ^O , –N(R ^N )2, –SR ^S , –CN, –N3, –NO2, –SCN, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C1-6 acyl, optionally substituted sulfonyl, or optionally substituted sulfinyl; and R ¹³ and R ¹⁴ are each independently hydrogen, halogen, –OR ^O , –N(R ^N )2, –SR ^S , –CN, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, or optionally substituted C1-6 acyl, or R ¹³ and R ¹⁴ are taken together to form =O, or R ¹³ and R ¹⁴ are joined together with the intervening atoms to form optionally substituted C3-8 carbocyclyl or optionally substituted 3-8 membered heterocyclyl; optionally wherein R ¹³ and R ¹⁵ are joined together with the intervening atoms to form optionally substituted C _5-8 carbocyclyl or optionally substituted 5-8 membered heterocyclyl. [151] In certain embodiments, R ⁵ is of the formula: , wherein: Y ³ is –O–, –NR ^N –, or –S–; each instance of R ¹⁷ is independently halogen, optionally substituted C _1-6 alkyl, –CN, –OR ^O , –N(R ^N ) ₂ , or –SR ^S , or two R ¹⁷ on the same carbon atom are taken together to form =O, or two R ¹⁷ on the same carbon atom are joined together with the intervening atoms to form optionally substituted C _{3- 8} carbocyclyl or optionally substituted 3-8 membered heterocyclyl; d is 0, 1, or 2; and e is 0, 1, 2, 3, 4, 5, 6, or 7, as valency permits. [152] In some embodiments, R ⁵ is of the formula: , wherein p is 0, 1, 2, 3, or 4. In some embodiments, R ⁵ is of the formula: . some embodiments, R ⁵ is of the formula: . [153] In certain embodiments, R ⁵ is of the formula: , wherein p 0, 1, 2, or 3. In certain embodiments, R ⁵ is of the formula: . embodiments, R ⁵ is of the formula: certain embodiments, R ⁵ is: In certain embodiments, R ⁵ is of the formula: [154] In certain embodiments, R ⁵ is of one of the following formulae: , ,

^ ^ ^ ^ [155] In certain embodiments, R ⁵ is of one of the following formulae: , , . [156] In certain embodiments, R ⁵ is of one of the following formulae: , [158] As defined herein, each instance of R ⁷ is independently halogen, optionally substituted C _1-6 alkyl, –CN, –OR ^O , –N(R ^N ) ₂ , or –SR ^S , or two R ⁷ on the same carbon atom are taken together to form =O, or two R ⁷ on the same carbon atom are joined together with the intervening atoms to form optionally substituted C _3-8 carbocyclyl or optionally substituted 3-8 membered heterocyclyl. In certain embodiments, each instance of R ⁷ is independently halogen or optionally substituted C _1-6 alkyl, or two R ⁷ on the same carbon atom are taken together to form =O. In certain embodiments, at least one instance of R ⁷ is halogen. In certain embodiments, at least one instance of R ⁷ is optionally substituted C _1-6 alkyl. In certain embodiments, In certain embodiments, at least one instance of R ⁷ is unsubstituted C _1-6 alkyl (e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl). certain embodiments, In certain embodiments, at least one instance of R ⁷ is methyl. In certain embodiments, two R ⁷ on the same carbon atom are taken together to form =O. [159] As defined herein, c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as valency permits. In certain embodiments, c is 0. In certain embodiments, c is 1. In certain embodiments, c is 2. In certain embodiments, c is 3. In certain embodiments, c is 4. In certain embodiments, c is 5. In certain embodiments, c is 6. In certain embodiments, c is 7. In certain embodiments, c is 8. In certain embodiments, c is 9. In certain embodiments, c is 10. [160] In certain embodiments, a is 0, 1, or 2In certain embodiments, a is 1 or 2. In certain embodiments, a is 0. In certain embodiments, a is 1. In certain embodiments, a is 2. [161] In certain embodiments, b is 0, 1, or 2. In certain embodiments, b is 1 or 2. In certain embodiments, b is 0. In certain embodiments, b is 1. In certain embodiments, b is 2. [162] In certain embodiments, a is 1; and b is 1. In certain embodiments, a is 1; and b is 2. In certain embodiments, a is 2; and b is 1. In certain embodiments, a is 2; and b is 2. [163] As defined herein, G ¹ is CH, CR ¹⁵ , or N. In some embodiments, G ¹ is CR ¹⁵ . In some embodiments, G ¹ is CH. In some embodiments, G ¹ is N. [164] As defined herein, G ² is CH, CR ¹⁶ , or N. In some embodiments, G ² is CR ¹⁶ . In some embodiments, G ² is CH. In some embodiments, G ² is N. [165] As defined herein, G ³ is CH, CR ¹⁶ , or N. In some embodiments, G ³ is CR ¹⁶ . In some embodiments, G ³ is CH. In some embodiments, G ³ is N. [166] As defined herein, G ⁴ is CH, CR ¹⁶ , or N. In some embodiments, G ⁴ is CR ¹⁶ . In some embodiments, G ⁴ is CH. In some embodiments, G ⁴ is N. [167] As defined herein, G ⁵ is CH, CR ¹⁶ , or N. In some embodiments, G ⁵ is CR ¹⁶ . In some embodiments, G ⁵ is CH. In some embodiments, G ⁵ is N. [168] In some embodiments, G ² , G ³ , G ⁴ , and G ⁵ are independently CR ¹⁶ or CH. In some embodiments, G ² , G ³ , G ⁴ , and G ⁵ are CH. In some embodiments, G ² , G ³ , and G ⁴ are independently CR ¹⁶ or CH; and G ⁵ is N. In some embodiments, G ² , G ³ , and G ⁴ are CH; and G ⁵ is N. [169] As defined herein, R ¹⁵ is halogen, –OR ^O , –N(R ^N )2, –SR ^S , –CN, –N3, –NO2, –SCN, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C1-6 acyl, optionally substituted sulfonyl, or optionally substituted sulfinyl. In certain embodiments, R ¹⁵ is halogen, –OR ^O , –N(R ^N )2, –SR ^S , –CN, –N3, –NO2, –SCN, optionally substituted C1-6 alkyl, or optionally substituted C1-6 acyl. In certain embodiments, R ¹⁵ is halogen, optionally substituted C1-6 alkyl, –OR ^O , or –N(R ^N )2. In certain embodiments, R ¹⁵ is halogen (e.g., –F, –Br, –Cl, –I). In certain embodiments, R ¹⁵ is optionally substituted C1-6 alkyl. In certain embodiments, R ¹⁵ is unsubstituted C1-6 alkyl (e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso- butyl, sec-butyl, tert-butyl). In certain embodiments, R ¹⁵ is substituted C1-6 alkyl (e.g., C1-6 haloalkyl, e.g., –CF ₃ ). In certain embodiments, R ¹⁵ is –OR ^O (e.g., –OC _1-6 alkyl, e.g., –OMe). In certain embodiments, R ¹⁵ is –N(R ^N ) ₂ (e.g., –N(C _1-6 alkyl) ₂ , e.g., –NMe ₂ ). [170] As defined herein, each instance of R ¹⁶ is independently halogen, –OR ^O , –N(R ^N ) ₂ , –SR ^S , –CN, –N ₃ , –NO ₂ , –SCN, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _2-6 alkenyl, optionally substituted alkynyl, optionally substituted C _3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C _1-6 acyl, optionally substituted sulfonyl, or optionally substituted sulfinyl. In certain embodiments, each instance of R ¹⁶ is independently halogen, –OR ^O , –N(R ^N ) ₂ , –SR ^S , –CN, –N ₃ , –NO ₂ , –SCN, optionally substituted C _1-6 alkyl, or optionally substituted C _1-6 acyl. In certain embodiments, each instance of R ¹⁶ is independently halogen, optionally substituted C _1-6 alkyl, –OR ^O , or –N(R ^N ) ₂ . In certain embodiments, at least one instance of R ¹⁶ is halogen (e.g., –F, –Br, –Cl, –I). In certain embodiments, at least one instance of R ¹⁶ is optionally substituted C _1-6 alkyl. In certain embodiments, at least one instance of R ¹⁶ is unsubstituted C _1-6 alkyl (e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert- butyl). In certain embodiments, at least one instance of R ¹⁶ is substituted C _1-6 alkyl (e.g., C _1-6 haloalkyl, e.g., –CF3). In certain embodiments, at least one instance of R ¹⁶ is –OR ^O (e.g., –OC1-6 alkyl, e.g., –OMe). In certain embodiments, at least one instance of R ¹⁶ is –N(R ^N ) ₂ (e.g., –N(C _1-6 alkyl) ₂ , e.g., –NMe ₂ ). [171] As defined herein, p is 0, 1, 2, 3, or 4. In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4. [172] As defined herein, R ¹³ is hydrogen, halogen, –OR ^O , –N(R ^N )2, –SR ^S , –CN, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, or optionally substituted C1-6 acyl. In certain embodiments, R ¹³ is hydrogen, halogen, –CN, optionally substituted C1-6 alkyl, or optionally substituted C3-6 carbocyclyl. In certain embodiments, R ¹³ is hydrogen, –CN, optionally substituted C1-6 alkyl, or optionally substituted C3-6 carbocyclyl. In certain embodiments, R ¹³ is hydrogen. In certain embodiments, R ¹³ is –CN. In certain embodiments, R ¹³ is optionally substituted C1-6 alkyl. In certain embodiments, R ¹³ is unsubstituted C1-6 alkyl (e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl). In certain embodiments, R ¹³ is substituted C1-6 alkyl (e.g., C1-6 haloalkyl, e.g., –CF3). In certain embodiments, R ¹³ is optionally substituted C3-6 carbocyclyl. In certain embodiments, R ¹³ is unsubstituted C3-6 carbocyclyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl). In certain embodiments, R ¹³ is selected from the group consisting of hydrogen, –CN, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, [173] As described herein, R ¹⁴ is hydrogen, halogen, –OR ^O , –N(R ^N ) ₂ , –SR ^S , –CN, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _2-6 alkenyl, optionally substituted alkynyl, optionally substituted C _3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, or optionally substituted C _1-6 acyl. In certain embodiments, R ¹⁴ is hydrogen, halogen, –CN, optionally substituted C _1-6 alkyl, or optionally substituted C _3-6 carbocyclyl. In certain embodiments, R ¹⁴ is hydrogen, –CN, optionally substituted C _1-6 alkyl, or optionally substituted C _3-6 carbocyclyl. In certain embodiments, R ¹⁴ is hydrogen. In certain embodiments, R ¹⁴ is optionally substituted C _1-6 alkyl. In certain embodiments, R ¹⁴ is unsubstituted C _1-6 alkyl (e.g., methyl, ethyl, n-propyl, iso-propyl, n- butyl, iso-butyl, sec-butyl, tert-butyl). [174] In certain embodiments, R ¹⁴ is hydrogen; and R ¹³ is hydrogen, –CN, optionally substituted C _1-6 alkyl, or optionally substituted C _3-6 carbocyclyl. In certain embodiments, R ¹⁴ is hydrogen; and R ¹³ is hydrogen. In certain embodiments, R ¹⁴ is hydrogen; and R ¹³ is –CN. In certain embodiments, R ¹⁴ is hydrogen; and R ¹³ is optionally substituted C _1-6 alkyl. In certain embodiments, R ¹⁴ is hydrogen; and R ¹³ is unsubstituted C1-6 alkyl. In certain embodiments, R ¹⁴ is hydrogen; and R ¹³ is optionally substituted C _3-6 carbocyclyl. In certain embodiments, R ¹⁴ is hydrogen; and R ¹³ is unsubstituted C _3-6 carbocyclyl. In certain embodiments, R ¹⁴ is hydrogen; and R ¹³ is selected from the group consisting of hydrogen, –CN, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, –CF3, [175] In certain embodiments, R ¹³ and R ¹⁴ are taken together to form =O; or R ¹³ and R ¹⁴ are joined together with the intervening atoms to form optionally substituted C3-8 carbocyclyl or optionally substituted 3-8 membered heterocyclyl. In certain embodiments, R ¹³ and R ¹⁴ are taken together to form =O. In certain embodiments, R ¹³ and R ¹⁴ are joined together with the intervening atoms to form optionally substituted C3-8 carbocyclyl or optionally substituted 3-8 membered heterocyclyl. [176] In certain embodiments, R ¹³ and R ¹⁵ are joined together with the intervening atoms to form optionally substituted C5-8 carbocyclyl or optionally substituted 5-8 membered heterocyclyl. In some embodiments, R ¹³ and R ¹⁵ are joined together with the intervening atoms to form optionally substituted 5-7 membered heterocyclyl comprising 1 or 2 heteroatoms independently selected from O, N, and S. In some embodiments, R ¹³ and R ¹⁵ are joined together with the intervening atoms to form optionally substituted 5-7 membered heterocyclyl comprising 1 heteroatom selected from O, N, and S. In some embodiments, R ¹³ and R ¹⁵ are joined together with the intervening atoms to form optionally substituted 5-7 membered heterocyclyl comprising 1 O atom. In some embodiments, R ¹³ and R ¹⁵ are joined together with the intervening atoms to form optionally substituted 6-membered heterocyclyl comprising 1 or 2 heteroatoms independently selected from O, N, and S. In some embodiments, R ¹³ and R ¹⁵ are joined together with the intervening atoms to form optionally substituted 6-membered heterocyclyl comprising 1 heteroatom selected from O, N, and S. In some embodiments, R ¹³ and R ¹⁵ are joined together with the intervening atoms to form optionally substituted 6-membered heterocyclyl comprising 1 O atom. [177] As defined herein, Y ³ is –O–, –NR ^N –, or –S–. In certain embodiments, Y ³ is –O–. In certain embodiments, Y ³ is –NR ^N –. In certain embodiments, Y ³ is –NH–. In certain embodiments, Y ³ is –S–. [178] As defined herein, d is 0, 1, or 2. In certain embodiments, d is 0. In certain embodiments, d is 1. In certain embodiments, d is 2. [179] As defined herein, each instance of R ¹⁷ is independently halogen, optionally substituted C _1-6 alkyl, –CN, –OR ^O , –N(R ^N ) ₂ , or –SR ^S , or two R ¹⁷ on the same carbon atom are taken together to form =O, or two R ¹⁷ on the same carbon atom are joined together with the intervening atoms to form optionally substituted C _3-8 carbocyclyl or optionally substituted 3-8 membered heterocyclyl. In certain embodiments, each instance of R ¹⁷ is independently halogen or optionally substituted C _1-6 alkyl. In certain embodiments, at least one instance of R ¹⁷ is optionally substituted C _1-6 alkyl. In certain embodiments, at least one instance of R ¹⁷ is unsubstituted C _1-6 alkyl (e.g., methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl). In certain embodiments, at least one instance of R ¹⁷ is methyl. In certain embodiments, two R ¹⁷ on the same carbon atom are joined together with the intervening atoms to form optionally substituted C _3-8 carbocyclyl. In certain embodiments, two R ¹⁷ on the same carbon atom are joined together with the intervening atoms to form optionally substituted C5- 7 carbocyclyl. In certain embodiments, two R ¹⁷ on the same carbon atom are joined together with the intervening atoms to form unsubstituted C5-7 carbocyclyl. In certain embodiments, two R ¹⁷ on the same carbon atom are joined together with the intervening atoms to form optionally substituted 3-8 membered heterocyclyl comprising 1 or 2 heteroatoms independently selected from O, N, and S. In certain embodiments, two R ¹⁷ on the same carbon atom are joined together with the intervening atoms to form optionally substituted 5-7 membered heterocyclyl comprising 1 or 2 heteroatoms independently selected from O, N, and S. In certain embodiments, two R ¹⁷ on the same carbon atom are joined together with the intervening atoms to form optionally substituted 5-7 membered heterocyclyl comprising 1 heteroatom selected from O and N. In certain embodiments, two R ¹⁷ on the same carbon atom are joined together with the intervening atoms to form unsubstituted 5-7 membered heterocyclyl comprising 1 heteroatom selected from O and N. [180] As described herein, e is 0, 1, 2, 3, 4, 5, 6, or 7, as valency permits. In certain embodiments, e is 0. In certain embodiments, e is 1. In certain embodiments, e is 2. In certain embodiments, e is 3. In certain embodiments, e is 4. In certain embodiments, e is 5. In certain embodiments, e is 6. In certain embodiments, e is 7. [181] As defined herein, each instance of R ^O is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C _1-6 acyl, or an oxygen protecting group. In certain embodiments, each instance of R ^O is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or an oxygen protecting group. In certain embodiments, at least one instance of R ^O is hydrogen. In certain embodiments, at least one instance of R ^O is optionally substituted C _1-6 alkyl. In certain embodiments, at least one instance of R ^O is unsubstituted C _1-6 alkyl. In certain embodiments, at least one instance of R ^O is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, or tert-butyl. In certain embodiments, at least one instance of R ^O is optionally substituted C _1-6 acyl. In certain embodiments, at least one instance of R ^O is an oxygen protecting group. [182] As defined herein, each instance of R ^N is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C _1-6 acyl, or a nitrogen protecting group, or two R ^N bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted 3-8 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl. In certain embodiments, each instance of R ^N is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or a nitrogen protecting group. In certain embodiments, at least one instance of R ^N is hydrogen. In certain embodiments, at least one instance of R ^N is optionally substituted C1-6 alkyl. In certain embodiments, at least one instance of R ^N is unsubstituted C1-6 alkyl. In certain embodiments, at least one instance of R ^N is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, or tert-butyl. In certain embodiments, at least one instance of R ^N is optionally substituted C1-6 acyl. In certain embodiments, at least one instance of R ^N is a nitrogen protecting group. In certain embodiments, two R ^N bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted 3-8 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl. In certain embodiments, two R ^N bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted 3-8 membered heterocyclyl. In certain embodiments, two R ^N bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted 5-7 membered heterocyclyl comprising 1 or 2 heteroatoms independently selected from O, N, and S. In certain embodiments, two R ^N bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted 5-7 membered heterocyclyl comprising 1 or 2 heteroatoms selected from O and N. In certain embodiments, two R ^N bonded to the same nitrogen atom are joined together with the intervening atoms to form unsubstituted 5-7 membered heterocyclyl comprising 1 or 2 heteroatoms selected from O and N. [183] As defined herein, each instance of R ^S is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C _1-6 acyl, or a sulfur protecting group. In certain embodiments, each instance of R ^S is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or an oxygen protecting group. In certain embodiments, at least one instance of R ^S is hydrogen. In certain embodiments, at least one instance of R ^S is optionally substituted C _1-6 alkyl. In certain embodiments, at least one instance of R ^S is unsubstituted C _1-6 alkyl. In certain embodiments, at least one instance of R ^S is selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, or tert-butyl. In certain embodiments, at least one instance of R ^S is optionally substituted C _1-6 acyl. In certain embodiments, at least one instance of R ^S is an oxygen protecting group. [184] The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. Pharmaceutical Compositions, Kits, and Administration [185] The present disclosure provides pharmaceutical compositions comprising a compound provided herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof). The pharmaceutical composition may comprise one or more pharmaceutically acceptable carriers/excipients. In certain embodiments, a compound described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount. [186] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping, and/or packaging the product into a desired single- or multi-dose unit. [187] Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage. [188] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w/w) active ingredient. [189] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition. [190] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof. [191] Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof. [192] Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween ^® 20), polyoxyethylene sorbitan (Tween ^® 60), polyoxyethylene sorbitan monooleate (Tween ^® 80), sorbitan monopalmitate (Span ^® 40), sorbitan monostearate (Span ^® 60), sorbitan tristearate (Span ^® 65), glyceryl monooleate, sorbitan monooleate (Span ^® 80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj ^® 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol ^® ), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor ^® ), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij ^® 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic ^® F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof. [193] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum ^® ), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof. [194] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent. [195] Exemplary antioxidants include alpha tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite. [196] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal. [197] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. [198] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. [199] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. [200] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant ^® Plus, Phenonip ^® , methylparaben, Germall ^® 115, Germaben ^® II, Neolone ^® , Kathon ^® , and Euxyl ^® . [201] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer’s solution, ethyl alcohol, and mixtures thereof. [202] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof. [203] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof. [204] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor ^® , alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof. [205] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [206] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle. [207] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent. [208] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like. [209] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes. [210] Dosage forms for topical and/or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and/or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel. [211] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder/particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable. [212] Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions. Formulations for topical administration may further comprise one or more of the additional ingredients described herein. [213] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient. [214] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions can be conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form. Low-boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. The propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient). [215] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers. [216] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares. [217] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods. Alternately, formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein. [218] A pharmaceutical composition described herein can be prepared, packaged, and/or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are also contemplated as being within the scope of this disclosure. [219] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. [220] Compounds provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts. [221] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically, contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration). In certain embodiments, the compound or pharmaceutical composition described herein is suitable for topical administration to the eye of a subject. [222] The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. [223] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and/or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and/or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify metabolism, inhibit excretion, and/or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both. In some embodiments, the additional pharmaceutical agent achieves a desired effect for the same disorder. In some embodiments, the additional pharmaceutical agent achieves different effects. [224] The compound or composition can be administered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. Pharmaceutical agents include therapeutically active agents. Pharmaceutical agents also include prophylactically active agents. Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins, and cells. [225] The additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti-cancer agents, anti-angiogenesis agents, steroidal or non-steroidal anti-inflammatory agents (NSAIDs), immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti-allergic agents, contraceptive agents, pain- relieving agents, anesthetics, anti–coagulants, inhibitors of an enzyme, steroidal agents, steroidal or antihistamine, antigens, vaccines, antibodies, decongestant, sedatives, opioids, analgesics, anti– pyretics, and hormones. [226] In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In certain embodiments, the additional pharmaceutical agent is an anti-cancer agent. “Anti-cancer agents” encompass biotherapeutic anti-cancer agents as well as chemotherapeutic agents. [227] In certain embodiments, the additional pharmaceutical agent is a protein kinase inhibitor. In certain embodiments, the additional pharmaceutical agent is selected from the group consisting of epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs, hormone receptor modulators (e.g., estrogen receptor modulators and androgen receptor modulators), cell signaling pathway inhibitors (e.g., tyrosine protein kinase inhibitors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, and other agents that promote differentiation. [228] Exemplary biotherapeutic anti-cancer agents include, but are not limited to, interferons, cytokines, vaccines, hematopoietic growth factors, monoclonal serotherapy, immunostimulants and/or immunomodulatory agents, immune cell growth factors, and antibodies. [229] In certain embodiments, a compound or composition is used in combination with an immunotherapy. In certain embodiments, a compound or composition is used in combination with an immune checkpoint inhibitor. Checkpoint inhibitors can be broken down into at least 4 major categories: i) agents such as antibodies that block an inhibitory pathway directly on T cells or natural killer (NK) cells (e.g., PD-1 targeting antibodies, antibodies targeting TIM-3, and antibodies targeting LAG-3, 2B4, CD160, A2aR, BTLA, CGEN-15049, or KIR); ii) agents such as antibodies that activate stimulatory pathways directly on T cells or NK cells (e.g., antibodies targeting OX40, GITR, or 4- 1BB); iii) agents such as antibodies that block a suppressive pathway on immune cells or rely on antibody-dependent cellular cytotoxicity to deplete suppressive populations of immune cells (e.g., CTLA-4 targeting antibodies, antibodies targeting VISTA, and antibodies targeting PD-L2, Gr1, or Ly6G), and iv) agents such as antibodies that block a suppressive pathway directly on cancer cells or that rely on antibody-dependent cellular cytotoxicity to enhance cytotoxicity to cancer cells (e.g., antibodies targeting PD-L1, and antibodies targeting B7-H3, B7-H4, Gal-9, or MUC1). [230] In certain embodiments, the checkpoint inhibitor is an inhibitory antibody, a fusion protein, an agent that interacts with a checkpoint protein, an agent that interacts with the ligand of a checkpoint protein, an inhibitor of CTLA-4, an inhibitor of PD-1, an inhibitor of PDL1, an inhibitor of PDL2, or an inhibitor of B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, or B-7 family ligands. [231] Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or composition or administered separately in different doses or compositions. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually. [232] In certain embodiments, the compounds described herein or pharmaceutical compositions can be administered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, and transplantation (e.g., stem cell transplantation, bone marrow transplantation). [233] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a pharmaceutical composition or compound described herein and a container (e.g., a vial, ampule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a pharmaceutical composition or compound described herein. In some embodiments, the pharmaceutical composition or compound described herein provided in the first container and the second container are combined to form a single unit dosage form. Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating a disease (e.g., cancer) in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease in a subject in need thereof. [234] In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In certain embodiments, the information included in the kits is prescribing information. In certain embodiments, the kits provide instructions for treating a disease (e.g., cancer) in a subject in need thereof. In certain embodiments, the kits provide instructions for preventing a disease in a subject in need thereof. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition. Methods of Treatment and Uses [235] Compounds provided herein are G protein-coupled receptor kinase (e.g., GRK2, GRK3) inhibitors and are therefore useful in, e.g., treating and/or preventing diseases (e.g., proliferative diseases (e.g., cancer), cardiovascular diseases) in a subject, inhibiting tumor growth in a subject, inhibiting GRK2 or GRK3 activity in vitro or in vivo, etc. [236] Provided herein are methods of treating and/or preventing a disease in a subject comprising administering to the subject a therapeutically and/or prophylactically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof. Also provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof, and pharmaceutical compositions thereof, for use in treating and/or preventing a disease in a subject. Also provided herein are uses of compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments. [237] In certain embodiments, the disease is a GRK2-related disease. In certain embodiments, the disease is a GRK3-related disease. In certain embodiments, the disease is a hematological disease, an infection, a cardiovascular disease, (e.g., cardiac failure, cardiac hypertrophy, hypertension), a proliferative disease (e.g., cancer), an endocrinological disease, a metabolic disease, a gastroenterological disease, a respiratory disease, inflammation (e.g., inflammatory bowel disease), a neurological disease, opioid addiction, or an urological disease. [238] In certain embodiments, the disease is a proliferative disease (e.g., cancer). Provided herein are methods of treating a proliferative disease (e.g., cancer) in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof. Also provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof, and pharmaceutical compositions thereof, for use in treating a proliferative disease (e.g., cancer) in a subject. Also provided herein are uses of compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co- crystals, and prodrugs thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for treating proliferative diseases (e.g., cancer). In certain embodiments, the proliferative disease is cancer. In certain embodiments, the cancer is pancreatic cancer. In certain embodiments, the cancer is colon cancer. [239] Also provided herein are method comprising administering to a subject a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof, wherein the subject has a proliferative disease (e.g., cancer). In certain embodiments, the proliferative disease is cancer. In certain embodiments, the cancer is pancreatic cancer. In certain embodiments, the cancer is colon cancer. [240] A “proliferative disease” refers to a disease that occurs due to abnormal growth or extension by the multiplication of cells (See, e.g., Walker, Cambridge Dictionary of Biology$^^&^^^^'^^^(^^)^^*^^+^ Press: Cambridge, UK, 1990). A proliferative disease may be associated with: 1) the pathological ^^,^-^^&^^^^^^-^^^^^&,,+^.^^^*^^^^^^^,,*$^/^^^^^^ &^^^,^^^^&,^^^^^&^^^^^^-^^^,,*^-^^^^^^^^^^^^^^&a mp;,^ location (e.g.0^^^^&*^&*^*^^-^^^^ ,&*^^^^^^,,*^$^"^^^^^^ &^^^,^^^^&,^^1 ^^**^^^^^-^ ^^^^^,+^^^^^^2+^^*^ such as the matrix metalloproteinases (e.g.0^^^,,&^^^&*^*0^^^,&^^^&*^*0^&^'^^, &*^&*^*^$^^^^3^^^^^^ pathological angiogenesis as in proliferative retinopathy and tumor metastasis. Exemplary proliferative diseases include cancers (i.e., “malignant neoplasms”), benign neoplasms, angiogenesis, inflammatory diseases, and autoimmune diseases. [241] The term “angiogenesis” refers to the physiological process through which new blood vessels form from pre-existing vessels. Angiogenesis is distinct from vasculogenesis, which is the de novo formation of endothelial cells from mesoderm cell precursors. The first vessels in a developing embryo form through vasculogenesis, after which angiogenesis is responsible for most blood vessel growth during normal or abnormal development. Angiogenesis is a vital process in growth and development, as well as in wound healing and in the formation of granulation tissue. However, angiogenesis is also a fundamental step in the transition of tumors from a benign state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer. Angiogenesis may be chemically stimulated by angiogenic proteins, such as growth factors (e.g., VEGF). “Pathological angiogenesis” refers to abnormal (e.g., excessive or insufficient) angiogenesis that amounts to and/or is associated with a disease. [242] The terms “neoplasm” and “tumor” are used herein interchangeably and refer to an abnormal mass of tissue wherein the growth of the mass surpasses and is not coordinated with the growth of a normal tissue. A neoplasm or tumor may be “benign” or “malignant,” depending on the following characteristics: degree of cellular differentiation (including morphology and functionality), rate of growth, local invasion, and metastasis. A “benign neoplasm” is generally well differentiated, has characteristically slower growth than a malignant neoplasm, and remains localized to the site of origin. In addition, a benign neoplasm does not have the capacity to infiltrate, invade, or metastasize to distant sites. Exemplary benign neoplasms include, but are not limited to, lipoma, chondroma, adenomas, acrochordon, senile angiomas, seborrheic keratoses, lentigos, and sebaceous hyperplasias. In some cases, certain “benign” tumors may later give rise to malignant neoplasms, which may result from additional genetic changes in a subpopulation of the tumor’s neoplastic cells, and these tumors are referred to as “pre-malignant neoplasms.” An exemplary pre-malignant neoplasm is a teratoma. In contrast, a “malignant neoplasm” is generally poorly differentiated (anaplasia) and has characteristically rapid growth accompanied by progressive infiltration, invasion, and destruction of the surrounding tissue. Furthermore, a malignant neoplasm generally has the capacity to metastasize to distant sites. The term “metastasis,” “metastatic,” or “metastasize” refers to the spread or migration of cancerous cells from a primary or original tumor to another organ or tissue and is typically identifiable by the presence of a “secondary tumor” or “secondary cell mass” of the tissue type of the primary or original tumor and not of that of the organ or tissue in which the secondary (metastatic) tumor is located. [243] In certain embodiments, the proliferative disease to be treated is cancer. In certain embodiments, the cancer is a GRK2-related cancer. In certain embodiments, the cancer is a GRK3- related cancer. [244] The term “cancer” refers to a class of diseases characterized by the development of abnormal cells that proliferate uncontrollably and have the ability to infiltrate and destroy normal body tissues. In certain embodiments, the cancer is a solid tumor. In certain embodiments, the cancer is a hematopoietic cancer (i.e., hematological cancer). [245] In certain embodiments, the cancer is a hematopoietic cancer (e.g., leukemia (e.g., acute lymphocytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-^^,,^^44^^$^,+^ ^^^&^^e.g., Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL)), non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma)), follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomads, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenström’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma, T-cell NHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungoides, Sezary syndrome)), angioimmunoblastic T-cell lymphoma, extranodal natural killer T-cell lymphoma, enteropathy type T- cell lymphoma, subcutaneous panniculitis-like T-^^,,^,+^ ^^^&0^&^& ,&*^^^^,&^^^^^^,,^,+^ ^^^&^$^ heavy chain disease (e.g.0^&, ^&^^^&^^^'^*^&*^0^^&^^&^^^&^^^'^*^&a mp;*^0^^^^^^&^^^'^*^&*^^$^&^ myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF), chronic idiopathic myelofibrosis, chronic myelocytic leukemia (CML), chronic neutrophilic leukemia (CNL), hypereosinophilic syndrom^^^56^^^$^^^,^^ ,^^^+^,^^&^^77^$^ ,&*^&^^^,,^^^^ ,&*^&$^-&^^,^&^^^+ ^^^^*^^^ ^^,^&$^ ^^-,&^^&^^^+^^+^-^^^^^,&*^^^^^^^^^*$^^^^^^^^+^^^ ^&^+,^^'^*^*^^^^^^^^^^&^^^^^^^'^^^^^*0^^^^^^&^^^ ^^ is leukemia. In certain embodiments, the cancer is acute lymphoblastic leukemia (ALL). In certain embodiments, the cancer is early T-cell precursor (ETP)-acute lymphoblastic leukemia (ALL). [246] In certain embodiments, the cancer is liver cancer (e.g., hepatocellular cancer (HCC) (e.g., hepatocellular carcinoma, hepatoblastoma, hepatocellular adenoma), malignant hepatoma, hemangiomas, biliary cancer (e.g., cholangiocarcinoma)). [247] In certain embodiments, the cancer is musculoskeletal cancer (e.g., bone cancer (e.g., osteosarcoma, osteoid osteoma, malignant fibrous histiocytoma, Ewing’s sarcoma, chordoma, malignant giant cell tumor chordoma, chondrosarcoma osteochondroma, benign chondroma, chondroblastoma chondromyxofibroma, myelodysplastic syndrome (MDS)), muscle cancer (e.g., rhabdomyosarcoma, rhabdomyoma), connective tissue cancer, synovioma). [248] In certain embodiments, the cancer is a nervous system cancer (e.g., brain cancer (e.g., astrocytoma, medulloblastoma, glioma (e.g., astrocytoma, oligodendroglioma), glioblastomas, glioblastoma multiform, medulloblastoma, ependymoma, germinoma (i.e., pinealoma), oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, craniopharyngioma), spinal cord cancer, neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroblastoma, primitive neuroectodermal tumors (PNT), meningeal cancer (e.g., meningioma, meningiosarcoma, gliomatosis), skull cancer, acoustic neuroma, ependymoma, hemangioblastoma, ocular cancer (e.g., intraocular melanoma, retinoblastoma)). In certain embodiments, the disease to be treated is a brain tumor. In certain embodiments, the disease is pleomorphic xenoanthrocytoma (PXA). In certain embodiments, the disease is pediatric pleomorphic xenoanthrocytoma (PXA). [249] In certain embodiments, the cancer is selected from endocrine/exocrine cancers (e.g., thyroid cancer (e.g.0^ & ^,,&^+^^^+^^^'^^&^^^^^^&0^-^,,^^^,&^^^^+^^^' ^^&^^^^^^&$^^^'^,,&^+^^^+^^^'^^&^^^^^^&0 ^ multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type 2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma), pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell tumors, ductal adenocarcinoma, insulinoma, glucagonoma, vipoma), adrenal gland cancer, neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor), sebaceous gland carcinoma, sweat gland carcinoma). In certain embodiments, the cancer is sweat gland cancer (e.g., sweat gland carcinoma). [250] In certain embodiments, the cancer is head and neck cancer (e.g., squamous cell carcinoma of the head and neck (SCCHN), adenoid cystic carcinoma). [251] In certain embodiments, the cancer is oral cancer (e.g., buccal cavity cancer, lip cancer, tongue cancer, mouth cancer, pharynx cancer, hypopharynx cancer (e.g., hypopharyngeal carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal cancer, nasopharyngeal cancer, oropharyngeal cancer), salivary gland cancer). [252] In certain embodiments, the cancer is esophageal cancer (e.g., esophageal squamous cell carcinoma, esophageal adenocarcinoma, Barrett’s adenocarcinoma, esophageal leiomyosarcoma). [253] In certain embodiments, the cancer is gastrointestinal cancer (e.g., anal cancer, colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), gall bladder cancer, gastric cancer (e.g., stomach cancer (e.g., stomach adenocarcinoma)), gastrointestinal stromal tumor (GIST), small bowel cancer (e.g., appendix cancer, small bowel carcinoma, e.g., small bowel adenocarcinoma), small intestine cancer, large bowel cancer, large intestine cancer). [254] In certain embodiments, the cancer is cardiovascular cancer (e.g., primary cardiac tumors, angiosarcoma (e.g., lymphangiosarcoma, lymphangioendotheliosarcoma, hemangiosarcoma), endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple idiopathic hemorrhagic sarcoma), cardiac myxoma, cardiac rhabdomyoma). [255] In certain embodiments, the cancer is lung cancer (e.g., bronchus cancer (e.g., bronchogenic carcinoma, bronchial adenoma), alveolar carcinoma, mesothelioma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), lung adenocarcinoma, chondromatous hamartoma, papillary adenocarcinoma). [256] In certain embodiments, the cancer is a genitourinary cancer (e.g., bladder cancer (e.g., urothelial carcinoma), urethral cancer, kidney cancer (e.g., nephroblastoma a.k.a. Wilms’ tumor, renal cell carcinoma), testicular cancer (e.g., seminoma, testicular embryonal carcinoma), germ cell cancer, prostate cancer (e.g., prostate adenocarcinoma), penile cancer (e.g., Paget’s disease of the penis and scrotum)). [257] In certain embodiments, the cancer is a gynecological cancer (e.g., breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast, triple negative breast cancer, HER-2 positive breast cancer, HER2-negative breast cancer), endometrial cancer (e.g., uterine cancer (e.g., uterine sarcoma, choriocarcinoma), endometrial carcinoma), cervical cancer (e.g., cervical adenocarcinoma), ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), germ cell cancer, vulvar cancer (e.g., Paget’s disease of the vulva) vaginal cancer, fallopian tube cancer). [258] In certain embodiments, the cancer is skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC), dermatofribroma). [259] In certain embodiments, the cancer is a soft tissue cancer (e.g., intraepithelial neoplasms, epithelial carcinomas, epithelial sarcomas, adenocarcinomas, adenomas, fibrosarcomas, fibromas, liposarcomas, lipomas, myxomas, teratomas). [260] In certain embodiments, the cancer is skin cancer (e.g., melanoma), breast cancer, ovarian cancer, prostate cancer, gliomas, thyroid cancer, pancreatic cancer, bile duct cancer, urinary tract cancer, head and neck cancer, gastric cancer, rhabdoid cancer, mesothelioma, cervical cancer, liver cancer, colorectal cancer, lymphoma, lung cancer, leukemia, or kidney cancer. In certain embodiments, the cancer is pancreatic cancer. [261] Additionally, provided herein are methods of inhibiting tumor growth in a subject comprising administering to the subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof. Also provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof, and pharmaceutical compositions thereof, for use in inhibiting tumor growth in a subject. Also provided herein are uses of compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for inhibiting tumor growth. [262] In certain embodiments, the tumor is a GRK2-related tumor. In certain embodiments, the tumor is a GRK3-related tumor. In certain embodiments, the tumor is a pancreatic tumor. In certain embodiments, the tumor is a colorectal tumor. [263] In certain embodiments, treating cancer and/or inhibiting tumor growth can result in a reduction in size or volume of a tumor. For example, after treatment, tumor size is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to its size prior to treatment. Size of a tumor may be measured by any reproducible means of measurement. The size of a tumor may be measured as a diameter of the tumor or by any reproducible means of measurement. In certain embodiments, the tumor size is reduced by at least 25% relative to its size prior to treatment. [264] In certain embodiments, treating cancer and/or inhibiting tumor growth may further result in a decrease in number of tumors. For example, after treatment, tumor number is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment. Number of tumors may be measured by any reproducible means of measurement. The number of tumors may be measured by counting tumors visible to the naked eye or at a specified magnification (e.g., 2x, 3x, 4x, 5x, 10x, or 50x). [265] In certain embodiments, treating cancer can result in a decrease in number of metastatic nodules in other tissues or organs distant from the primary tumor site. For example, after treatment, the number of metastatic nodules is reduced by 5% or greater (e.g., 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater) relative to number prior to treatment. The number of metastatic nodules may be measured by any reproducible means of measurement. The number of metastatic nodules may be measured by counting metastatic nodules visible to the naked eye or at a specified magnification (e.g., 2x, 10x, or 50x). [266] In certain embodiments, treating cancer can result in an increase in average survival time of a population of subjects treated according to the present disclosure in comparison to a population of untreated subjects. For example, the average survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in average survival time of a population may be measured by any reproducible means. An increase in average survival time of a population may be measured, for example, by calculating for a population the average length of survival following initiation of treatment with the compound of the present disclosure. An increase in average survival time of a population may also be measured, for example, by calculating for a population the average length of survival following completion of a first round of treatment with the compound of the present disclosure. [267] In certain embodiments, treating cancer can also result in a decrease in the mortality rate of a population of treated subjects in comparison to an untreated population. For example, the mortality rate is decreased by more than 2% (e.g., more than 5%, 10%, or 25%). A decrease in the mortality rate of a population of treated subjects may be measured by any reproducible means, for example, by calculating for a population the average number of disease-related deaths per unit time following initiation of treatment with the compound of the present disclosure. A decrease in the mortality rate of a population may also be measured, for example, by calculating for a population the average number of disease-related deaths per unit time following completion of a first round of treatment with the compound of the present disclosure. [268] In certain embodiments, treating cancer can also result in an increased average progression-free survival time of a population of treated subjects in comparison to an untreated population. For example, the average progression-free survival time is increased by more than 30 days (more than 60 days, 90 days, or 120 days). An increase in average progression-free survival time of a population may be measured by any reproducible means. An increase in average progression-free survival time of a population may be measured, for example, by calculating for a population the average length of progression-free survival following initiation of treatment with the compound of the present disclosure. An increase in average progression-free survival time of a population may also be measured, for example, by calculating for a population the average length of progression-free survival following completion of a first round of treatment with the compound of the present disclosure. “Progression-free survival” as used herein refers to the length of time during and after medication or treatment during which the disease being treated (e.g., cancer) does not get worse. [269] Also provided herein are methods of treating and/or preventing a cardiovascular disease in a subject comprising administering to the subject a therapeutically and/or prophylactically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof. Also provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof, and pharmaceutical compositions thereof, for use in treating and/or preventing a cardiovascular disease in a subject. Also provided herein are uses of compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for treating a cardiovascular disease. [270] In certain embodiments, the cardiovascular disease is a GRK2-related cardiovascular disease. In certain embodiments, the cardiovascular disease is a GRK3-related cardiovascular disease. In certain embodiments, the cardiovascular disease is heart failure, cardiac hypertrophy, or hypertension. [271] Also provided herein are methods comprising administering to a subject a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof, wherein the subject has a cardiovascular disease. [272] In certain embodiments, the disease is a cardiovascular disease. A “cardiovascular disease” is a disease involving the heart and/or blood vessels. In certain embodiments, the disease is atherogenesis or atherosclerosis. In certain embodiments, the disease is arterial stent occlusion, heart failure (e.g., congestive heart failure), a coronary arterial disease, myocarditis, pericarditis, a cardiac valvular disease, stenosis, restenosis, in-stent-stenosis, angina pectoris, myocardial infarction, acute coronary syndromes, coronary artery bypass grafting, a cardio-pulmonary bypass procedure, endotoxemia, ischemia-reperfusion injury, cerebrovascular ischemia (stroke), renal reperfusion injury, embolism (e.g., pulmonary, renal, hepatic, gastro-intestinal, or peripheral limb embolism), or myocardial ischemia. [273] Also provided herein are methods of treating opioid addiction in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof. Also provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof, and pharmaceutical compositions thereof, for use in treating opioid addiction in a subject. Also provided herein are uses of compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for treating opioid addiction. [274] Also provided herein are methods comprising administering to a subject a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof, wherein the subject has an opioid addiction. [275] Also provided herein are methods of inhibiting GRK2 activity in vivo or in vitro with a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof. Also provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof, and pharmaceutical compositions thereof, for use in inhibiting the activity of GRK2 in vivo or in vitro. Also provided herein are uses of compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for inhibiting the activity of GRK2 in vivo. In certain embodiments, the inhibiting occurs in vivo. In certain embodiments, the inhibiting occurs in vitro. In certain embodiments, the inhibition is selective for GRK2, i.e., selective for GRK2 over other proteins (e.g., over other protein kinases, e.g., over other GRK family member proteins). Methods of inhibiting GRK2 activity can include a step of contacting a GRK2 protein with a compound or composition described herein. [276] Also provided herein are methods of inhibiting GRK3 activity in vivo or in vitro with a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof. Also provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof, and pharmaceutical compositions thereof, for use in inhibiting the activity of GRK3 in vivo or in vitro. Also provided herein are uses of compounds of Formula (I), and pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled derivatives, solvates, hydrates, polymorphs, co-crystals, and prodrugs thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for inhibiting the activity of GRK3 in vivo. In certain embodiments, the inhibiting occurs in vivo. In certain embodiments, the inhibiting occurs in vitro. In certain embodiments, the inhibition is selective for GRK3, i.e., selective for GRK3 over other proteins (e.g., over other protein kinases, e.g., over other GRK family member proteins). Methods of inhibiting GRK3 activity can include a step of contacting a GRK3 protein with a compound or composition described herein. [277] It would be understood that in vivo methods provided herein comprise administering to a subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof. [278] In certain embodiments, in vitro methods provided herein can be carried out, for example, in a cell line, assay, biological sample, etc. [279] In certain embodiments, methods for inhibiting the activity of GRK2 activity in vitro comprise contacting a GRK2 protein with a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, methods for inhibiting GRK2 activity in a cell comprise contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, methods for inhibiting GRK2 activity in a biological sample comprise contacting the biological sample with a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof. [280] In certain embodiments, methods for inhibiting the activity of GRK3 activity in vitro comprise contacting a GRK3 protein with a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, methods for inhibiting GRK3 activity in a cell comprise contacting the cell with a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof. In some embodiments, methods for inhibiting GRK3 activity in a biological sample comprise contacting the biological sample with a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled derivative, solvate, hydrate, polymorph, co-crystal, or prodrug thereof, or a pharmaceutical composition thereof. EXAMPLES [281] In order that the present disclosure may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting in their scope. GRK2 Enzymatic Inhibition Example 1. GRK2 Inhibition Assays Assay I [282] GRK2 enzyme (1 nM final concentration) was diluted in 25 mM HEPES, 10mM MgCl2, 2mM DTT, 0.01% Tween-20, and 1mM EGTA. Then the GRK2 mixture was added into ProxiPlate-384 white plate and pre-incubated for 30 min with test compounds at room temperature. ATP (78M final concentration) and Ulight TopoII^ (50 nM final concentration) were added into the assay plate to initiate the reaction and the mixture was incubated at room temperature for 90 min. Then, Eu anti- TopoII^ (0.12 nM final concentration), BSA (0.01% final concentration), and EDTA (11 mM final concentration) in LANCE assay bu9er were added into each well. After 60 min incubation time at room temperature, TR-FRET signal was measured by EnVision plate reader. Assay II [283] GRK2 (7.5 nM) was incubated with ATP (10 µM) and GRKtide (0.3 mg/mL) in 5 µL of assay buffer (see below) for 180 min at room temperature. HTS was performed using 1 µM compound. Compounds were dissolved in 100 % DMSO, serially diluted three-fold from 100 µM concentration to 46 nM and transferred (50 nL) into assay ready plate. [284] Materials: GRK2 was purchased from SignalChem (Cat # A14-10G, Lot # X645-3). Substrate GRKtide was from SignalChem (Cat # G46-58, Lot # R339-6). ADP-Glo Kinase Assay was from Promega (Cat # V9102). Assay buffer consisted of 25 mM HEPES (pH7.5), 10 mM MgCl ₂ , 0.01% Tween-20, 1mM DDT.384-well white plates were from Greiner Bio-Rad (Item # 784075). [285] HTS protocol: Take 384 well plate with 50 nL of compound in columns 3-22 / DMSO solution in columns 1-2,23-24. Add 2.5 µL assay buffer to columns 23 and 24 using Thermo Scientific Multidrop Combi Dispenser. Add 2.5 µL of 2x enzyme solution (15 nM in 1x assay buffer) using Thermo Scientific Multidrop Combi Reagent Dispenser to all columns except of 23 and 24. Incubate for 15 minutes. Fill plate with 2.5 µL of 2x substrate mix (20 µM ATP and 0.6 mg/mL GRKtide in 1x assay buffer) using Thermo Scientific Multidrop Combi Reagent Dispenser. Spin 15 seconds at 1000rpm and incubate for 180 min at room temperature. Add 5 µL ADP-Glo reagent to all the wells. Spin 15 seconds at 1000rpm and incubate for 40 min at room temperature. Add 10 µL Detection solution to all the wells. Incubate for 30 min at room temperature. Read plate in Luminescent mode on BMG PheraStar FSX (gain = 3600). [286] Data Analysis: Data were analyzed in GraphPad Prism 8.0.2. Each HTS plate contains compounds in columns 3-22, controls (enzyme, no compound) in columns 1 and 2, and blanks (no enzyme) in columns 23 and 24. HTS percent inhibition was calculated for each compound from the signal in luminescence units and the mean of the plate controls and the mean of the plate blanks using the following equation: % Inhibition = 100*(1-((signal-blank mean)/(control mean-blank mean))). At the final stage of data processing, we obtain dose-response curves, tables and SDF-files with the results of screening for each substance. Results [287] As shown in Table 1 below, compounds of the present disclosure inhibit GRK2 enzymatic activity. Example 2: Selective Inhibition of GRK2/GRK3 Enzymatic Activity [288] Study Design: Compound 1, a direct kinase inhibitor, was profiled against 368 other kinases, demonstrating selectivity against >92% of the kinome. Compound 1 was tested against seven GRK kinases (GRK1-7). Compound was tested in single dose duplicate mode at a concentration of 18M. Control compound, Staurosporine, was tested in 10-dose IC50 mode with 4-fold serial dilution starting at 20 or 1008M. Alternate control compounds were tested in 10-dose IC50 mode with 3 or 4- fold serial dilution starting at 10, 20, 50, or 1008M. Reactions were carried out at 108M ATP. [289] Results: Against 368 other kinases, GRK2 inhibitor Compound 1 demonstrated selectivity against >92% of the kinome. Enzymatic inhibition data in Table 2 shows that Compound 1 selectively inhibits GRK2 enzymatic activity over other GRK kinases. The data also show that Compound 1 is a GRK3 inhibitor that seletively inhibits GRK3 enzymatic activity over other GRK kinases. Cellular Proliferation Example 3: Cellular Proliferation Assay [290] In order to identify compounds specific for GRK2, we generated an isogenic cell line pair of the pancreatic cancer cell line PAXF1657, a pair of cells of PAXF1657 GRK2 knockout clonal cells versus PAXF1657 cells expressing control empty vector. The goal was to identify compounds that effectively impair proliferation in PAXF1657 empty vector cells, but not in GRK2 knockout cells, thereby identifying compounds superior to compounds of Okawa et al. J. Med. Chem.2017, 60, 6942- 6990. [291] Proliferation Assay: Cellular anti-proliferative activity of compounds was assessed by using the pancreatic cancer cell line, PAXF1657 expressing a control empty vector and a GRK2 knockout PAXF1657 cell line that was generated via CRISPR. Cell lines were seeded into tissue culture treated, white-walled, 96-well plates at a density of 500 cells/well in RPMI1640 media supplemented with 10% H.I. FBS and penicillin/streptomycin. Plates were incubated overnight at 37 ^o C, 5% CO2 to allow cells to adhere to the wells. GRK2 inhibitors were added to the cells using a 10-point dilution series with a final concentration ranging from 30 µM – 0.0002 µM in 0.3% DMSO. At the time of compound addition, a set of plates, that were not treated with compounds, were collected and cell viability was measured using CellTiter-Glo (Promega). CellTiter-Glo reagent was added to the designed plates and luminescence was measured using a Biotek Synergy plate reader. The compound treated cells were incubated for 3 days at 37 ^o C, 5% CO ₂ . The media was then aspirated from each well and replaced with fresh media containing GRK2 inhibitors. The compound treated cells were then incubated for an additional 4 days at 37 ^o C, 5% CO2. Cell viability was assessed and at end of the 7-day compound treatment by CellTiterGlo. [292] Results: As shown in Table 1, compounds provided herein were found to inhibit proliferation of the PAXF1657 control cell line significantly more than a PAXF1657 with GRK2 knockout. This indicates the inhibition of proliferation by the compounds provided herein is the result of GRK2 inhibition by the compounds. Example 3A: GRK2 inhibitor Compound 1 delays progression of PAXF1657 through G2/M [293] It was demonstrated that GRK2 inhibitor Compound 1 delays progression of PAXF1657 through G2/M cell cycle phase following G2 cell cycle arrest with CDK1 inhibitor RO-3306. See FIG.10. [294] G2 arrest and cell cycle analysis by FACS: 65,000 PAXF1657 cells were seeded per 6-well plate in RPMI1640/10%FBS. The next day 9uM Ro-3306 was added. After 18-24 hours, media was removed and cells were washed 2x with PBS. Fresh RPMI1640 +/- GRK2 inhibitor was added and cells were collected over a time course. At collection time points, cells were trypsinized, washed three times with PBS and resuspended in 200ul ice cold 70% EtOH. Cells were stored at -20 °C. For PI staining, cells stored at -20 °C were centrifuged at 800xg for 5 min. Cells were washed with 200ul PBS and centrifuged again at 800xg for 5 min. Then, cells were resuspended in 100ul/well PI stain (FxCycle™ PI/RNase Staining Solution), incubated at room temperature in the dark for 30 min, and cell cycle was analyzed by flow cytometer. Table 1. GRK2 Inhibitors, Enzymatic and Cellular Proliferation Data

Table 2. Selective Inhibition of GRK2/GRK3 Enzymatic Activity In Vivo Tumor Growth Inhibition Example 4: Efficacy of Compound 1 in pancreatic PAXF1657 tumor model in NOD-SCID mice [295] Study Design: Species/strain: NOD SCID; Supplier: Jackson; Animal No.: 70; Age: 6-10 weeks; Body weight: 18-23 g; Sex: female; Dosing: GRK2 dosing normalized to body weight. PAX1657: 5x10 ⁶ cells/mouse (subQ), treatment starts at 10 mm ³ . Daily bodyweights; dosage normalized to body weight. Plasma collection at 1hr/4hr/6hrs post final timepoints. Take down of tumors [½ flash frozen, ½ fixed (10% formalin for 24-48 hr then store in 70% EtOH at 4 °C)]. Table 3 shows study design. Table 3. Pancreatic PAXF1657 tumor model in NOD-SCID mice study design [296] Results: GRK2 inhibitor Compound 1 inhibits pancreatic tumor growth in NOD-SCID mice. Tumor growth inhibition (TGI)%: 1 mpk: 39%; 3 mpk: 71%. Treatment was well tolerated. See FIG. 1A and FIG.1B. Example 5: Efficacy of Compound 1 in colon MC38 murine tumor model in C57BL/6 mice [297] Study Design: Species/strain: C57BL/6; Supplier: Jackson; Animal No.: 75; Age: 6-10 weeks; Body weight: 18-23 g; Sex: female; Dosing: GRK2 dosing normalized to body weight. MC-38: 5x10 ⁶ cells/mouse (subQ), treatment starts at 50 mm ³ . Daily bodyweights; dosage normalized to body weight. Plasma collection at 1hr/8hrs post final timepoints. Take down of tumors [½ flash frozen, ½ fixed (10% formalin for 24-48 hr then store in 70% EtOH at 4 °C)]. Table 4 shows study design. Table 4. Colon MC38 murine tumor model in C57BL/6 mice study design [298] Results: GRK2 inhibitor Compound 1 inhibits colon tumor growth in C57BL/6 mice. Tumor growth inhibition (TGI)%: 3 mpk: 39%; 6 mpk: 27%; anti-PD1: 47% (32% against RIgG2a). Treatment was well tolerated. See FIG.2A and FIG.2B. However, GRK2 inhibitor Compound 1 does not inhibit tumor growth of colon MC38 murine cancer in immunodeficient NSG mice, demonstrating immune-dependent anti-tumor activity of the GRK2 inhibitor in vivo. See FIG.2C. Example 6: Compound 1 improves anti-tumor activity of anti-PD1 antibody in colon MC38 murine tumor model in C57BL/6 mice [299] As shown in FIG.3, GRK2 inhibitor Compound 1 improves anti-tumor activity of anti-PD1 antibody in combination therapy (colon MC38 murine tumor model in C57BL/6 mice). %TGI (Day 24): anti-PD1: 34%; anti-PD1 + Compound 1: 54%. FIG.4 shows a comparison demonstrating that Compound 1 (“Cmpd 1”) in combination with anti-PD1 has immune-dependent anti-tumor activity and synergistic efficacy in the MC38 colorectal (CRC) tumor model. Synergistic efficay of the combination is seen in colorectal cancer (CRC) MC38 murine tumor model in C57BL/6 mice, but neither GRK2 inhibitor Compound 1 nor aPD1 inhibit tumor growth in immunodeficient NSG mice. Pharmacokinetic Data Example 7: Pharmacokinetic (PK) profile of Compound 1 in vivo [300] Table 5 shows the pharmacokinetic (PK) profile of Compound 1 in vivo in PAXF1657 NOD- SCID mice. Table 6 shows the pharmacokinetic (PK) profile of Compound 1 in vivo in MC38 C57BL/6 mice. BQLa = Below Quantitation Limit (<0.979 nM). Table 5. Pharmacokinetic profile in PAXF1657 NOD-SCID mice Table 6. Pharmacokinetic profile in MC38 C57BL/6 mice Immune Modulatory Effects Example 8: GRK2 inhibitors induce pro-inflammatory genes in human PBMCs [301] Immune modulatory effects of GRK2 inhibitors were profiled in vitro. Treatment of human immune cells with GRK2 inhibitors (including Compound 1, Compound A, Compound B, and Compound C) increased pro-inflammatory gene expression in PMBCs. See FIG.5 and FIG.6. GRK2 inhibitors appear to mediate an anti-tumor response through multiple immune cell mechanisms. [302] RNA isolation and qPCR: 200-250K human PBMC cells were plated per 96-well plate in a volume of 100ul. The next day, compounds were added at different concentrations. After 18 hr incubation, cells were lysed by adding 1258l of lysis buffer (0.05M Tris-HCl, pH8.0, 0.075M KCl, 6% Ficoll PM-400, 0.15% TritonX-100) + 1/250 RNAse out (Life Technologies, Cat# 10777019) and incubated for 10 min at room temperature while shaking. For qPCR, lysates were thawed and Taqman-RNA-to-CT-1-step-kit (Thermofisher, Cat Nr.4392653) was used to assess gene expression via qPCR. Example 9: GRK2 inhibitors induce subtle increase of IL-2 secretion in T-cells [303] GRK2 inhibitors (Compound 1, Compounds A-C) induce subtle increase of IL-2 secretion in T- cells compared to DMSO. See FIG.7. [304] Human T-cell activation assay: Coat 96-well U-bottom TC-treated plates with anti-CD3, by adding 100ul of 18g/ml anti-CD3 antibody solution to the wells. Wrap parafilm around the plates to prevent evaporation and incubate over night at 4 °C. The next day, wash wells 3 times with 1258l PBS prior to plating T cells. Thaw PBMC donors in 37 °C water batch. For each human donor, place 7mls of Immunocult XF media (Stemcell, Cat #10981) into a 15ml falcon tube. Add 1ml of media slowly to cells and transfer cells to prepared falcon tube. Wash vial with 1ml of fresh media and transfer to falcon tube. Count cells and determine total cell number. Centrifuge cells at 300g for 3min. Resuspend cells to 100x10 ⁶ cells/ml in EasySep buffer and proceed to isolation. Isolate T cells according to manufacturer’s instructions (Easy Sep Human T-cell isolation kit, Cat# 17951). Resuspend T cells at concentration of 2e6 T-cells/ml and add 1008l per well. Dilute GRK2 inhibitors to 4X concentration and add 508L per well on top of cells in 96 well plate. Dilute stock anti-CD28 to 88g/ml and add 508L per well of a 96 well plate except to the no stimulation/no anti-CD3 control wells. Final concentration of CD28 in the well is 28g/ml. Add 2008l PBS to edge wells.24 h later, collect supernatant and transfer to fresh 96 well plate at designated timepoints. Store at -20 °C until use. Proceed with manufactures protocol for IL-2 ELISA (Biolegend, Cat #: 431815). Example 10: GRK2 inhibitors induce expression of pro-inflammatory genes in human pancreatic cancer cell line PAXF1657 and in vivo [305] It was found that GRK2 inhibitors induce expression of pro-inflammatory genes in human pancreatic cancer cell line PAXF1657 (see FIG.8) and in human pancreatic xenograft PAXF1657 in vivo (see FIG.9). [306] RNA isolation and qPCR: For PAXF16572000 cells were plated per 96-well. The next day, compounds were added at different concentrations. After 24 and 72 h incubation time, respectively, cells were lysed by adding 508l of lysis buffer (0.05M Tris-HCl, pH8.0, 0.075M KCl, 6% Ficoll PM- 400, 0.15% TritonX-100) + 1/250 RNAse out (Life Technologies, Cat# 10777019) and incubated for 10 min at room temperature while shaking. Lysates were stored at -80C. For qPCR, lysates were thawed and Taqman-RNA-to-CT-1-step-kit (Thermofisher, Cat Nr.4392653) was used to assess gene expression via qPCR. Synthesis of Compounds [307] General procedure for amide coupling. To a solution of 3-(1-methyl-4-[5-(pyridin-4-yl)-4H- 1,2,4-triazol-3-yl]piperidin-4-ylamino)benzoic acid (91.79 µmol, 1 equiv) in N,N-dimethylformamide (1.5 mL) were added amine (91.79 µmol, 1 equiv), 1-[Bis(dimethylamino)methylene]-1H-1,2,3- triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (110.15 µmol, 1.2 equiv), and diisopropylethylamine (183.72 µmol, 2.0 equiv). The reaction mixture was stirred for 16 hours at 25 °C. Then the resulting solution was quenched by water, extracted by EtOAc (3×5ml) and evaporated. Residue was purified by HPLC (column: YMC-ACTUS TRIART C18100*205 microM; 0.5-6.5 min 0-25% water-acetonitrile+NH ₃ ). [308] Step 1 (general procedure). To a solution of 3-(1-[(Tert-butoxy)carbonyl]-4-[5-(pyridin-4-yl)- 4H-1,2,4-triazol-3-yl]piperidin-4-ylamino)benzoic acid (645.83 µmol, 1 equiv) in N,N- dimethylformamide (1.5 mL) were added amine (645.37 µmol, 1 equiv), 1- [Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridi nium 3-oxide hexafluorophosphate (774.44 µmol, 1.2 equiv), and diisopropylethylamine (1.29 mmol, 2.0 equiv). The reaction mixture was stirred for 16 hours at 25 °C. Solution was quenched by water, extracted by EtOAc (3×5ml) and evaporated. Residue was purified by HPLC. [309] Step 2 (general procedure). Trifluoroacetic acid (1.0 mmol) was added to a solution of product from previous step (100.09 µmol) in DCM (2 mL). Reaction mixture was stirred at ambient temperature for 8 hours and concentrated under reduced pressure. The resulting residue was purified by HPLC. (Column: YMC-ACTUS TRIART C18100*205 microM; 0.5-6.5 min 0-25% water- acetonitrile+NH ₃ ).

Example 12: Schemes and Procedures for the Preparation of Compounds and Intermediates Scheme 1: Synthesis of Intermediate A1 (3-((1-(tert-butoxycarbonyl)-4-(5-(pyridin-4-yl)-4H-1,2,4- triazol-3-yl)piperidin-4-yl)amino)benzoic acid)

[310] Step 1: 1-(tert-butoxycarbonyl)-4-[[3-(tert-butoxycarbonyl)phenyl]am ino]piperidine-4- carboxylic acid. To a solution of 4-amino-1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (30.0 g, 122.8 mmol, 1.0 equiv.) and tert-butyl-3-bromobenzoate (34.7 g, 135.1 mmol, 1.1 equiv.) in DMF (400 mL) and water (30 mL), were added CuI (4.7 g, 24.6 mmol, 0.2 equiv.), 2-acetylcyclohexan-1- one (3.4 g, 24.6 mmol, 0.2 equiv.), K2CO3 (50.9 g, 368.4 mmol, 3.0 equiv.) and TEA(2.5 g, 24.6 mmol, 0.2 equiv.) under an atmosphere of nitrogen. The resulting mixture was stirred for 14 hours at 90 °C, then cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 /MeOH (12:1) to afford 1-(tert- butoxycarbonyl)-4-[[3-(tert-butoxycarbonyl)phenyl]amino]pipe ridine -4-carboxylic acid (50 g, 96.82%) as a yellow green oil. MS-ESI: 314.1 [M+H] ⁺ . [311] Step 2: N-aminopyridine-4-carboximidamide. To a solution of 4-cyanopyridine (30.0 g, 288.2 mmol, 1.0 equiv.) in EtOH (500 mL), was added NH2NH2·H2O (72.1 g, 1440.7 mmol, 5.0 equiv.). The resulting mixture was stirred for 12 hours at 80 °C, then cooled to room temperature and concentrated under vacuum to give N-aminopyridine-4-carboximidamide (30.5 g) as a yellow solid. MS-ESI: 137.1 [M+H] ⁺ . [312] Step 3: tert-butyl-4-[N-[(1Z)-amino(pyridin-4-yl)methylidene]hydrazi necarbonyl]-4-[[3- (tert-butoxycarbonyl)phenyl] amino]piperidine-1-carboxylate. To a solution of 1-(tert- butoxycarbonyl)-4-[[3-(tert-butoxycarbonyl)phenyl]amino]pipe ridine-4-carboxylic acid (30.0 g, 71.3 mmol, 1.0 equiv.) in THF (400 mL), were added TEA (14.4 g, 142.7 mmol, 2.0 equiv.), N- aminopyridine-4-carboximidamide (10.7 g, 78.5 mmol, 1.1 equiv.) and HATU (29.8 g, 78.5 mmol, 1.1 equiv.). The resulting mixture was stirred for overnight at room temperature and then concentrated under vacuum to give crude tert-butyl-4-[N-[(1Z)-amino(pyridin-4- yl)methylidene]hydrazinecarbonyl]-4-[[3-(tert-butoxycarbonyl )phenyl] amino]piperidine-1- carboxylate (30.1 g, 78.1%) as a dark yellow oil. MS-ESI: 224.1 [M+H] ⁺ . [313] Step 4: tert-butyl 4-[[3-(tert-butoxycarbonyl)phenyl]amino]-4-[5-(pyridin-4-yl) -4H-1,2,4- triazol-3-yl]piperidine-1-carboxylate. To a solution of tert-butyl 4-[N-[(1Z)-amino(pyridin-4- yl)methylidene]hydrazinecarbonyl]-4-[[3-(tert-butoxycarbonyl )phenyl]amino]piperidine-1- carboxylate (30.0 g, 55.7 mmol, 1.0 equiv.) in EtOH (250 mL), was added AcOH (33.5 g, 556.9 mmol, 10.0 equiv.) dropwise. The resulting mixture was stirred for overnight at 80 °C, then cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc (1:1) to afford tert-butyl 4-[[3-(tert- butoxycarbonyl)phenyl]amino]-4-[5-(pyridin-4-yl)-4H-1,2,4-tr iazol-3-yl]piperidine-1-carboxylate (7.5 g, 25.9%) as yellow solid. MS-ESI: 342.2 [M+H] ⁺ . [314] Step 5: 3-([4-[5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]piperidin-4-yl ]amino)benzoic acid. To a solution of tert-butyl 4-[[3-(tert-butoxycarbonyl)phenyl]amino]-4-[5-(pyridin-4-yl) -4H-1,2,4- triazol-3-yl]piperidine-1-carboxylate (23.0 g, 44.2 mmol, 1.0 equiv.) in DCM (200 mL), was added TFA (70 mL) dropwise at 0 °C. The resulting mixture was stirred for 2 hours at room temperature and then concentrated under vacuum. This resulted in crude 3-([4-[5-(pyridin-4-yl)-4H-1,2,4-triazol-3- yl]piperidin-4-yl]amino)benzoic acid (13.0 g, 80.8%) as a yellow solid. MS-ESI: 324.1 [M+H] ⁺ . [315] Step 6: 3-[[1-(tert-butoxycarbonyl)-4-[5-(pyridin-4-yl)-4H-1,2,4-tri azol-3-yl]piperidin-4- yl]amino]benzoic acid. To a solution of 3-([4-[5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]piperidin-4- yl]amino)benzoic acid (13.0 g, 35.7 mmol, 1.0 equiv.) in water (100 mL) and THF (100ml ), were added NaOH (7.1 g, 178.4 mmol, 5.0 equiv.) and Boc2O (10.1 g, 46.4 mmol, 1.3 equiv.). The resulting mixture was stirred for 2 hours at room temperature and then concentrated under vacuum. The residue was adjusted to pH 5 with HCl aqueous (4M). The resulting mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (12:1) to afford 3-[[1-(tert-butoxycarbonyl)-4-[5-(pyridin-4-yl)-4H-1,2,4-tri azol-3-yl]piperidin-4-yl]amino]benzoic acid (8.9 g, 53.9%) as a yellow solid. MS-ESI: 465.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) : 14.50 (brs, 1H), 12.69 (brs, 1H), 8.80 (d, J = 5.2 Hz, 2H), 8.17-8.16 (m, 2H), 7.22 (s, 1H), 7.14-7.06 (m, 2H), 6.57 (d, J = 7.2 Hz, 1H), 6.37 (brs, 1H), 3.63-3.59 (m, 2H), 3.43-3.39 (m, 2H), 2.22-2.10 (m, 4H), 1.41 (s, 9H). [316] The intermediates in Table S1 were prepared using the same method described for Intermediate A1. Table S1 Scheme 2: Synthesis of intermediate A2 (3-((1-methyl-4-(5-(pyridin-4-yl)-4H-1,2,4-triazol-3- yl)piperidin-4-yl)amino)benzoic acid) [317] Step 1: methyl 3-([4-[5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]piperidin-4-yl ]amino)benzoate. To a solution of tert-butyl 4-[[3-(tert-butoxycarbonyl)phenyl]amino]-4-[5-(pyridin-4-yl) -4H-1,2,4- triazol-3-yl]piperidine-1-carboxylate (30.0 g, 57.6 mmol, 1.0 equiv.) in MeOH (300 mL), was added HCl/1,4-dioxane (4M, 300 mL) dropwise. The resulting mixture was stirred for overnight at room temperature and then concentrated under vacuum. This resulted in crude methyl 3-([4-[5-(pyridin-4- yl)-4H-1,2,4-triazol-3-yl]piperidin-4-yl]amino)benzoate (20.5 g, 91.7%) as a yellow solid, which was used in the next step directly without further purification. MS-ESI: 379.2 [M+H] ⁺ . [318] Step 2: methyl 3-((1-methyl-4-(5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)piper idin-4- yl)amino)benzoate. To a solution of methyl 3-([4-[5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]piperidin-4- yl]amino)benzoate (20.0 g, 52.8 mmol, 1.0 equiv.) and formaldehyde solution (37% wt., 21.4 g, 264.2 mmol, 5.0 equiv.) in MeOH (200 mL), was added NaBH ₃ CN (16.6 g, 264.6 mmol, 5.0 equiv.) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. Then the reaction solution was used in the next step directly without further working up. MS-ESI: 393.1 [M+H] ⁺ . [319] Step 3: 3-([1-methyl-4-[5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]piper idin-4-yl]amino)benzoic acid formic acid salt. The above solution was diluted with water (100 mL) and MeOH (100 mL), then NaOH (8.2 g, 203.8 mmol, 4.0 equiv.) was added. The resulting mixture was stirred for 2 hours at room temperature and then concentrated under vacuum. The crude product was purified by Prep- HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5um; Mobile Phase A: Water (10 mmol/L FA), Mobile Phase B: ACN; Flow rate: 100 mL/min; Gradient: 2% B to 9.8% B in 11 min; Wave Length: 220 nm; RT1: 2.98 min. This resulted in 3-([1-methyl-4-[5- (pyridin-4-yl)-4H-1,2,4-triazol-3-yl]piperidin-4-yl]amino)be nzoic acid formic acid salt (5.1 g, 25.9%) as a light yellow solid. MS-ESI: 379.2 [M+H] ⁺ . [320] The intermediates in Table S2 were prepared using the same method described for Intermediate A2. Table S2 Scheme 3: Synthesis of intermediate A3 (3-((1-(tert-butoxycarbonyl)-4-(5-(pyrimidin-4-yl)-4H-1,2,4- triazol-3-yl)piperidin-4-yl)amino)benzoic acid) [321] Step 1: N-aminopyrimidine-4-carboximidamide.4-Pyrimidinecarbonitrile (6.0 g, 57.1 mmol, 1.0 equiv.) was dissolved in EtOH (200 mL), then NH ₂ NH ₂ .H ₂ O (14.3 g, 285.4 mmol, 5.0 equiv.) was added. The resulting mixture was stirred for 2 hours at room temperature and concentrated under vacuum to give N-aminopyrimidine-4-carboximidamide (7.5 g, 95.8%) as a yellow solid. MS-ESI: 138.2 [M+H] ⁺ . [322] Step 2: tert-butyl 4-((3-(tert-butoxycarbonyl)phenyl)amino)-4-(2-(imino(pyrimid in-4- yl)methyl)hydrazine-1-carbonyl)piperidine-1-carboxylate. To a solution of 1-(tert- Butoxycarbonyl)-4-[[3-(tert-butoxycarbonyl)phenyl]amino]pipe ridine-4-carboxylic acid (17.0 g, 40.4 mmol, 1.0 equiv.) and N-aminopyrimidine-4-carboximidamide (6.1 g, 44.5 mmol, 1.1 equiv.) in THF (400 mL), were dissolved HATU (18.5 g, 48.5 mmol, 1.2 equiv.) and TEA (8.2 g, 80.9 mmol, 2.0 equiv.). The resulting mixture was stirred for 3 hours at room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (20:1) to afford tert-butyl 4-((3-(tert-butoxycarbonyl)phenyl)amino)-4-(2- (imino(pyrimidin-4-yl)methyl)hydrazine-1-carbonyl)piperidine -1-carboxylate (20.2 g, 91.7%) as a yellow solid. MS-ESI: 540.1 [M+H] ⁺ . [323] Step 3: tert-butyl 4-[[3-(tert-butoxycarbonyl)phenyl]amino]-4-[5-(pyrimidin-4-y l)-4H-1,2,4- triazol-3-yl]piperidine-1-carboxylate. To a solution of PPh ₃ (15.2 g, 57.9 mmol, 2.5 equiv.) and I ₂ (14.7 g, 57.9 mmol, 2.5 equiv.) in DCM (500 mL), was added TEA (15.2 g, 150.6 mmol, 6.5 equiv.) at 0 °C under nitrogen atmosphere. This was followed by the addition of tert-butyl 4-((3-(tert- butoxycarbonyl)phenyl)amino)-4-(2-(imino(pyrimidin-4-yl)meth yl)hydrazine-1-carbonyl)piperidine- 1-carboxylate (12.5 g, 23.2 mmol, 1.0 equiv.) at 0°C. The resulting mixture was stirred for additional 3 hours at 0 °C and the quenched by the addition of water. The resulting solution was extracted with DCM and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc (1:1) to afford tert-butyl 4-{[3-(tert- butoxycarbonyl)phenyl]amino}-4-[5-(pyrimidin-4-yl)-4H-1,2,4- triazol-3-yl]piperidine-1-carboxylate (6.1 g, 49.7%) as a yellow solid. MS-ESI: 522.1 [M+H] ⁺ . [324] Step 4: 3-({4-[5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]piperidin-4- yl}amino)benzoic acid. tert-Butyl 4-{[3-(tert-butoxycarbonyl)phenyl]amino}-4-[5-(pyrimidin-4-y l)-4H-1,2,4-triazol-3- yl]piperidine-1-carboxylate (6.1 g, 11.5 mmol, 1.0 equiv.) was dissolved in DCM (50 mL), then TFA (10 mL) was added. The resulting mixture was stirred for 1 hour at room temperature and concentrated under vacuum. This resulted in crude 3-({4-[5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3- yl]piperidin-4-yl}amino)benzoic acid (4.1 g, 95.2%) as a yellow solid. MS-ESI: 366.1 [M+H] ⁺ . [325] Step 5: 3-((1-(tert-butoxycarbonyl)-4-(5-(pyrimidin-4-yl)-4H-1,2,4-t riazol-3-yl)piperidin-4- yl)amino)benzoic acid. To a solution of 3-({4-[5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl]piperidin-4- yl}amino)benzoic acid (4.1 g, 10.9 mmol, 1.0 equiv.) and NaOH (2.2 g, 54.7 mmol, 5.0 equiv.) in THF (50 mL) and water (50 mL), was added Boc2O (3.6 g, 16.4 mmol, 1.5 equiv.) at 0°C. The resulting mixture was stirred for overnight at room temperature. The resulting solution was washed with DCM, then the aqueous layer was adjusted to pH 5 with HCl aqueous (6 M). The resulting mixture was extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to give crude 3-((1-(tert-butoxycarbonyl)-4-(5-(pyrimidin-4-yl)-4H-1,2,4- triazol-3-yl)piperidin-4-yl)amino)benzoic acid (4.3 g, 85.0%) as a brown yellow solid. MS-ESI: 466.2 [M+H] ⁺ . Scheme 4: Synthesis of intermediate A4 (3-((1-methyl-4-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3- yl)piperidin-4-yl)amino)benzoic acid)

[326] Step 1: methyl 3-((4-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)piperidin-4- yl)amino)benzoate. To a solution of tert-butyl 4-((3-(tert-butoxycarbonyl)phenyl)amino)-4-(5- (pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)piperidine-1-carboxyl ate (3.0 g, 5.8 mmol, 1.0 equiv.) in MeOH (30 mL), was added HCl/1,4-dioxane (4M, 30 mL). The resulting solution was stirred for overnight at room temperature and then concentrated under vacuum to give crude methyl 3-((4-(5- (pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)piperidin-4-yl)amino) benzoate (2.1 g) as a yellow solid, which was used to next step without further purification. MS-ESI: 380.2 [M+H] ⁺ . [327] Step 2: methyl 3-((1-methyl-4-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)pip eridin-4- yl)amino)benzoate. To a solution of methyl 3-((4-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3- yl)piperidin-4-yl)amino)benzoate (2.0 g, 5.3 mmol, 1.0 equiv.) and formaldehyde solution (2.1 g, 26.4 mmol, 5.0 equiv.) in MeOH(60 ml), was added NaBH ₃ CN (1.7 g, 26.4 mmol, 5.0 equiv.). The resulting mixture was stirred for 1 hour at room temperature. Then the reaction solution was used in the next step directly without further working up. MS-ESI: 394.2 [M+H] ⁺ . [328] Step 3: 3-((1-methyl-4-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)pip eridin-4- yl)amino)benzoic acid. The above solution was diluted with water (20 mL) and THF (20 ml), then NaOH (1.0 g, 25.4 mmol, 5.0 equiv.) was added in portions. The resulting mixture was stirred for 2 hours at room temperature and concentrated under vacuum. The crude product was purified by Prep- HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 5um; Mobile Phase A: Water (10 mM FA), Mobile Phase B: ACN; Flow rate: 100 mL/min; Gradient: 2% B to 9.8% B in 11 min; Wave Length: 220 nm; RT1: 2.98 min. This resulted in 3-((1-methyl-4-(5- (pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)piperidin-4-yl)amino) benzoic acid (712.5 mg, 36.23%) as a red solid. MS-ESI: 380.2 [M+H] ⁺ . Scheme 5: Synthesis of intermediate A8 (3-((4-(5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahydro-2H - pyran-4-yl)amino)benzoic acid) [329] Step 1: 4-((3-(tert-butoxycarbonyl)phenyl)amino)tetrahydro-2H-pyran- 4-carboxylic acid. To a solution of 4-aminooxane-4-carboxylic acid (3.0 g, 20.7 mmol, 1.0 equiv.) and tert-butyl 3- bromobenzoate (8.0 g, 31.0 mmol, 1.5 equiv.) in DMF (60 mL) and H ₂ O (6 mL), were added CuI (1.6 g, 8.3 mmol, 0.4 equiv.), 2-acetylcyclohexan-1-one (1.2 g, 8.3 mmol, 0.4 equiv.), K ₂ CO ₃ (8.6 g, 62.0 mmol, 3.0 equiv.) and TEA (0.4 g, 4.1 mmol, 0.2 equiv.) under an atmosphere of nitrogen. The resulting mixture was stirred for 12 hours at 90 °C, then cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (8:1) to afford 4-((3-(tert-butoxycarbonyl)phenyl)amino)tetrahydro-2H-pyran- 4- carboxylic acid (3.0 g, 45.2%) as a yellow oil. MS-ESI: 322.2 [M+H] ⁺ . [330] Step 2: tert-butyl 3-((4-(2-(imino(pyridin-4-yl)methyl)hydrazine-1-carbonyl)tet rahydro- 2H-pyran-4-yl)amino)benzoate. To a solution of 4-((3-(tert- butoxycarbonyl)phenyl)amino)tetrahydro-2H-pyran-4-carboxylic acid (2.0 g, 6.2 mmol, 1.0 equiv.), HOBT(1.3 g, 9.3 mmol, 1.5 equiv.) and EDCI(1.8 g, 9.3 mmol, 1.5 equiv.) in DMF (20 mL), was added DIEA (2.4 g, 18.7 mmol, 3.0 equiv.) dropwise. After stirred for 10 min at room temperature, N- aminopyridine-4-carboximidamide (1.0 g, 7.5 mmol, 1.2 equiv.) was added. The resulting mixture was stirred for overnight at room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM2/MeOH (8:1) to afford tert-butyl 3- ((4-(2-(imino(pyridin-4-yl)methyl)hydrazine-1-carbonyl)tetra hydro-2H-pyran-4-yl)amino)benzoate (1.6 g, 58.5%) as a yellow oil. MS-ESI: 440.2 [M+H] ⁺ . [331] Step 3: tert-butyl 3-((4-(5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahydro-2H- pyran-4- yl)amino)benzoate. tert-Butyl 3-((4-(2-(imino(pyridin-4-yl)methyl)hydrazine-1-carbonyl)tet rahydro- 2H-pyran-4-yl)amino)benzoate (400.0 mg, 0.9 mmol, 1.0 equiv.) was dissolved in AcOH (1 mL) and toluene (15 mL). The resulting mixture was stirred for overnight at 90 °C, then cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM ₂ /MeOH (8:1) to afford tert-butyl 3-((4-(5-(pyridin-4-yl)-4H-1,2,4- triazol-3-yl)tetrahydro-2H-pyran-4-yl)amino)benzoate (102.2 mg, 26.1%) as a yellow oil. MS-ESI: 422.2 [M+H] ⁺ . [332] Step 4: 3-((4-(5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahydro-2H- pyran-4- yl)amino)benzoic acid. tert-Butyl 3-((4-(5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahydro-2H- pyran- 4-yl)amino)benzoate (100.0 mg, 0.2 mmol, 1.0 equiv.) was dissolved in DCM (15 mL) and TFA (3 mL). The resulting mixture was stirred for 2 hours at room temperature and concentrated under vacuum. This resulted in 3-((4-(5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahydro-2H- pyran-4- yl)amino)benzoic acid (50.0 mg, 57.7%) as a yellow solid. MS-ESI: 366.2 [M+H] ⁺ . Scheme 6: Synthesis of intermediate B3 ((S)-isochroman-4-amine hydrochloride) [333] Step 1: (R)-N-(1,3-dihydro-2-benzopyran-4-ylidene)-2-methylpropane-2 -sulfinamide. To a solution of 1,3-dihydro-2-benzopyran-4-one (7.0 g, 47.2 mmol, 1.0 equiv.) and (R)-2-methylpropane- 2-sulfinamide (17.2 g, 141.7 mmol, 3.0 equiv.) in THF (100 mL), was added Ti(OEt) ₄ (11.9 g, 52.0 mmol, 1.1 equiv.). The resulting mixture was stirred for overnight at 70 °C, then cooled to room temperature and quenched by the addition of water. After removing the solid by filtration, the filtrate was extracted with EtOAc, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum to give (R)-N-(1,3-dihydro-2-benzopyran-4-ylidene)-2-methylpropane-2 -sulfinamide (7.0 g, 59.0%) as a yellow oil. MS-ESI: 252.1 [M+H] ⁺ . [334] Step 2: (R)-N-[(4S)-3,4-dihydro-1H-2-benzopyran-4-yl]-2-methylpropan e-2-sulfinamide. To a solution of (R)-N-(1,3-dihydro-2-benzopyran-4-ylidene)-2-methylpropane-2 -sulfinamide (7.0 g, 27.9 mmol, 1.0 equiv.) in THF (200 mL) was added L-selectride (1M in THF, 55.7 mL, 55.7 mmol, 2.0 equiv.) dropwise at -78 °C under an atmosphere of nitrogen atmosphere. The resulting mixture was stirred for 2 hours at -78 °C and then quenched by the addition of ice-water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with petroleum ether (10:1) to afford (R)-N-[(4S)-3,4-dihydro-1H-2-benzopyran-4-yl]-2- methylpropane-2-sulfinamide (5.0 g, 70.9%) as a yellow oil. MS-ESI: 254.1 [M+H] ⁺ . [335] Step 3: (S)-isochroman-4-amine hydrochloride. (R)-N-[(4S)-3,4-dihydro-1H-2-benzopyran- 4-yl]-2-methylpropane-2-sulfinamide (5.0 g, 19.7 mmol, 1.0 equiv.) was dissolved HCl/1,4-dioxane (30 mL). The resulting mixture was stirred for 1 hour at room temperature and then quenched by the addition of water. The resulting solution was adjusted to pH 8 with NaOH aqueous, extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum to give (S)- isochroman-4-amine hydrochloride (2.0 g, 67.9%) as a yellow oil. MS-ESI: 150.1 [M+H] ⁺ . [336] The intermediates in Table S3 were prepared using the same method described for Intermediate B3. Table S3 Scheme 7: Synthesis of intermediate B4 ((S)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine hydrochloride)

[337] Step 1: tert-butyl (3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)carbamate. To a solution of 2H,3H,4H-pyrano[3,2-b]pyridin-4-amine (18.0 g, 119.9 mmol, 1.0 equiv.) in DCM (100 mL), were added TEA (36.4 g, 359.6 mmol, 3.0 equiv.) and Boc2O (31.4 g, 143.8 mmol , 1.2 equiv.) at 0 °C. The resulting mixture was stirred for 1 hour at room temperature under nitrogen atmosphere and then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc (8:1) to afford tert-butyl (3,4-dihydro-2H-pyrano[3,2-b]pyridin-4- yl)carbamate (27.0 g, 90.0%) as a white solid. MS-ESI: 252.1 [M+H] ⁺ . [338] Step 2: tert-butyl (S)-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)carbamate. tert-Butyl (3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)carbamate (27.0 g, 107.9 mmol, 1.0 equiv.) was separated Chiral-HPLC with the following conditions: Column: CHIRALPAK IG, 3*25 cm, 58m; Mobile Phase A: CO2, Mobile Phase B: MEOH (0.1% DEA); Flow rate: 60 mL/min; Gradient: isocratic 25% B; Column Temperature(;): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT2(min): 6.68. This resulted in tert-butyl (S)-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)carbamate (9.0 g, 33.3%) as a white solid. MS-ESI: 254.1 [M+H] ⁺ . [339] Step 3: (S)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine hydrochloride. To a solution of tert-butyl (S)-(3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)carbamate (9.0 g, 36.0 mmol, 1.0 equiv.) in 1,4-dioxane (50 mL), was added HCl/1,4-dioxane (50mL) dropwise. The resulting mixture was stirred for 1 hour at room temperature under nitrogen atmosphere and then concentrated under vacuum to give (S)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine hydrochloride (4.5 g, 83.33%) as a white solid. MS-ESI: 151.1 [M+H] ⁺ . Scheme 8: Synthesis of intermediate B5 ((R)-5-fluorochroman-4-amine) [340] Step 1: (R)-5-fluorochroman-4-amine (second peak). Racemic 5-fluorochroman-4-amine (1.0 g, 6.0 mmol, 1.0 equiv.) was separated by Prep-SFC with the following conditions: Column: CHIRAL ART Amylose-SA, 3*25 cm, 58m; Mobile Phase A: CO ₂ , Mobile Phase B: MEOH (0.1% 2M NH ₃ - MEOH); Flow rate: 60 mL/min; Gradient: isocratic 20% B; Column Temperature(;): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT2: 5.25 min. This resulted in (R)-5-fluorochroman-4- amine (second peak) (405.1 mg, 40.0%) as a light yellow oil. MS-ESI: 168.1 [M+H] ⁺ . [341] The intermediates in Table S4 were prepared using the same method described for Intermediate B5. Table S4 Scheme 9: Synthesis of intermediate B8 (2,3-dihydrofuro[2,3-c]pyridin-3-amine) [342] Step 1: ethyl 3-chloropyridine-4-carboxylate. To a solution of 3-chloropyridine-4-carboxylic acid (4.0 g, 25.4 mmol, 1.0 equiv.) in EtOH (50 mL) was added conc. H ₂ SO ₄ (12.5 g, 126.9 mmol, 5.0 equiv.) at 0 °C. The resulting mixture was stirred for overnight at 80 °C, then cooled to room temperature and quenched by the addition of ice-water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10:1) to afford ethyl 3-chloropyridine-4-carboxylate (4.1 g, 84.88%) as a yellow solid. MS-ESI: 186.0 [M+H] ⁺ . [343] Step 2: ethyl 3-hydroxyfuro[2,3-c]pyridine-2-carboxylate. To a solution of ethyl 2- hydroxyacetate (2.7 g, 25.9 mmol, 1.2 equiv.) in DME (50 mL) was added NaH (wt.60%, 1.7 g, 43.1 mmol, 2.0 equiv.) at 0 °C. After stirred for 30min at room temperature, ethyl 3-chloropyridine-4- carboxylate (4.0 g, 21.6 mmol, 1.0 equiv.) was added. The resulting mixture was stirred for additional overnight at 60 °C, then cooled to room temperature and quenched by the addition of ice-water. The resulting solution was extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10:1) to afford ethyl 3-hydroxyfuro[2,3-c]pyridine-2-carboxylate (2.5 g, 55.99%) as a yellow solid. MS-ESI: 208.1 [M+H] ⁺ . [344] Step 3: 2H-furo[2,3-c]pyridin-3-one. To a solution of ethyl 3-hydroxyfuro[2,3-c]pyridine-2- carboxylate (2.5 g, 12.1 mmol, 1.0 equiv.) in H2O (30 mL) was added conc. HCl (10 mL) dropwise at room temperature. The resulting mixture was stirred for overnight at 100 °C, then cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10:1) to afford 2H-furo[2,3-c]pyridin-3-one (1.5 g, 92.0%) as yellow oil. MS-ESI: 136.0 [M+H] ⁺ . [345] Step 4: N-[(3E)-2H-furo[2,3-c]pyridin-3-ylidene]hydroxylamine. To a solution of 2H- furo[2,3-c]pyridin-3-one (1.5 g, 11.1 mmol, 1.0 equiv.) in MeOH (20 mL) was added NH ₂ OH.HCl (2.3 g, 33.3 mmol, 3.0 equiv.). The resulting mixture was stirred for overnight at room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10:1) to afford N-[(3E)-2H-furo[2,3-c]pyridin-3-ylidene]hydroxylamine (1.0 g, 60.0%) as a yellow solid. MS-ESI: 151.1 [M+H] ⁺ . [346] Step 5: 2H,3H-furo[2,3-c]pyridin-3-amine. To a solution of N-[(3E)-2H-furo[2,3-c]pyridin-3- ylidene]hydroxylamine (1.0 g, 6.7 mmol, 1.0 equiv.) and NH4OAc (2.6 g, 33.3 mmol, 5.0 equiv.) in ammonia (10 mL) and EtOH (2.5 mL), was added Zn (1.3 g, 20.0 mmol, 3.0 equiv.). The resulting mixture was stirred for overnight at room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10:1) to afford 2H,3H-furo[2,3-c]pyridin-3-amine (500 mg, 55.1%) as yellow oil. MS-ESI: 137.2 [M+H] ⁺ . Scheme 10: Synthesis of intermediate B14 (8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine) [347] Step 1: 2-bromo-4-chloropyridin-3-ol. To a solution of 2,2,6,6-tetramethylpiperidine (3.7 g, 26.0 mmol, 1.0 equiv.) in THF (50 mL) was added n-BuLi (2.5 M in hexane, 12.5 mL, 31.2 mmol, 1.2 equiv.) dropwise at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 hours at -78 °C, then 3-bromo-4-chloropyridine (5.0 g, 26.0 mmol, 1.0 equiv.) was added at -78 °C. The resulting mixture was stirred for additional 2 hours at -78 °C, that was followed by the addition of trimethyl borate (5.4 g, 52.0 mmol, 2.0 equiv.) dropwise at -78 °C. After stirred for additional 2 hours at -78°C, peracetic acid (3.6 g, 46.8 mmol, 1.8 equiv.) was added. The mixture was stirred for additional 14 hours at room temperature and then cooled to 0 °C and quenched by the addition of aqueous NaS ₂ O ₅ . The resulting solution was extracted with EtOAc, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc (5:1) to afford 2-bromo-4-chloropyridin-3-ol (3.5 g, 64.6%) as a yellow oil. MS-ESI: 208.1 [M+H] ⁺ . [348] Step 2: 2-bromo-3-(but-3-en-1-yloxy)-4-chloropyridine. To a solution of 2-bromo-4- chloropyridin-3-ol (3.5 g, 16.8 mmol, 1.0 equiv.), 3-buten-1-ol (1.3 g, 18.5 mmol, 1.1 equiv.) and PPh3 (5.3 g, 20.1 mmol, 1.2 equiv.) in THF (50 mL) was added DIAD (3.7 g, 18.5 mmol, 1.1 equiv.) dropwise at 0 °C. The resulting mixture was stirred for 2 hours at room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc (10:1) to afford 2-bromo-3-(but-3-en-1-yloxy)-4-chloropyridine (3.5 g, 79.4%) as a yellow oil. MS-ESI: 262.1 [M+H] ⁺ . [349] Step 3: 8-chloro-4-methylidene-2H,3H-pyrano[3,2-b]pyridine. To a solution of 2-bromo-3- (but-3-en-1-yloxy)-4-chloropyridine (3.5 g, 13.3 mmol, 1.0 equiv.), AcOK (6.5 g, 66.7 mmol, 5.0 equiv.), PPh3 (1.1 g, 4.0 mmol, 0.3 equiv.) and tetraethylammonium chloride (3.5 g, 21.3 mmol, 1.6 equiv.) in DMF (35 mL) was added Palladium acetate (0.3 g, 1.3 mmol, 0.1 equiv.) under an atmosphere of nitrogen. The resulting mixture was stirred for 2 hours at 110 °C, then cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc (20:1) to afford 8-chloro-4-methylidene-2H,3H- pyrano[3,2-b]pyridine (1.8 g, 74.3%) as a yellow oil. MS-ESI: 182.0 [M+H] ⁺ . [350] Step 4: 8-chloro-4-(hydroxymethyl)-2H,3H-pyrano[3,2-b]pyridin-4-ol. To a solution of 8- chloro-4-methylidene-2H,3H-pyrano[3,2-b]pyridine(1.8 g, 9.9 mmol, 1.0 equiv.) and NMO (3.5 g, 29.7 mmol, 3.0 equiv.) in CH ₂ Cl ₂ (20 mL) was added OsO ₄ (0.13 g, 0.5 mmol, 0.05 equiv.) at 0 °C. The resulting mixture was stirred for 12 hours at room temperature and then quenched by the addition of aqueous Na ₂ S ₂ O ₃ . The resulting solution was extracted with DCM, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. This resulted in 8-chloro-4-(hydroxymethyl)- 2H,3H-pyrano[3,2-b]pyridin-4-ol (2.0 g, 93.6%) as a yellow green solid. MS-ESI: 216.0 [M+H] ⁺ . [351] Step 5: 8-chloro-2H,3H-pyrano[3,2-b]pyridin-4-one. To a solution 8-chloro-4- (hydroxymethyl)-2H,3H-pyrano[3,2-b]pyridin-4-ol (1.9 g, 8.8 mmol, 1.0 equiv.) in THF (10 mL) and H ₂ O (10 mL) was added NaIO ₄ (5.7 g, 26.4 mmol, 3.0 equiv.) in portions at 0 °C. The resulting mixture was stirred for 2 hours at room temperature and then quenched by the addition of aqueous Na ₂ S ₂ O ₃ . The resulting solution was extracted with DCM, washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with petroleum ether/EtOAc (1:1) to afford 8-chloro-2H,3H-pyrano[3,2- b]pyridin-4-one (1.2 g, 74.2%) as a brown yellow solid. MS-ESI: 184.0 [M+H] ⁺ . [352] Step 6: N-[(4Z)-8-chloro-2H,3H-pyrano[3,2-b]pyridin-4-ylidene]hydrox ylamine. To a solution of 8-chloro-2H,3H-pyrano[3,2-b]pyridin-4-one (1.2 g, 6.5 mmol, 1.0 equiv.) in MeOH (15 mL) was added NH2OH.HCl (2.3 g, 32.7 mmol, 5.0 equiv.). The resulting mixture was stirred for overnight at room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10:1) to afford N-[(4Z)-8-chloro- 2H,3H-pyrano[3,2-b]pyridin-4-ylidene]hydroxylamine (600 mg, 46.2%) as a yellow solid. MS-ESI: 199.0 [M+H] ⁺ . Step 7: 8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine. To a solution of N-[(4Z)-8-chloro-2H,3H-pyrano[3,2-b]pyridin-4-ylidene]hydrox ylamine (600 mg, 3.0 mmol, 1.0 equiv.) and AcONH4 (1164.3 mg, 15.1 mmol, 5.0 equiv.) in ammonia (8 mL) and EtOH (2 mL), was added Zn (987.6 mg, 15.1 mmol, 5.0 equiv.). The resulting mixture was stirred for overnight at room temperature under nitrogen atmosphere. The resulting mixture was filtered and the filter cake was washed with EtOAc. The combined filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography, eluted with DCM/MeOH (8:1) to afford 8-chloro-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4-amine (400 mg, 71.7%) as yellow oil. MS-ESI: 185.0 [M+H] ⁺ . Example E1: (R)-N-(2,3-dihydrobenzofuran-3-yl)-3-((4-(5-(pyridin-4-yl)-4 H-1,2,4-triazol-3- yl)piperidin-4-yl)amino)benzamide [353] Step 1: tert-butyl 4-[(3-[[(3R)-2,3-dihydro-1-benzofuran-3-yl]carbamoyl]phenyl) amino]-4- [5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]piperidine-1-carboxy late. To a solution of 3-[[1-(tert- butoxycarbonyl)-4-[5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl]pi peridin-4-yl]amino]benzoic acid (50.0 mg, 0.1 mmol, 1.0 equiv.), EDCI (31.0 mg, 0.2 mmol, 1.5 equiv.) and HOBt (21.8 mg, 0.2 mmol, 1.5 equiv.) in DMF (3 mL), was added DIEA (41.7 mg, 0.3 mmol, 3.0 equiv.). The mixture was stirred for 10 min at room temperature, then (3R)-2,3-dihydro-1-benzofuran-3-amine (16.0 mg, 0.1 mmol, 1.1 equiv.) was added. The resulting mixture was stirred for additional 3 hours at room temperature and concentrated under vacuum. The residue was purified by Prep-TLC (CH ₂ Cl ₂ /MeOH = 8:1) to afford tert-butyl 4-[(3-[[(3R)-2,3-dihydro-1-benzofuran-3-yl]carbamoyl]phenyl) amino]-4-[5-(pyridin- 4-yl)-4H-1,2,4-triazol-3-yl]piperidine-1-carboxylate (60.0 mg, 95.8%) as a yellow solid. MS-ESI: 582 [M+H] ⁺ . [354] Step 2: N-[(3R)-2,3-dihydro-1-benzofuran-3-yl]-3-([4-[5-(pyridin-4-y l)-4H-1,2,4-triazol-3- yl]piperidin-4-yl]amino)benzamide. tert-Butyl 4-[(3-[[(3R)-2,3-dihydro-1-benzofuran-3- yl]carbamoyl]phenyl)amino]-4-[5-(pyridin-4-yl)-4H-1,2,4-tria zol-3-yl]piperidine-1-carboxylate (60.0 mg, 0.1 mmol, 1.0 equiv.) was dissolved in HCl/1,4-dioxane (4M, 1 mL). The resulting mixture was stirred for 1 hour at room temperature and concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150mm 5um; Mobile Phase A: Water (10 mM NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 35% B in 8 min; 220 nm; RT1: 7.23 min. This gave N-[(3R)-2,3-dihydro-1- benzofuran-3-yl]-3-([4-[5-(pyridin-4-yl)-4H-1,2,4-triazol-3- yl]piperidin-4-yl]amino)benzamide (19.3 mg, 38.9%) as a white solid. MS-ESI: 482 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) : 8.74 (d, J = 7.6 Hz, 1H), 8.67 (d, J = 6.4 Hz, 2H), 7.92 (d, J = 6.4 Hz, 2H), 7.24–7.17 (m, 2H), 7.13 (s, 1H), 6.70– 6.96 (m, 2H), 6.84–6.81 (m, 2H), 6.49–6.47 (m, 1H), 6.10 (s, 1H), 5.74–5.69 (m, 1H), 4.70 (t, J = 9.2 Hz, 1H), 4.30–4.27 (m, 1H), 2.92–2.86 (m, 2H), 2.76–2.72 (m, 2H), 2.20–2.17 (m, 2H), 2.07–2.04 (m, 2H). [355] The compounds prepared in Table S5 were prepared using the same method described for Example E1. Table S5 Example E10: (S)-N-(chroman-4-yl)-3-((1-methyl-4-(5-(pyridin-4-yl)-4H-1,2 ,4-triazol-3-yl)piperidin- 4-yl)amino)benzamide [356] Step 1: (S)-N-(chroman-4-yl)-3-((1-methyl-4-(5-(pyridin-4-yl)-4H-1,2 ,4-triazol-3- yl)piperidin-4-yl)amino)benzamide. To a solution of 3-((1-methyl-4-(5-(pyridin-4-yl)-4H-1,2,4- triazol-3-yl)piperidin-4-yl)amino)benzoic acid (3.0 g, 7.9 mmol, 1.0 equiv.), EDCI (2.3 g, 11.9 mmol, 1.5 equiv.) and HOBT (1.6 g, 11.9 mmol, 1.5 equiv.) in DMF (50 mL), was added DIEA (3.1 g, 23.8 mmol, 3.0 equiv.). The mixture was stirred for 20 min at room temperature, (4S)-3,4-dihydro-2H-1- benzopyran-4-amine (1.4 g, 9.5 mmol, 1.2 equiv.) was added. The resulting mixture was stirred for additional 3 hours at room temperature and concentrated under vacuum. The residue was purified by reverse flash chromatography with the following: Column: YMC-Actus Triart C18 ExRS, 30*150 mm, 58m; Mobile Phase A: Water (10 mM NH ₄ HCO ₃ + 0.1% NH ₃ .H ₂ O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 30% B in 11 min; Wave Length: 220 nm; RT1: 10.2 min. This gave (S)-N-(chroman-4-yl)-3-((1-methyl-4-(5-(pyridin-4-yl)-4H-1,2 ,4-triazol-3-yl)piperidin-4- yl)amino)benzamide (3.2 g, 78.2%) as a white solid. MS-ESI: 510.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) : 14.21 (s, 1H), 8.66 (d, J = 5.6 Hz, 2H), 8.55 (d, J = 8.4 Hz, 1H), 7.94–7.91 (m, 2H), 7.17–7.07 (m, 3H), 7.02–6.99 (m, 2H), 6.82–6.76 (m, 2H), 6.52–6.50 (m, 1H), 6.07 (s, 1H), 5.26–5.16 (m, 1H), 4.27–4.25 (m, 1H), 4.20–4.18 (m, 1H), 2.45–2.38 (m, 2H), 2.34–2.28 (m, 3H), 2.18–2.11 (m, 5H), 2.06–1.99 (m, 3H). [357] The compounds prepared in Table S6 were prepared using the same method described for Example E10. Table S6 Example E23: (R)-N-(8-chloro-5-fluorochroman-4-yl)-3-((4-(5-(pyridin-4-yl )-4H-1,2,4-triazol-3- yl)piperidin-4-yl)amino)benzamide [358] Step 1-2: N-(8-chloro-5-fluorochroman-4-yl)-3-((4-(5-(pyridin-4-yl)-4H -1,2,4-triazol-3- yl)piperidin-4-yl)amino)benzamide. The title compound was prepared using the same method desired for Example E1. [359] Step 3: (R)-N-(8-chloro-5-fluorochroman-4-yl)-3-((4-(5-(pyridin-4-yl )-4H-1,2,4-triazol-3- yl)piperidin-4-yl)amino)benzamide. The racemic N-(8-chloro-5-fluorochroman-4-yl)-3-((4-(5- (pyridin-4-yl)-4H-1,2,4-triazol-3-yl)piperidin-4-yl)amino)be nzamide (120 mg) was separated by Chiral-HPLC with the following conditions: Column: CHIRALPAK IH, 2*25 cm, 58m; Mobile Phase A: Hex(0.2% DEA)--HPLC, Mobile Phase B: EtOH: DCM=1: 1--HPLC; Flow rate: 20 mL/min; Gradient: 30% B to 30% B in 8 min; Wave Length: 220/254 nm; RT2: 6.58 min. This resulted in (R)-N-(8-chloro-5-fluorochroman-4-yl)-3-((4-(5-(pyridin-4-yl )-4H-1,2,4-triazol-3- yl)piperidin-4-yl)amino)benzamide (18.1 mg, second peak) as a white solid. MS-ESI: 548.3 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) : 8.71–8.67 (m, 3H), 7.93–7.91- (m, 2H), 7.42–7.39 (m, 1H), 7.13 (s, 1H), 7.00–6.95 (m, 2H), 6.76–6.72 (m, 1H), 6.46–6.43 (m, 1H), 6.14 (s, 1H), 5.28–5.24 (m, 1H), 4.43–4.40 (m, 1H), 4.28–4.25 (m, 1H), 2.91–2.89 (m, 2H), 2.80–2.77 (m, 2H), 2.19–2.15 (m, 2H), 2.09–2.00 (m, 3H), 1.93–1.89 (m, 1H). [360] The compounds prepared in Table S7 were prepared using the same method described for Example E23. Table 7 Example E25/E26: N-((S)-chroman-4-yl)-3-(((S)-3-(5-(pyridin-4-yl)-4H-1,2,4-tr iazol-3-yl)pyrrolidin- 3-yl)amino)benzamide and N-((S)-chroman-4-yl)-3-(((R)-3-(5-(pyridin-4-yl)-4H-1,2,4-tr iazol-3- yl)pyrrolidin-3-yl)amino)benzamide [361] Step 1: tert-butyl 3-((3-(((S)-chroman-4-yl)carbamoyl)phenyl)amino)-3-(5-(pyrid in-4-yl)- 4H-1,2,4-triazol-3-yl)pyrrolidine-1-carboxylate. To a solution of 3-[[1-(tert-butoxycarbonyl)-3-[5- (pyridin-4-yl)-4H-1,2,4-triazol-3-yl]pyrrolidin-3-yl]amino]b enzoic acid (2.0 g, 4.4 mmol, 1.0 equiv.) in DMF (20 mL), were added EDCI (1.9 g, 6.7 mmol, 1.5 equiv.), DIEA (1.7 g, 13.3 mmol, 3.0 equiv.) and HOBT (0.9 g, 6.7 mmol, 1.5 equiv.). This was followed by the addition of (4S)-3,4- dihydro-2H-1-benzopyran-4-amine (0.8 g, 5.3 mmol, 1.2 equiv.). The resulting mixture was stirred for 2 hour at room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10:1) to afford tert-butyl 3-((3-(((S)-chroman- 4-yl)carbamoyl)phenyl)amino)-3-(5-(pyridin-4-yl)-4H-1,2,4-tr iazol-3-yl)pyrrolidine-1-carboxylate (1.8 g, 69.70%) as a yellow solid. MS-ESI: 582.2 [M+H] ⁺ . [362] Step 2: tert-butyl (S)-3-((3-(((S)-chroman-4-yl)carbamoyl)phenyl)amino)-3-(5-(p yridin-4- yl)-4H-1,2,4-triazol-3-yl)pyrrolidine-1-carboxylate (second peak) and tert-butyl (R)-3-((3-(((S)- chroman-4-yl)carbamoyl)phenyl)amino)-3-(5-(pyridin-4-yl)-4H- 1,2,4-triazol-3-yl)pyrrolidine-1- carboxylate (front peak). The racemic tert-butyl 3-((3-(((S)-chroman-4- yl)carbamoyl)phenyl)amino)-3-(5-(pyridin-4-yl)-4H-1,2,4-tria zol-3-yl)pyrrolidine-1-carboxylate (1.8 g) was separated by Prep-SFC with the following conditions: Column: Lux 5um i-Cellulose-5, 3*25 cm, 58m; Mobile Phase A: CO2, Mobile Phase B: MEOH: DCM=7: 1(0.1% 2M NH3-MeOH); Flow rate: 100 mL/min; Gradient: isocratic 30% B; Column Temperature (°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT1(min): 15.53, RT2(min): 17.92. This resulted in tert-butyl (S)-3-((3- (((S)-chroman-4-yl)carbamoyl)phenyl)amino)-3-(5-(pyridin-4-y l)-4H-1,2,4-triazol-3-yl)pyrrolidine-1- carboxylate (second peak) (600 mg) as a light yellow solid and tert-butyl (R)-3-((3-(((S)-chroman-4- yl)carbamoyl)phenyl)amino)-3-(5-(pyridin-4-yl)-4H-1,2,4-tria zol-3-yl)pyrrolidine-1-carboxylate (front peak) (800 mg) as a light yellow solid. MS-ESI: 582.3 [M+H] ⁺ . [363] Step 3: N-((S)-chroman-4-yl)-3-(((S)-3-(5-(pyridin-4-yl)-4H-1,2,4-tr iazol-3-yl)pyrrolidin-3- yl)amino)benzamide. To a solution of tert-butyl (S)-3-((3-(((S)-chroman-4- yl)carbamoyl)phenyl)amino)-3-(5-(pyridin-4-yl)-4H-1,2,4-tria zol-3-yl)pyrrolidine-1-carboxylate (second peak) (600.0 mg) in 1,4-dioxane (10 mL), was added HCl/1,4-dioxane (4M, 10 mL). The resulting mixture was stirred for 2 hours at room temperature and then concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 58m; Mobile Phase A: Water (10 mmol/L NH ₄ HCO ₃ ), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 10% B to 40% B in 7 min; Wave Length: 220 nm; RT1: 6.33 min. This resulted in N-((S)-chroman-4-yl)-3-(((S)-3-(5-(pyridin-4-yl)-4H-1,2,4-tr iazol-3- yl)pyrrolidin-3-yl)amino)benzamide (445.6 mg) as a white solid. MS-ESI: 482.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) : 8.68–8.66 (m, 2H), 8.59 (d, J = 8.4 Hz, 1H), 7.92–7.91 (m, 2H), 7.14–7.04 (m, 5H), 6.83–6.76 (m, 2H), 6.44–6.40 (m, 2H), 5.23–5.19 (m, 1H), 4.28–4.25 (m, 1H), 4.19–4.15 (m, 1H), 3.29–3.26 (m, 1H), 3.19–3.16 (m, 1H), 3.11–3.01 (m, 3H), 2.54–2.51 (m, 2H), 2.26–2.22 (m, 1H), 2.04–2.01 (m, 2H). [364] Step 4: N-((S)-chroman-4-yl)-3-(((R)-3-(5-(pyridin-4-yl)-4H-1,2,4-tr iazol-3-yl)pyrrolidin-3- yl)amino)benzamide. To a solution of tert-butyl (S)-3-((3-(((R)-chroman-4- yl)carbamoyl)phenyl)amino)-3-(5-(pyridin-4-yl)-4H-1,2,4-tria zol-3-yl)pyrrolidine-1-carboxylate (second peak) (800.0 mg) in 1,4-dioxane (10 mL), was added HCl/1,4-dioxane (4M, 10 mL). The resulting mixture was stirred for 2 hours at room temperature and then concentrated under vacuum. The residue was purified by Prep-HPLC with the following conditions: Column: XBridge Prep OBD C18 Column, 30*150 mm, 58m; Mobile Phase A: Water (10 mmol/L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 15% B to 40% B in 7 min; Wave Length: 220 nm; RT1: 6.23 min. This resulted in N-((S)-chroman-4-yl)-3-(((R)-3-(5-(pyridin-4-yl)-4H-1,2,4-tr iazol-3- yl)pyrrolidin-3-yl)amino)benzamide (524.5 mg) as a white solid. MS-ESI: 482.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) : 8.67–8.66 (m, 2H), 8.59 (d, J = 8.4 Hz, 1H), 7.92–7.91 (m, 2H), 7.14–7.04 (m, 5H), 6.83–6.76 (m, 2H), 6.44–6.40 (m, 2H), 5.23–5.19 (m, 1H), 4.27–4.25 (m, 1H), 4.20–4.16 (m, 1H), 3.29–3.25 (m, 1H), 3.19–3.15 (m, 1H), 3.11–3.00 (m, 3H), 2.54–2.51 (m, 2H), 2.26–2.22 (m, 1H), 2.04–2.01 (m, 2H). Example E27/E28: (S)-N-(8-chloro-5-fluorochroman-4-yl)-3-((1-methyl-4-(5-(pyr idin-4-yl)-4H-1,2,4- triazol-3-yl)piperidin-4-yl)amino)benzamide and (R)-N-(8-chloro-5-fluorochroman-4-yl)-3-((1- methyl-4-(5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)piperidin-4 -yl)amino)benzamide [365] Step 1: N-(8-chloro-5-fluorochroman-4-yl)-3-((1-methyl-4-(5-(pyridin -4-yl)-4H-1,2,4- triazol-3-yl)piperidin-4-yl)amino)benzamide. The title compound was prepared using the same method desired for Example E9. [366] Step 2: (S)-N-(8-chloro-5-fluorochroman-4-yl)-3-((1-methyl-4-(5-(pyr idin-4-yl)-4H-1,2,4- triazol-3-yl)piperidin-4-yl)amino)benzamide and (R)-N-(8-chloro-5-fluorochroman-4-yl)-3-((1- methyl-4-(5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)piperidin-4 -yl)amino)benzamide. The racemic N- (8-chloro-5-fluorochroman-4-yl)-3-((1-methyl-4-(5-(pyridin-4 -yl)-4H-1,2,4-triazol-3-yl)piperidin-4- yl)amino)benzamide (100 mg) was separated by Prep-Chiral-HPLC with the following conditions: Column: CHIRALPAK IH, 2*25 cm, 58m; Mobile Phase A: Hex(0.2% DEA)--HPLC, Mobile Phase B: EtOH:DCM = 1:1--HPLC; Flow rate: 20 mL/min; Gradient: 25% B to 25% B in 8 min; Wave Length: 220/254 nm; RT1: 4.65 min, RT2: 6.71 min. This resulted in (S)-N-(8-chloro-5- fluorochroman-4-yl)-3-((1-methyl-4-(5-(pyridin-4-yl)-4H-1,2, 4-triazol-3-yl)piperidin-4- yl)amino)benzamide (A; 42.4 mg) as a white solid and (R)-N-(8-chloro-5-fluorochroman-4-yl)-3-((1- methyl-4-(5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)piperidin-4 -yl)amino)benzamide (B; 39.9 mg) as a white solid. [367] A: MS-ESI: 562.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d ₆ ) : 14.20 (brs, 1H), 8.71–8.67 (m, 3H), 7.92–7.91 (m, 2H), 7.42–7.39 (m, 1H), 7.13 (s, 1H), 7.01–6.95 (m, 2H), 6.74 (t, J = 8.8 Hz, 1H), 6.47–6.44 (m, 1H), 6.08 (s, 1H), 5.28–5.24 (m, 1H), 4.43–4.40 (m, 1H), 4.29–4.25 (m, 1H), 2.43–2.38 (m, 2H), 2.34–2.28 (m, 2H), 2.18 (s, 3H), 2.18–2.14 (m, 2H), 2.06–2.00 (m, 1H), 1.93–1.89 (m, 1H). B: MS-ESI: 562.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) : 14.20 (brs, 1H), 8.71–8.67 (m, 3H), 7.92–7.91 (m, 2H), 7.42–7.39 (m, 1H), 7.13 (s, 1H), 7.01–6.95 (m, 2H), 6.74 (t, J = 8.8 Hz, 1H), 6.47–6.44 (m, 1H), 6.08 (s, 1H), 5.28–5.24 (m, 1H), 4.43–4.40 (m, 1H), 4.29–4.25 (m, 1H), 2.43–2.38 (m, 2H), 2.34–2.28 (m, 2H), 2.18 (s, 3H), 2.18–2.14 (m, 2H), 2.06–2.00 (m, 1H), 1.93–1.89 (m, 1H). [368] The compounds prepared in Table S8 were prepared using the same method described for Example E27/E28. Table S8 Example E31: tert-butyl (S)-4-((3-((5-chloro-2,3-dihydrobenzofuran-3-yl)carbamoyl)ph enyl)amino)- 4-(5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)piperidine-1-carbo xylate [369] Step 1: tert-butyl (S)-4-((3-((5-chloro-2,3-dihydrobenzofuran-3- yl)carbamoyl)phenyl)amino)-4-(5-(pyridin-4-yl)-4H-1,2,4-tria zol-3-yl)piperidine-1-carboxylate. The racemic tert-butyl 4-((3-((5-chloro-2,3-dihydrobenzofuran-3-yl)carbamoyl)phenyl )amino)-4-(5- (pyridin-4-yl)-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylat e (68 mg) was separated by Prep-Chiral- HPLC with the following conditions: Column: CHIRALPAK IF, 2*25 cm, 58m; Mobile Phase A: HEX: DCM=3: 1(0.2% DEA)--HPLC, Mobile Phase B: IPA--HPLC; Flow rate: 20 mL/min; Gradient: 20% B to 40% B in 14 min; Wave Length: 220/254 nm; RT1: 7.17 min. This resulted in tert-butyl (S)-4-((3-((5-chloro-2,3-dihydrobenzofuran-3-yl)carbamoyl)ph enyl)amino)-4-(5-(pyridin-4- yl)-4H-1,2,4-triazol-3-yl)piperidine-1-carboxylate (5.0 mg, 7.3%) as an off-white solid. MS-ESI: 616.2 [M+H] ⁺ . ¹ H NMR (400 MHz, DMSO-d6) : 8.85 (d, J = 7.2 Hz, 1H), 8.67 (d, J = 5.6 Hz, 2H), 7.93 (d, J = 6.0 Hz, 2H), 7.28–7.23 (m, 2H), 7.15 (s, 1H), 7.09–7.02 (m, 2H), 6.87 (d, J = 8.4 Hz, 1H), 6.42 (d, J = 8.0 Hz, 1H), 6.31 (s, 1H), 5.70–5.66 (m, 1H), 4.77–4.72 (m, 1H), 4.37–4.33 (m, 1H), 3.66–3.62 (m, 2H), 3.35–3.33 (m, 2H), 2.21–2.14 (m, 4H), 1.41 (s, 9H).

Example E32: (S)-N-(chroman-4-yl)-3-((1-ethyl-4-(5-(pyridin-4-yl)-4H-1,2, 4-triazol-3-yl)piperidin-4- yl)amino)benzamide [370] Step 1-2: (S)-N-(chroman-4-yl)-3-((4-(5-(pyridin-4-yl)-4H-1,2,4-triazo l-3-yl)piperidin-4- yl)amino)benzamide. The title compound was prepared using the same method desired for Example E1. [371] Step 3: (S)-N-(chroman-4-yl)-3-((1-ethyl-4-(5-(pyridin-4-yl)-4H-1,2, 4-triazol-3- yl)piperidin-4-yl)amino)benzamide. To a solution of (S)-N-(chroman-4-yl)-3-((4-(5-(pyridin-4-yl)- 4H-1,2,4-triazol-3-yl)piperidin-4-yl)amino)benzamide (100.0 mg, 0.2 mmol, 1.0 equiv.) in MeOH (8.00 mL) was added acetaldehyde (16.0 mg, 0.4 mmol, 1.8 equiv.). After stirred for 10 min, NaBH3CN (19.0 mg, 0.3 mmol, 1.5 equiv.) was added. The resulting mixture was stirred for overnight at room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (6:1) to afford the crude product, which was further purified by Prep-HPLC with the following conditions: Column: XBridge Shield RP18 OBD Column, 30*150mm, 58m; Mobile Phase A: Water (10 mmol/L NH4HCO3+0.1% NH3.H2O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 20% B to 45% B in 7 min; Wavelength: 220 nm; RT1: 6.57 min. This resulted in (S)-N-(chroman-4-yl)-3-((1-ethyl-4-(5-(pyridin-4-yl)-4H-1,2, 4- triazol-3-yl)piperidin-4-yl)amino)benzamide (23.2 mg, 21.5%) as a white solid. MS-ESI: 522.2 [M- H]-. ¹ H NMR (400 MHz, DMSO-d6) : 14.20 (s, 1H), 8.68–8.67 (m, 2H), 8.56 (d, J = 8.4 Hz, 1H), 7.93–7.91 (m, 2H), 7.14–7.00 (m, 5H), 6.82–6.76 (m, 2H), 6.50–6.48 (m, 1H), 6.09 (s, 1H), 5.22–5.18 (m, 1H), 4.26–4.22 (m, 1H), 4.20–4.18 (m, 1H), 2.70–2.68 (m, 2H), 2.53–2.51 (m, 2H), 2.46–2.41 (m, 2H), 2.37–2.32 (m, 2H), 2.21–2.17 (m, 2H), 2.03–1.99 (m, 2H), 1.01 (t, J = 7.2 Hz, 3H). [372] The compounds prepared in Table S9 were prepared using the same method described for Example E32. Table S9

Example 13: Synthesis of Additional Compounds Synthesis of E40 (3-((1,1-dioxido-3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl )tetrahydrothiophen-3- yl)amino)benzoic acid) [373] Step 1: 3-((3-(tert-butoxycarbonyl)phenyl)amino)tetrahydrothiophene- 3-carboxylic acid. To a stirred solution of tert-butyl 3-aminobenzoate (8.0 g, 41.4 mmol, 1 equiv.) and thiolan-3-one (12.7 g, 124.2 mmol, 3 equiv.) in THF (150 mL), was added NaOH (16.6 g, 414.0 mmol, 10 equiv.) in portions at 0 °C under nitrogen atmosphere. This was followed by the addition of CHCl ₃ (49.4 g, 414.0 mmol, 10 equiv.) dropwise at 0 °C. The reaction mixture was stirred overnight at room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with CH ₂ Cl ₂ /MeOH (10:1) to afford 3-((3-(tert- butoxycarbonyl)phenyl)amino)tetrahydrothiophene-3-carboxylic acid (3.2 g, 24%) as a brown solid. MS-ESI: 324.1 [M+H] ⁺ . [374] Step 2: 3-((3-(tert-butoxycarbonyl)phenyl)amino)tetrahydrothiophene- 3-carboxylic acid 1,1-dioxide. To a stirred solution of 3-((3-(tert-butoxycarbonyl)phenyl)amino)tetrahydrothiophene- 3-carboxylic acid (3.2 g, 9.9 mmol, 1 equiv.) and diethylamine (0.16 g, 2.2 mmol, 0.22 equiv.) in ACN (20 mL) and H ₂ O (40 mL) was added oxone (9.98 g, 59.4 mmol, 6 equiv.) at 0 °C under nitrogen atmosphere. The reaction mixture was stirred for 2 hours at room temperature and then quenched by the addition of saturated Na2SO3 aqueous at 0 °C. The resulting solution was extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with CH2Cl2/MeOH (15:1) to afford 3-((3-(tert-butoxycarbonyl)phenyl)amino)tetrahydrothiophene- 3-carboxylic acid 1,1-dioxide (2.0 g, 57%) as a brown solid. MS-ESI: 356.2 [M+H] ⁺ . [375] Step 3: 3-((3-(tert-butoxy(hydroxy)methyl)phenyl)amino)-N'-(imino(py rimidin-4- yl)methyl)tetrahydrothiophene-3-carbohydrazide 1,1-dioxide. To a stirred solution of 3-((3-(tert- butoxycarbonyl)phenyl)amino)tetrahydrothiophene-3-carboxylic acid 1,1-dioxide (2.0 g, 5.6 mmol, 1 equiv.), HOBT (1.1 g, 8.4 mmol, 1.5 equiv.), EDCI (1.6 g, 8.4 mmol, 1.5 equiv.) and DIEA (2.2 g, 16.9 mmol, 3 equiv.) in DMF (20 mL), was added N-aminopyrimidine-4-carboximidamide (0.93 g, 6.8 mmol, 1.2 equiv.) at room temperature. The reaction mixture was stirred for 2 hours at room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with CH2Cl2/MeOH (20:1) to afford 3-((3-(tert- butoxy(hydroxy)methyl)phenyl)amino)-N'-(imino(pyrimidin-4-yl )methyl)tetrahydrothiophene-3- carbohydrazide 1,1-dioxide (600 mg, 22%) as a yellow solid. MS-ESI: 477.3 [M+H] ⁺ . [376] Step 4: tert-butyl 3-((1,1-dioxido-3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3- yl)tetrahydrothiophen-3-yl)amino)benzoate.3-((3-(tert-butoxy (hydroxy)methyl)phenyl)amino)- N'-(imino(pyrimidin-4-yl)methyl)tetrahydrothiophene-3-carboh ydrazide 1,1-dioxide (600 mg, 1.3 mmol, 1 equiv.) was dissolved in toluene (5 mL) and CH3COOH (1 mL) at room temperature. The resulting mixture was stirred overnight at 100 °C, then cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with CH ₂ Cl ₂ /MeOH (15:1) to afford tert-butyl 3-((1,1-dioxido-3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3- yl)tetrahydrothiophen-3-yl)amino)benzoate (200 mg, 35%) as a yellow solid. MS-ESI: 457.2 [M+H] ⁺ . [377] Step 5: 3-((1,1-dioxido-3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl) tetrahydrothiophen-3- yl)amino)benzoic acid. tert-butyl 3-((1,1-dioxido-3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3- yl)tetrahydrothiophen-3-yl)amino)benzoate (200 mg, 0.44 mmol, 1 equiv.) was dissolved in DCM (5 mL) and TFA (1 mL). The resulting mixture was stirred for 1 hour at room temperature and then concentrated under vacuum to afford 3-((1,1-dioxido-3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3- yl)tetrahydrothiophen-3-yl)amino)benzoic acid (165 mg) as a yellow oil. MS-ESI: 401.1 [M+H] ⁺ . Synthesis of E41 ((S)-3-((1,1-dioxido-3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol- 3- yl)tetrahydrothiophen-3-yl)amino)benzoic acid) and E42 ((R)-3-((1,1-dioxido-3-(5-(pyrimidin-4-yl)- 4H-1,2,4-triazol-3-yl)tetrahydrothiophen-3-yl)amino)benzoic acid) [378] Step 1: tert-butyl (S)-3-((1,1-dioxido-3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3 - yl)tetrahydrothiophen-3-yl)amino)benzoate and tert-butyl (R)-3-((1,1-dioxido-3-(5-(pyrimidin- 4-yl)-4H-1,2,4-triazol-3-yl)tetrahydrothiophen-3-yl)amino)be nzoate. The racemic tert-butyl 3- ((1,1-dioxido-3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)te trahydrothiophen-3-yl)amino)benzoate (200 mg, 0.44 mmol, 1 equiv.) was separated by Chiral-HPLC with following conditions: Column: CHIRALPAK IG, 2*25 cm, 58m; Mobile Phase A: Hex(0.2% DEA). HPLC, Mobile Phase B: EtOH: DCM=1: HPLC; Flow rate: 20 mL/min; Gradient: 70% B to 70% B in 23 min; Wave Length: 220/254 nm; RT1(min): 5.24, RT2(min): 15.77. This resulted in tert-butyl (S)-3-((1,1-dioxido-3-(5- (pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahydrothiophen-3- yl)amino)benzoate (front peak, assigned as 6A) (70 mg, 35%) as yellow solid and tert-butyl (R)-3-((1,1-dioxido-3-(5-(pyrimidin-4- yl)-4H-1,2,4-triazol-3-yl)tetrahydrothiophen-3-yl)amino)benz oate (second peak, assigned as 6B) (60 mg, 30%) as yellow solid. MS-ESI: 457.2 [M+H] ⁺ . [379] Step 2: (S)-3-((1,1-dioxido-3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3 - yl)tetrahydrothiophen-3-yl)amino)benzoic acid. tert-butyl (S)-3-((1,1-dioxido-3-(5-(pyrimidin-4- yl)-4H-1,2,4-triazol-3-yl)tetrahydrothiophen-3-yl)amino)benz oate (front peak, assigned as 6A) (70 mg, 0.15 mmol, 1 equiv.) was dissolved in DCM (1 mL) and TFA (0.2 mL). The resulting mixture was stirred for 1 h at room temperature and then concentrated under vacuum. This resulted in (S)-3- ((1,1-dioxido-3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)te trahydrothiophen-3-yl)amino)benzoic acid (60 mg) as a yellow oil. MS-ESI: 401.1 [M+H] ⁺ . [380] Step 3: (R)-3-((1,1-dioxido-3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3 - yl)tetrahydrothiophen-3-yl)amino)benzoic acid. tert-butyl (R)-3-((1,1-dioxido-3-(5-(pyrimidin-4- yl)-4H-1,2,4-triazol-3-yl)tetrahydrothiophen-3-yl)amino)benz oate (second peak, assigned as 6B) (60 mg, 0.13 mmol, 1 equiv.) was dissolved in DCM (1 mL) and TFA (0.2 mL). The resulting mixture was stirred for 1 h at room temperature and then concentrated under vacuum. This resulted in (R)-3- ((1,1-dioxido-3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)te trahydrothiophen-3-yl)amino)benzoic acid (50 mg) as a yellow oil. MS-ESI: 401.1 [M+H] ⁺ . Synthesis of E43 (3-((3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahydrof uran-3- yl)amino)benzoic acid) [381] Step 1: 3-((3-(tert-butoxycarbonyl)phenyl)amino)tetrahydrofuran-3-ca rboxylic acid. To a stirred solution of tert-butyl 3-aminobenzoate (10 g, 51.7 mmol, 1 equiv.), dihydrofuran-3-one (13.4 g, 155.2 mmol, 3 equiv.) and NaOH (20.7 g, 517.5 mmol, 10 equiv.) in THF (100 mL) was added CHCl3 (61.8 g, 517.5 mmol, 10 equiv.) dropwise at 0°C. The reaction mixture was stirred overnight at room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with CH2Cl2/MeOH (8:1) to afford 3-((3-(tert- butoxycarbonyl)phenyl)amino)tetrahydrofuran-3-carboxylic acid (5.1 g, 31%) as a brown solid. MS- ESI: 308.2 [M+H] ⁺ . [382] Step 2: tert-butyl 3-((3-(2-(imino(pyrimidin-4-yl)methyl)hydrazine-1- carbonyl)tetrahydrofuran-3-yl)amino)benzoate. To a stirred solution of 3-((3-(tert- butoxycarbonyl)phenyl)amino)tetrahydrofuran-3-carboxylic acid (3.5 g, 11.4 mmol, 1 equiv.), EDCI (3.3 g, 17.1 mmol, 1.5 equiv.), HOBT (2.3 g, 17.1 mmol, 1.5 equiv.) and DIEA (4.4 g, 34.2 mmol, 3 equiv.) in DMF (50 mL), was added N-aminopyrimidine-4-carboximidamide (1.72 g, 12.5 mmol, 1.1 equiv.) in portions at room temperature. The reaction mixture was stirred for 2 h at room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with CH ₂ Cl ₂ /MeOH (10:1) to afford tert-butyl 3-((3-(2-(imino(pyrimidin-4- yl)methyl)hydrazine-1-carbonyl)tetrahydrofuran-3-yl)amino)be nzoate (510 mg, 10.5%) as a brown solid. MS-ESI: 427.2 [M+H] ⁺ . [383] Step 3: tert-butyl 3-((3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahydrofu ran-3- yl)amino)benzoate. tert-butyl 3-((3-(2-(imino(pyrimidin-4-yl)methyl)hydrazine-1- carbonyl)tetrahydrofuran-3-yl)amino)benzoate (170 mg, 0.4 mmol, 1 equiv.) was dissolved in toluene (5 mL) and AcOH (1 mL). The resulting mixture was stirred overnight at 100 °C under nitrogen atmosphere, then cooled to room temperature and concentrated under vacuum. The residue was purified by Prep-TLC (CH2Cl2/MeOH = 12:1) to afford tert-butyl 3-((3-(5-(pyrimidin-4-yl)-4H- 1,2,4-triazol-3-yl)tetrahydrofuran-3-yl)amino)benzoate (70 mg, 43%) as a yellow solid. MS-ESI: 409.2 [M+H] ⁺ . [384] Step 4: 3-((3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahydrofu ran-3- yl)amino)benzoic acid. tert-butyl 3-((3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahydrofu ran-3- yl)amino)benzoate (210 mg, 0.5 mmol, 1 equiv.) was dissolved in DCM (9 mL) and TFA (3 mL) at room temperature. The resulting mixture was stirred for 1 h at room temperature and then concentrated under vacuum to afford 3-((3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3- yl)tetrahydrofuran-3-yl)amino)benzoic acid (160 mg, 88%) as a yellow solid. MS-ESI: 353.1 [M+H] ⁺ . Synthesis of E44 ((S)-3-((1,1-dioxido-3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol- 3- yl)tetrahydrothiophen-3-yl)amino)benzoic acid) and E45 ((R)-3-((1,1-dioxido-3-(5-(pyrimidin-4-yl)- 4H-1,2,4-triazol-3-yl)tetrahydrothiophen-3-yl)amino)benzoic acid) [385] Step 1: tert-butyl (S)-3-((3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahyd rofuran-3- yl)amino)benzoate (front peak, assigned as 10A) and tert-butyl (R)-3-((3-(5-(pyrimidin-4-yl)- 4H-1,2,4-triazol-3-yl)tetrahydrofuran-3-yl)amino)benzoate (second peak, assigned as 10B). Racemic tert-butyl 3-((3-(2-(imino(pyrimidin-4-yl)methyl)hydrazine-1-carbonyl)t etrahydrofuran-3- yl)amino)benzoate (220 mg, 0.5 mmol, 1 equiv.) was separated by Chiral-HPLC with the following conditions: Column: CHIRALPAK IG, 2*25 cm, 58m; Mobile Phase A: Hex(0.2% DEA); HPLC, Mobile Phase B: EtOH: DCM=1: HPLC; Flow rate: 20 mL/min; Gradient: 70% B to 70% B in 23 min; Wave Length: 220/254 nm; RT1(min): 5.24, RT2(min): 15.77. This resulted in tert-butyl (S)-3- ((3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahydrofura n-3-yl)amino)benzoate (front peak, assigned as 10A) (80 mg, 36%) as yellow solid and tert-butyl (R)-3-((3-(5-(pyrimidin-4-yl)-4H- 1,2,4-triazol-3-yl)tetrahydrofuran-3-yl)amino)benzoate (second peak, assigned as 10B) (70 mg, 32%) as yellow solid. MS-ESI: 409.2 [M+H] ⁺ . [386] Step 2: (S)-3-((3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahyd rofuran-3- yl)amino)benzoic acid. tert-butyl (S)-3-((3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3- yl)tetrahydrofuran-3-yl)amino)benzoate (front peak, assigned as 10A) (70 mg, 0.17 mmol, 1 equiv.) was added in DCM (2 mL) and TFA (0.4 mL). The resulting mixture was stirred for 1 h at room temperature and then concentrated under vacuum to afford (S)-3-((3-(5-(pyrimidin-4-yl)-4H-1,2,4- triazol-3-yl)tetrahydrofuran-3-yl)amino)benzoic acid (60 mg) as a yellow solid. MS-ESI: 353.1 [M+H] ⁺ . [387] Step 3: (R)-3-((3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahyd rofuran-3- yl)amino)benzoic acid. tert-butyl (R)-3-((3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3- yl)tetrahydrofuran-3-yl)amino)benzoate (second peak, assigned as 10B) (70 mg, 0.17 mmol, 1 equiv.) was dissolved in DCM (2 mL) and TFA (0.4 mL). The resulting mixture was stirred for 1 h at room temperature and concentrated under vacuum to afford (R)-3-((3-(5-(pyrimidin-4-yl)-4H- 1,2,4-triazol-3-yl)tetrahydrofuran-3-yl)amino)benzoic acid (60 mg) as a yellow solid. MS-ESI: 353.1 [M+H] ⁺ . Synthesis of E47 (3-((3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)oxetan-3-yl )amino)benzoic acid)

[388] Step 1: 3-((3-(tert-butoxycarbonyl)phenyl)amino)oxetane-3-carboxylic acid. Exact Mass: 293.13. To a solution of 3-aminooxetane-3-carboxylic acid (2 g, 17.079 mmol, 1 equiv) and tert- butyl 3-bromobenzoate (5.27 g, 20.495 mmol, 1.2 equiv) in DMF (25 mL), were added CuI (0.33 g, 1.7 mmol, 0.1 equiv.), K ₂ CO ₃ (4.72 g, 34.16 mmol, 2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 110 °C under nitrogen atmosphere, then cooled to room temperature and quenched by the addition of water. The resulting solution was adjusted to pH 5 with 1M HCl aqueous. The solid was removed by filtration and the filter cake was washed with CH2Cl2. The combined filtrate was concentrated under vacuum and the residue was purified by silica gel column chromatography, eluting with CH2Cl2/MeOH (10:1) to afford 3-((3- (tert-butoxycarbonyl)phenyl)amino)oxetane-3-carboxylic acid (1.6 g, 33 %) as a yellow solid. MS- ESI: 294.2 [M+H] ⁺ . [389] Step 2: tert-butyl 3-((3-(2-(imino(pyrimidin-4-yl)methyl)hydrazine-1-carbonyl)o xetan-3- yl)amino)benzoate. To a solution of 3-((3-(tert-butoxycarbonyl)phenyl)amino)oxetane-3-carboxylic acid (1.5 g, 5.1 mmol, 1 equiv.) in DMF (15 mL) were added TEA (1.03 g, 10.23 mmol, 2 equiv.) and HATU (3.9 g, 10.23 mmol, 2 equiv.). This was followed by the addition of N-aminopyrimidine- 4-carboximidamide (0.84 g, 6.13 mmol, 1.2 equiv.). The resulting mixture was stirred for 5 h at room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with CH2Cl2/MeOH (10:1) to afford tert-butyl 3-((3-(2-(imino(pyrimidin-4- yl)methyl)hydrazine-1-carbonyl)oxetan-3-yl)amino)benzoate (900 mg, 43%) as a yellow solid. MS- ESI: 413.2 [M+H] ⁺ . Step 3: tert-butyl 3-((3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)oxetan-3- yl)amino)benzoate. tert-butyl 3-((3-(2-(imino(pyrimidin-4-yl)methyl)hydrazine-1-carbonyl)o xetan- 3-yl)amino)benzoate (900 mg, 2.2 mmol, 1 equiv.) was dissolved in added in EtOH (12 mL) and AcOH (3 mL). The resulting mixture was stirred for 18 h at 80°C under nitrogen atmosphere, then cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with CH ₂ Cl _2/ MeOH (10:1) to afford tert-butyl 3-((3-(5-(pyrimidin- 4-yl)-4H-1,2,4-triazol-3-yl)oxetan-3-yl)amino)benzoate (240 mg, 28%) as a yellow solid. MS-ESI: 395.2 [M+H] ⁺ . [390] Step 4: 3-((3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)oxetan-3-yl) amino)benzoic acid. tert-butyl 3-((3-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)oxetan-3-yl) amino)benzoate (190 mg, 0.48 mmol, 1 equiv.) was dissolved DCM (3 mL) and TFA (1 mL). The resulting mixture was stirred for 4 h at room temperature and then concentrated under vacuum to afford 3-((3-(5-(pyrimidin-4-yl)- 4H-1,2,4-triazol-3-yl)oxetan-3-yl)amino)benzoic acid (165 mg) as a white solid. MS-ESI: 339.2 [M+H] ⁺ . Synthesis of E48 (3-((4-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahydro- 2H-pyran-4- yl)amino)benzoic acid) [391] Step 1: 4-((3-(tert-butoxycarbonyl)phenyl)amino)tetrahydro-2H-pyran- 4-carboxylic acid. To a solution of 4-aminooxane-4-carboxylic acid (2 g, 13.8 mmol, 1 equiv.) and tert-butyl 3- bromobenzoate (5.3 g, 20.7 mmol, 1.5 equiv.) in DMF (20 mL) and H2O (2 mL), were added CuI (1.05 g, 5.5 mmol, 0.4 equiv.), 2-acetylcyclohexan-1-one (0.77 g, 5.5 mmol, 0.4 equiv.), K2CO3 (5.1 g, 41.3 mmol, 3 equiv.) and TEA (0.28 g, 2.8 mmol, 0.2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 12 h at 90 ºC under nitrogen atmosphere, then cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with CH ₂ Cl ₂ /MeOH (8:1) to afford 4-((3-(tert- butoxycarbonyl)phenyl)amino)tetrahydro-2H-pyran-4-carboxylic acid (2 g, 45%) as a yellow oil. MS-ESI: 322.2 [M+H] ⁺ . [392] Step 2: tert-butyl 3-((4-(2-(imino(pyrimidin-4-yl)methyl)hydrazine-1- carbonyl)tetrahydro-2H-pyran-4-yl)amino)benzoate. To a solution of 4-((3-(tert- butoxycarbonyl)phenyl)amino)tetrahydro-2H-pyran-4-carboxylic acid (2 g, 6.2 mmol, 1 equiv.), EDCI (1.8 g, 9.3 mmol, 1.5 equiv.), DIEA (2.41 g, 18.669 mmol, 3 equiv.) and HOBT (1.26 g, 9.335 mmol, 1.5 equiv.) in DMF (30 mL), was added N-aminopyrimidine-4-carboximidamide (1.0 g, 7.5 mmol, 1.2 equiv.). The resulting mixture was stirred overnight at room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with CH2Cl2/MeOH (10:1) to afford tert-butyl 3-((4-(2-(imino(pyrimidin-4-yl)methyl)hydrazine-1- carbonyl)tetrahydro-2H-pyran-4-yl)amino)benzoate (1.3 g, 47%) as a yellow solid. MS-ESI: 441.2 [M+H] ⁺ . [393] Step 3: tert-butyl 3-((4-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahydro-2 H-pyran-4- yl)amino)benzoate. To a solution of tert-butyl 3-((4-(2-(imino(pyrimidin-4-yl)methyl)hydrazine-1- carbonyl)tetrahydro-2H-pyran-4-yl)amino)benzoate (250 mg, 0.6 mmol, 1 equiv.) and DBU (518.4 mg, 3.4 mmol, 6.0 equiv.) in MeCN (4 mL), were added PPh3 (595.4 mg, 2.3 mmol, 4 equiv.) and CCl4 (2 mL) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature and concentrated under vacuum. The residue was purified by Prep- TLC (CH2Cl2/MeOH 10:1) to afford tert-butyl 3-((4-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3- yl)tetrahydro-2H-pyran-4-yl)amino)benzoate (120 mg, 50%) as a yellow solid. MS-ESI: 423.2 [M+H] ⁺ . [394] Step 4: 3-((4-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahydro-2 H-pyran-4- yl)amino)benzoic acid. tert-butyl 3-((4-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahydro-2 H- pyran-4-yl)amino)benzoate (120 mg, 0.3 mmol, 1 equiv.) was dissolved in DCM (9 mL) and TFA (3 mL). The resulting mixture was stirred for 2 h at room temperature and concentrated under vacuum to afford 3-((4-(5-(pyrimidin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahydro-2 H-pyran-4-yl)amino)benzoic acid (80 mg, 77%) as a yellow solid. MS-ESI: 367.2 [M+H] ⁺ .

Synthesis of E49 (3-((4-(5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahydro-2H -pyran-4- yl)amino)benzoic acid) [395] Step 1: 4-((3-(tert-butoxycarbonyl)phenyl)amino)tetrahydro-2H-pyran- 4-carboxylic acid. To a solution of 4-aminooxane-4-carboxylic acid (10 g, 68.89 mmol, 1 equiv.) and tert-butyl 3- bromobenzoate (21.3 g, 82.67 mmol, 1.2 equiv.) in DMF (100 mL), were added CuI (2.6 g, 13.78 mmol, 0.2 equiv.), 2-acetylcyclohexan-1-one (1.93 g, 13.78 mmol, 0.2 equiv.), K ₂ CO ₃ (28.6 g, 206.67 mmol, 3 equiv.) and TEA (1.4 g, 13.78 mmol, 0.2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 90 ºC under nitrogen atmosphere, then cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with CH ₂ Cl ₂ /MeOH (8:1) to afford 4-((3-(tert- butoxycarbonyl)phenyl)amino)tetrahydro-2H-pyran-4-carboxylic acid (6.8 g, 31%) as a yellow oil. MS-ESI: 322.2 [M+H] ⁺ . [396] Step 2: tert-butyl 3-((4-(2-(imino(pyridin-4-yl)methyl)hydrazine-1-carbonyl)tet rahydro- 2H-pyran-4-yl)amino)benzoate. To a solution of 4-((3-(tert- butoxycarbonyl)phenyl)amino)tetrahydro-2H-pyran-4-carboxylic acid (6 g, 18.67 mmol, 1 equiv.), and N-aminopyridine-4-carboximidamide (3.1 g, 22.40 mmol, 1.2 equiv.) in DMF (100 mL) were added TCFH (10.5 g, 37.34 mmol, 2 equiv.) and NMI (3.1 g, 37.34 mmol, 2 equiv.) at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 h at room temperature and then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH ₂ Cl ₂ /MeOH (10:1) to afford tert-butyl 3-((4-(2-(imino(pyridin-4- yl)methyl)hydrazine-1-carbonyl)tetrahydro-2H-pyran-4-yl)amin o)benzoate (3 g, 37%) as a brown oil. MS-ESI: 440.2 [M+H] ⁺ . [397] Step 3: tert-butyl 3-((4-(5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahydro-2H- pyran-4- yl)amino)benzoate. tert-butyl 3-((4-(2-(imino(pyridin-4-yl)methyl)hydrazine-1- carbonyl)tetrahydro-2H-pyran-4-yl)amino)benzoate (2.0 g, 4.55 mmol, 1 equiv.) was dissolved in toluene (20 mL) and AcOH (2 mL). The resulting mixture was stirred overnight at 80 ºC, then cooled to room temperature and concentrated under vacuum. The residue was purified by Prep-TLC (CH2Cl2/MeOH 10:1) to afford tert-butyl 3-((4-(5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahydro- 2H-pyran-4-yl)amino)benzoate (220 mg, 11.47%) as a yellow solid. MS-ESI: 422.2 [M+H] ⁺ . [398] Step 4: 3-((4-(5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahydro-2H- pyran-4- yl)amino)benzoic acid. tert-butyl 3-((4-(5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahydro-2H- pyran-4-yl)amino)benzoate (200 mg, 0.47 mmol, 1 equiv.) was dissolved in DCM (10 mL) and TFA (2 mL). The resulting mixture was stirred for 2 h at room temperature and concentrated under vacuum to afford 3-((4-(5-(pyridin-4-yl)-4H-1,2,4-triazol-3-yl)tetrahydro-2H- pyran-4- yl)amino)benzoic acid (200 mg) as a light yellow oil. MS-ESI: 366.2 [M+H] ⁺ . [399] The compounds prepared in Table 8 were prepared according to the amide coupling reactions described above. Table 8

ADDITIONAL EMBODIMENTS [400] Additional embodiments of the disclosure are indicated by the following numbered paragraphs. 1. A compound of Formula (I): (I), or a pharmaceutically acceptable salt thereof, wherein: X ¹ is CH, CR ⁹ , or N; X ³ is –NR ¹ – or –O–; X ⁴ is –NR ⁸ –, –O–, –S–, –S(=O)–, or –S(=O)2–; R ¹ is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C1-6 acyl, or a nitrogen protecting group; R ² and R ⁴ are each independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 acyl, or a nitrogen protecting group; each instance of R ³ is independently halogen, –CN, –OR ^O , –N(R ^N )2, –SR ^S , optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, or optionally substituted C1-6 acyl; each instance R ⁶ and R ⁹ is independently halogen, –CN, –OR ^O , –N(R ^N ) ₂ , optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, or optionally substituted C1-6 acyl; optionally wherein R ¹ and R ⁹ are joined together with the intervening atoms to form optionally substituted 5-8 membered heterocyclyl; R ⁵ is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-8 carbocyclyl C1-6 alkyl, optionally substituted 3-8 membered heterocyclyl C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted 5-10 membered heteroaryl C1-6 alkyl, optionally substituted C1-6 acyl, or a nitrogen protecting group; optionally wherein R ⁴ and R ⁵ are joined together with the intervening atoms to form optionally substituted 3-8 membered heterocyclyl; each instance of R ⁷ is independently halogen, optionally substituted C1-6 alkyl, –CN, –OR ^O , –N(R ^N )2, or –SR ^S , or two R ⁷ on the same carbon atom are taken together to form =O, or two R ⁷ on the same carbon atom are joined together with the intervening atoms to form optionally substituted C3-8 carbocyclyl or optionally substituted 3-8 membered heterocyclyl; R ⁸ is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-8 carbocyclyl C1-6 alkyl, optionally substituted 3-8 membered heterocyclyl C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted 5-10 membered heteroaryl C1-6 alkyl, optionally substituted C1-6 acyl, or a nitrogen protecting group; each instance of R ^O is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C _1-6 acyl, or an oxygen protecting group; each instance of R ^N is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C _1-6 acyl, or a nitrogen protecting group, or two R ^N bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted 3-8 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl; each instance of R ^S is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C _1-6 acyl, or a sulfur protecting group; a and b are each independently 0, 1, or 2; c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as valency permits; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, or 4. 2. The compound of paragraph 1, wherein the compound is of Formula (I): or a pharmaceutically acceptable salt thereof, wherein: X ¹ is CH, CR ⁹ , or N; X ³ is –NR ¹ – or –O–; X ⁴ is –NR ⁸ – or –O–; R ¹ is hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C _1-6 acyl, or a nitrogen protecting group; R ² and R ⁴ are each independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 acyl, or a nitrogen protecting group; each instance of R ³ is independently halogen, –CN, –OR ^O , –N(R ^N ) ₂ , –SR ^S , optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, or optionally substituted C _1-6 acyl; each instance R ⁶ and R ⁹ is independently halogen, –CN, –OR ^O , –N(R ^N ) ₂ , optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, or optionally substituted C _1-6 acyl; optionally wherein R ¹ and R ⁹ are joined together with the intervening atoms to form optionally substituted 5-8 membered heterocyclyl; R ⁵ is hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C _3-8 carbocyclyl C _1-6 alkyl, optionally substituted 3-8 membered heterocyclyl C _1-6 alkyl, optionally substituted C _6-10 aryl C _1-6 alkyl, optionally substituted 5-10 membered heteroaryl C1-6 alkyl, optionally substituted C1-6 acyl, or a nitrogen protecting group; optionally wherein R ⁴ and R ⁵ are joined together with the intervening atoms to form optionally substituted 3-8 membered heterocyclyl; each instance of R ⁷ is independently halogen, optionally substituted C1-6 alkyl, –CN, –OR ^O , –N(R ^N )2, or –SR ^S , or two R ⁷ on the same carbon atom are taken together to form =O, or two R ⁷ on the same carbon atom are joined together with the intervening atoms to form optionally substituted C carbocyclyl or optionally substituted 3-8 membered heterocyclyl; R ⁸ is hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C3-8 carbocyclyl C1-6 alkyl, optionally substituted 3-8 membered heterocyclyl C1-6 alkyl, optionally substituted C6-10 aryl C1-6 alkyl, optionally substituted 5-10 membered heteroaryl C1-6 alkyl, optionally substituted C1-6 acyl, or a nitrogen protecting group; each instance of R ^O is independently hydrogen, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted C2-6 alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C1-6 acyl, or an oxygen protecting group; each instance of R ^N is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C _1-6 acyl, or a nitrogen protecting group, or two R ^N bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted 3-8 membered heterocyclyl or optionally substituted 5-10 membered heteroaryl; each instance of R ^S is independently hydrogen, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _2-6 alkenyl, optionally substituted C _2-6 alkynyl, optionally substituted C _3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C _1-6 acyl, or a sulfur protecting group; a and b are each independently 1 or 2; c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10, as valency permits; m is 0, 1, 2, or 3; and n is 0, 1, 2, 3, or 4. 3. The compound of paragraph 1 or 2, wherein the compound is of the formula: , or a pharmaceutically acceptable salt thereof. 4. The compound of paragraph 1 or 2, wherein the compound is of the formula: , or a pharmaceutically acceptable salt thereof. 5. The compound of paragraph 1 or 2, wherein the compound is of the formula: , or a pharmaceutically acceptable salt thereof. 6. The compound of paragraph 1 or 2, wherein the compound is of the formula: , or a pharmaceutically acceptable salt thereof. 7. The compound of any one of paragraphs 1-6, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is of the formula: , wherein: G ¹ is CH, CR ¹⁵ , or N; G ² , G ³ , G ⁴ , and G ⁵ are each independently CH, CR ¹⁶ , or N; each instance of R ¹⁵ and R ¹⁶ is independently halogen, –OR ^O , –N(R ^N )2, –SR ^S , –CN, –N3, –NO2, –SCN, optionally substituted C1-6 alkyl, optionally substituted C1-6 heteroalkyl, optionally substituted C2-6 alkenyl, optionally substituted alkynyl, optionally substituted C3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C6-10 aryl, optionally substituted 5-10 membered heteroaryl, optionally substituted C _1-6 acyl, optionally substituted sulfonyl, or optionally substituted sulfinyl; and R ¹³ and R ¹⁴ are each independently hydrogen, halogen, –OR ^O , –N(R ^N )2, –SR ^S , –CN, optionally substituted C _1-6 alkyl, optionally substituted C _1-6 heteroalkyl, optionally substituted C _2-6 alkenyl, optionally substituted alkynyl, optionally substituted C _3-8 carbocyclyl, optionally substituted 3-8 membered heterocyclyl, optionally substituted C _6-10 aryl, optionally substituted 5-10 membered heteroaryl, or optionally substituted C _1-6 acyl, or R ¹³ and R ¹⁴ are taken together to form =O, or R ¹³ and R ¹⁴ are joined together with the intervening atoms to form optionally substituted C _3-8 carbocyclyl or optionally substituted 3-8 membered heterocyclyl; optionally wherein R ¹³ and R ¹⁵ are joined together with the intervening atoms to form optionally substituted C _5-8 carbocyclyl or optionally substituted 5-8 membered heterocyclyl. 8. The compound of paragraph 7, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is of the formula: , wherein: Y ³ is –O–, –NR ^N –, or –S–; each instance of R ¹⁷ is independently halogen, optionally substituted C1-6 alkyl, –CN, –OR ^O , –N(R ^N )2, or –SR ^S , or two R ¹⁷ on the same carbon atom are taken together to form =O, or two R ¹⁷ on the same carbon atom are joined together with the intervening atoms to form optionally substituted C3- 8 carbocyclyl or optionally substituted 3-8 membered heterocyclyl; d is 0, 1, or 2; and e is 0, 1, 2, 3, 4, 5, 6, or 7, as valency permits. 9. The compound of paragraph 8, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is of the formula: , wherein p 0, 1, 2, or 3. 10. The compound of any one of paragraphs 1-9, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is of one of the following formulae: 11. The compound of any one of paragraphs 1-10, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is of the formula: . 12. The compound of any one of paragraphs 1-10, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is of the formula: . 13. The compound of paragraph 7, wherein the compound is of the formula: , or a pharmaceutically acceptable salt thereof. 14. The compound of paragraph 8, wherein the compound is of the formula: , or a pharmaceutically acceptable salt thereof. 15. The compound of paragraph 9, wherein the compound is of the formula: , or a pharmaceutically acceptable salt thereof. 16. The compound of paragraph 9, wherein the compound is of the formula: , or a pharmaceutically acceptable salt thereof. 17. The compound of paragraph 9, wherein the compound is of the formula: , or a pharmaceutically acceptable salt thereof. 18. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein X ¹ is CH. 19. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein X ¹ is CR ⁹ . 20. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein R ⁹ is halogen or –OR ^O . 21. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein R ⁹ is –F or –OMe. 22. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein X ³ is NH. 23. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein X ³ is NR ¹ . 24. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein R ¹ is hydrogen or optionally substituted C _1-6 alkyl. 25. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and . 26. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein X ⁴ is –NH– or –NMe–. 27. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein X ⁴ is –NR ⁸ –. 28. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is hydrogen or optionally substituted C _1-6 alkyl. 29. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein R ⁸ is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso- , , . 30. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein R ² is hydrogen. 31. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein R ⁴ is hydrogen. 32. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1. 33. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein n is 0. 34. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R ³ is halogen. 35. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R ³ is –F. 36. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein m is 0. 37. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein c is 0 or 1. 38. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein c is 0. 39. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R ⁷ is optionally substituted C _1-6 alkyl. 40. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R ⁷ is methyl. 41. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein a is 1. 42. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein b is 1. 43. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein b is 2. 44. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein G ¹ is CR ¹⁵ or CH. 45. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein G ² is CR ¹⁶ or CH. 46. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein G ³ is CR ¹⁶ or CH. 47. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein G ⁴ is CR ¹⁶ or CH. 48. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein G ⁵ is CR ¹⁶ or CH. 49. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein G ⁵ is N. 50. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein R ¹⁵ is halogen, optionally substituted C1-6 alkyl, –OR ^O , or –N(R ^N )2. 51. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein p is 0, 1, or 2. 52. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein p is 0. 53. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R ¹⁶ is halogen, optionally substituted C _1-6 alkyl, –OR ^O , or – N(R ^N ) ₂ . 54. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein R ¹⁴ is hydrogen. 55. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein R ¹³ is hydrogen, –CN, optionally substituted C _1-6 alkyl, or optionally substituted C _3-6 carbocyclyl. 56. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein R ¹³ is selected from the group consisting of hydrogen, –CN, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, –CF3, , , . 57. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein R ¹³ and R ¹⁵ are joined together with the intervening atoms to form optionally substituted 5-8 membered heterocyclyl. 58. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein Y ³ is –O–. 59. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein d is 0 or 1. 60. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein d is 1. 61. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein e is 0, 1, or 2. 62. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R ¹⁷ is optionally substituted C _1-6 alkyl. 63. The compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R ¹⁷ is methyl. 64. The compound of paragraph 1, wherein the compound is selected from the compounds in Table 1, and pharmaceutically acceptable salts thereof. 65. The compound of paragraph 1, wherein the compound is: , or a pharmaceutically acceptable salt thereof. 66. The compound of paragraph 1, wherein the compound is: , or a pharmaceutically acceptable salt thereof. 67. The compound of paragraph 1, wherein the compound is selected from:

and pharmaceutically acceptable salts thereof. 68. A pharmaceutical composition comprising a compound of any one of paragraphs 1-67, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient. 69. A method comprising administering to a subject a compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the subject has cancer. 70. A method of treating cancer in a subject in need thereof comprising administering to the subject a compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. 71. The method of paragraph 69 or 70, wherein the cancer is pancreatic cancer or colon cancer. 72. A method of inhibiting tumor growth in a subject in need thereof comprising administering to the subject a compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. 73. The method of paragraph 72, wherein the tumor growth is inhibited by at least 25%, relative to control. 74. The method of any one of paragraphs 69-73, wherein the compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, is administered in combination with an anti-PD1 antibody or antigen-binding fragment thereof. 75. A method comprising administering to a subject a compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, wherein the subject has a cardiovascular disease. 76. A method of treating a cardiovascular disease in a subject in need thereof comprising administering to the subject a compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. 77. The method of paragraph 75 or 76, wherein the cardiovascular disease is heart failure, cardiac hypertrophy, or hypertension. 78. A method of treating a GRK2- or GRK3-related disease in a subject in need thereof comprising administering to the subject a compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. 79. The method of paragraph 78 for treating a GRK2-related disease. 80. A method of inhibiting GRK2 or GRK3 activity comprising contacting a GRK2 or GRK3 protein with a compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof. 81. The method of paragraph 80 for inhibiting GRK2 activity. 82. The method of paragraph 80 or 81, wherein the inhibiting occurs in vitro. 83. The method of paragraph 80 or 81, wherein the inhibiting occurs in vivo in a subject. 84. The method of any one of the preceding paragraphs, wherein the subject is a human. 85. A compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in a method of any one of the preceding paragraphs. 86. Use of a compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament. 87. A kit comprising a compound of any one of the preceding paragraphs, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof; and optionally instructions for use. EQUIVALENTS AND SCOPE [401] In the claims, articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.^ [402] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the present disclosure, or aspects of the present disclosure, is/are referred to as comprising particular elements and/or features, certain embodiments of the present disclosure or aspects of the present disclosure consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.^ [403] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the present disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art.^ [404] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.^