WO2026039516A1 - Glucosylceramide synthase inhibitors and uses thereof - Google Patents

Abstract

Provided herein are compounds that inhibit glucosylceramide synthase (GCS). Also provided are pharmaceutical compositions comprising the compounds, and methods of treating diseases and disorders associated with GCS activity, such as lysosomal storage disorders.

Description

GLUCOSYLCERAMIDE SYNTHASE INHIBITORS AND USES THEREOF R^ELATED A^PPLICATION This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Application, U.S.S.N.63/683,166, filed August 14, 2024, which is incorporated herein by reference in its entirety. FEDERALLY SPONSORED RESEARCH This invention was made with government support under Grant Number NS080833, awarded by the National Institutes of Health. The Government has certain rights in the invention. BACKGROUND Many lysosomal storage disorders are due to mutations in lysosome enzymes that degrade glycosphingolipids, including Gaucher disease, Fabry disease, GM1 gangliosidosis, and GM2 gangliosidoses, leading to accumulation of these glycolipids that cause a myriad of symptoms. The current therapeutic approaches for treating such disorders include enzyme replacement therapy: intravenous administration of recombinantly produced lysosome enzymes to replace the defective one. This approach is expensive (costs over a quarter million dollars per year), requires weekly to monthly administration, and cannot treat neurological symptoms as these proteins cannot reach the central nervous system. Another approach is substrate reduction therapy: small molecule inhibitors against glucosylceramide synthase (GCS, also known as UGCG), which catalyzes the first step of glycosphingolipid biosynthesis. They act by reducing the level of glycosphingolipids. To date, two GCS inhibitors have been approved by the FDA: eliglustat (mimicking the substrate ceramide) and miglustat (mimicking another substrate D-glucose). However, neither eliglustate nor miglustat can pass through the blood-brain-barrier to enter the central nervous system, and therefore they are not effective for treating patients with neurological symptoms. Besides lysosomal storage disorders, mutations in glycosphingolipid-degrading enzymes are also associated with Parkinson’s disease. In addition, glycosphingolipids often serve as receptor/attachment factors for many viruses and bacterial pathogens. Therefore, in addition to lysosomal storage disorders, GCS inhibitors may be useful for treating Parkinson’s disease and viral and bacterial infections. SUMMARY Accordingly, in one aspect, provided herein are compounds of Formula (I): (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein: each R³ is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR^A, -N(R^A)2, -SR^A, -CN, -SCN, -C(=NR^A)R^A, -C(=NR^A)OR^A, - C(=NR^A)N(R^A)₂, -C(=O)R^A, -C(=O)OR^A, -C(=O)N(R^A)₂, -C(=O)NR^AS(O)₂R^A, -NO₂, - NR^AC(=O)R^A, -NR^AC(=O)OR^A, -NR^AC(=O)N(R^A)₂, -NR^AC(=NR^A)N(R^A)₂, -OC(=O)R^A, - OC(=O)OR^A, -OC(=O)N(R^A)2, -NR^AS(O)2R^A, -OS(O)2R^A, -S(O)2NR^AC(O)R^A, - S(O)₂N(R^A)₂, -S(O)₂OR^A, or -S(O)₂R^A; n is 1, 2, or 3; and each occurrence of R^A is, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R^A groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; provided that the compound is not of formula: . In another aspect disclosed are pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and a pharmaceutically acceptable excipient. In another aspect disclosed are kits comprising a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition of the disclosure, and instructions for administering the compound or pharmaceutical composition to a subject in need thereof. In another aspect disclosed are methods of treating a disease or disorder (e.g., associated with glucosylceramide synthase (GCS) activity), the methods comprising administering an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition of the disclosure, to a subject in need thereof. In another aspect disclosed are methods of inhibiting glucosylceramide synthase (GCS), the methods comprising contacting GCS with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition of the disclosure. DEFINITIONS 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 Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March’s Advanced Organic Chemistry, 5^th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3^rd Edition, Cambridge University Press, Cambridge, 1987. 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 invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers. Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of ¹⁹F with ¹⁸F, or the replacement of ¹²C with ¹³C or ¹⁴C are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays. When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example “C_1-6 alkyl” is intended to encompass, C₁, C₂, C₃, C₄, C₅, C₆, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl. The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups. The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C_1-10 alkyl”). In certain embodiments, an alkyl group has 1 to 9 carbon atoms (“C_1-9 alkyl”). In certain embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In certain embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In certain embodiments, an alkyl group has 1 to 6 carbon atoms (“C_1-6 alkyl”). In certain embodiments, an alkyl group has 1 to 5 carbon atoms (“C_1-5 alkyl”). In certain embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In certain embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In certain embodiments, an alkyl group has 1 to 2 carbon atoms (“C_1-2 alkyl”). In certain embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In certain embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (C1), ethyl (C2), propyl (C₃) (e.g., n-propyl, isopropyl), butyl (C₄) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C₅) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n- octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently 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 C1-10 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), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C_1-10 alkyl (such as substituted C_1-6 alkyl, e.g., −CF₃, Bn). 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. In certain embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C_1-8 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C_1-6 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1-4 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C_1-2 haloalkyl”). Examples of haloalkyl groups include −CF3, −CF2CF3, −CF2CF2CF3, −CCl3, −CFCl2, −CF2Cl, and the like. 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 (i.e., 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 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-10 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC_1-9 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-8 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC_1-7 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-6 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC_1-5 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1or 2 heteroatoms within the parent chain (“heteroC1-4 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC_1-3 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-2 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC₁ alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-10 alkyl. The term “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms (“C_2-9 alkenyl”). In certain embodiments, an alkenyl group has 2 to 8 carbon atoms (“C_2-8 alkenyl”). In certain embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In certain embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms (“C_2-5 alkenyl”). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In certain embodiments, an alkenyl group has 2 carbon atoms (“C₂ 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 (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C_2-4 alkenyl groups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is a substituted C_2-10 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified (e.g., −CH=CHCH3 or ) may be an (E)- or (Z)- double bond. 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 (i.e., 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 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC_2-10 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC_2-8 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC_2-7 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC_2-5 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1or 2 heteroatoms within the parent chain (“heteroC2-4 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC2-3 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC_2-6 alkenyl”). 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. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC_2-10 alkenyl. The term “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C_2-10 alkynyl”). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In certain embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (“C_2-7 alkynyl”). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (“C_2-6 alkynyl”). In certain embodiments, an alkynyl group has 2 to 5 carbon atoms (“C_2-5 alkynyl”). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In certain embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In certain 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 C_2-6 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. In certain embodiments, the alkynyl group is an unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is a substituted C2-10 alkynyl. 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 (i.e., 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 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-10 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC_2-8 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC_2- 7 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1or 2 heteroatoms within the parent chain (“heteroC_2-4 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC2-3 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC_2-6 alkynyl”). 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. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC_2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-10 alkynyl. The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C_3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C_3-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C_3-7 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C_5-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C_5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C₅), cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like. Exemplary C_3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C₁₀), cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl (C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or 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. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl. In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C_3-8 cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In certain embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In certain embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C_5-6 cycloalkyl”). In certain embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C_5-10 cycloalkyl”). Examples of C_5-6 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 C_3-8 cycloalkyl groups include the aforementioned C_3-6 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 cycloalkyl group is an unsubstituted C_3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl. “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 moiety. 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 group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl. In certain 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 certain 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 certain 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 certain embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, 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. “Heterocyclylalkyl” is a subset of “alkyl” and refers to an alkyl group substituted by an heterocyclyl group, wherein the point of attachment is on the alkyl moiety. 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 π 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 certain embodiments, an aryl group has 6 ring carbon atoms (“C₆ aryl”; e.g., phenyl). In certain embodiments, an aryl group has 10 ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In certain embodiments, an aryl group has 14 ring carbon atoms (“C₁₄ 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. In certain embodiments, the aryl group is an unsubstituted C_{6- 14} aryl. In certain embodiments, the aryl group is a substituted C_6-14 aryl. “Aralkyl” 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 moiety. 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 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 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, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl). In certain 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 certain 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 certain 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 certain embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain 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. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl. Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6- bicyclic heteroaryl groups include, without limitation, 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, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl. “Heteroaralkyl” 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 moiety. 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. 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 may be 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 invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen 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 invention is not intended to be limited in any manner by the exemplary substituents described herein. Exemplary carbon atom substituents include, but are not limited to, 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^bbC(=O)R^aa, −NR^bbCO₂R^aa, −NR^bbC(=O)N(R^bb)2, −C(=NR^bb)R^aa, −C(=NR^bb)OR^aa, −OC(=NR^bb)R^aa, −OC(=NR^bb)OR^aa, −C(=NR^bb)N(R^bb)2, −OC(=NR^bb)N(R^bb)2, −NR^bbC(=NR^bb)N(R^bb)2, −C(=O)NR^bbSO2R^aa, −NR^bbSO₂R^aa, −SO₂N(R^bb)₂, −SO₂R^aa, −SO₂OR^aa, −OSO₂R^aa, −S(=O)R^aa, −OS(=O)R^aa, −P(=O)(NR^bb)2, −OP(=O)(NR^bb)2, −NR^bbP(=O)(OR^cc)2, −NR^bbP(=O)(NR^bb)2, −P(R^cc)2, −P(R^cc)3, −OP(R^cc)2, −OP(R^cc)3, −B(R^aa)2, −B(OR^cc)2, −BR^aa(OR^cc), C1-10 alkyl, C1-10 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, 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; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(R^bb)2, =NNR^bbC(=O)R^aa, =NNR^bbC(=O)OR^aa, =NNR^bbS(=O)2R^aa, =NR^bb, or =NOR^cc; each instance of R^aa is, independently, selected from C_1-10 alkyl, C_1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, 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, 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^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)₂R^aa, −P(=O)(R^aa)₂, −P(=O)₂N(R^cc)₂, −P(=O)(NR^cc)₂, C_1-10 alkyl, C_1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, 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, 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, C_1-10 alkyl, C_1-10 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^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, −SO2H, −SO3H, −OH, −OR^ee, −ON(R^ff)2, −N(R^ff)2, −N(R^ff)3⁺X^−, −N(OR^ee)R^ff, −SH, −SR^ee, −P(=O)2R^ee, −P(=O)(R^ee)2, −OP(=O)(R^ee)2, −OP(=O)(OR^ee)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C_6-10 aryl, 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 can be joined to form =O or =S; each instance of R^ee is, independently, selected from C_1-6 alkyl, C_1-6 perhaloalkyl, C_2-6 alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6alkenyl, heteroC2-6 alkynyl, C3-10 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, C1-6 alkyl, C1-6 perhaloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, heteroC_1-6alkyl, heteroC_2-6alkenyl, heteroC_2-6alkynyl, 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; and each instance of R^gg is, independently, halogen, −CN, −NO₂, −N₃, −SO₂H, −SO₃H, −OH, −OC_1-6 alkyl, −ON(C_1-6 alkyl)₂, −N(C_1-6 alkyl)₂, −N(C_1-6 alkyl)₃ ⁺X^−, −NH(C_1-6 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)(C_1-6 alkyl), −OCO₂(C_1-6 alkyl), −C(=O)NH₂, −C(=O)N(C_1-6 alkyl)₂, −OC(=O)NH(C1-6 alkyl), −NHC(=O)( C1-6 alkyl), −N(C1-6 alkyl)C(=O)( C1-6 alkyl), −NHCO2(C1-6 alkyl), −NHC(=O)N(C1-6 alkyl)2, −NHC(=O)NH(C1-6 alkyl), −NHC(=O)NH2, −C(=NH)O(C_1-6 alkyl), −OC(=NH)(C_1-6 alkyl), −OC(=NH)OC_1-6 alkyl, −C(=NH)N(C_1-6 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(C_1-6 alkyl)₂, −SO₂NH(C_1-6 alkyl), −SO₂NH₂, −SO₂C_1-6 alkyl, −SO₂OC_1-6 alkyl, −OSO₂C_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(C1-6 alkyl), C(=S)NH2, −C(=O)S(C1-6 alkyl), −C(=S)SC1-6 alkyl, −SC(=S)SC1-6 alkyl, −P(=O)2(C1-6 alkyl), −P(=O)(C1-6 alkyl)2, −OP(=O)(C1-6 alkyl)2, −OP(=O)(OC1-6 alkyl)₂, C_1-6 alkyl, C_1-6 perhaloalkyl, C_2-6 alkenyl, C_2-6 alkynyl, heteroC_1-6alkyl, heteroC_2- 6alkenyl, heteroC2-6alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R^gg substituents can be joined to form =O or =S; wherein X⁻ is a counterion. The term “halo” or “halogen” refers to fluorine (fluoro, −F), chlorine (chloro, −Cl), bromine (bromo, −Br), or iodine (iodo, −I). The term “hydroxyl” or “hydroxy” refers to the group −OH. The term “substituted hydroxyl” or “substituted hydroxyl,” by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from −OR^aa, −ON(R^bb)2, −OC(=O)SR^aa, −OC(=NR^bb)N(R^bb)₂, −OS(=O)R^aa, −OSO₂R^aa, −OSi(R^aa)₃, −OP(R^cc)₂, −OP(R^cc)₃, −OP(=O)2R^aa, −OP(=O)(R^aa)2, −OP(=O)(OR^cc)2, −OP(=O)2N(R^bb)2, and −OP(=O)(NR^bb)2, wherein R^aa, R^bb, and R^cc are as defined herein. The term “amino” refers to the group −NH₂. The term “substituted amino,” by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the “substituted amino” is a monosubstituted amino or a disubstituted amino group. The term “monosubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from −NH(R^bb), −NHC(=O)R^aa, −NHCO₂R^aa, −NHC(=O)N(R^bb)₂, −NHC(=NR^bb)N(R^bb)₂, −NHSO₂R^aa, −NHP(=O)(OR^cc)₂, and −NHP(=O)(NR^bb)2, wherein R^aa, R^bb and R^cc are as defined herein, and wherein R^bb of the group −NH(R^bb) is not hydrogen. The term “disubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from −N(R^bb)2, −NR^bb C(=O)R^aa, −NR^bbCO2R^aa, −NR^bbC(=O)N(R^bb)₂, −NR^bbC(=NR^bb)N(R^bb)₂, −NR^bbSO₂R^aa, −NR^bbP(=O)(OR^cc)₂, and −NR^bbP(=O)(NR^bb)2, wherein R^aa, R^bb, and R^cc are as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen. The term “trisubstituted amino” refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with three groups, and includes groups selected from −N(R^bb)3 and −N(R^bb)3⁺X^−, wherein R^bb and X⁻ are as defined herein. The term “acyl” refers to a group having the general formula −C(=O)R^X1, −C(=O)OR^X1, −C(=O)−O−C(=O)R^X1, −C(=O)SR^X1, −C(=O)N(R^X1)₂, −C(=S)R^X1, −C(=S)N(R^X1)2, and −C(=S)S(R^X1), −C(=NR^X1)R^X1, −C(=NR^X1)OR^X1, −C(=NR^X1)SR^X1, and −C(=NR^X1)N(R^X1)2, wherein R^X1 is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or unsubstituted alkynyl; substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or di- alkylamino, mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or di-heteroarylamino; or two R^X1 groups taken together form a 5- to 6-membered heterocyclic ring. Exemplary acyl groups include aldehydes (−CHO), carboxylic acids (−CO₂H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the substituents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, arylalkyl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, acyloxy, and the like, each of which may or may not be further substituted). The term “oxo” refers to the group =O, and the term “thiooxo” refers to the group =S. Nitrogen atoms can be substituted or unsubstituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, −OH, −OR^aa, −N(R^cc)₂, −CN, −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)₂R^aa, −P(=O)(R^aa)₂, −P(=O)₂N(R^cc)₂, −P(=O)(NR^cc)₂, C_1-10 alkyl, C_1-10 perhaloalkyl, C_2-10 alkenyl, C_2-10 alkynyl, heteroC_1-10alkyl, heteroC_2-10alkenyl, heteroC_2- 10alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two R^cc groups attached to an N atom 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, and wherein R^aa, R^bb, R^cc and R^dd are as defined above. In certain embodiments, the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include, but are not limited to, −OH, −OR^aa, −N(R^cc)₂, −C(=O)R^aa, −C(=O)N(R^cc)₂, −CO₂R^aa, −SO₂R^aa, −C(=NR^cc)R^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, C1-10 alkyl (e.g., aralkyl, heteroaralkyl), C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC_2-10 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. For example, nitrogen protecting groups such as amide groups (e.g., −C(=O)R^aa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3- pyridylcarboxamide, N-benzoylphenylalanyl derivative, 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 derivative, o-nitrobenzamide and o- (benzoyloxymethyl)benzamide. Nitrogen protecting groups such as carbamate groups (e.g., −C(=O)OR^aa) include, but are not limited to, methyl carbamate, ethyl carbamante, 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. Nitrogen protecting groups such as sulfonamide groups (e.g., −S(=O)₂R^aa) include, but are not limited to, 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), β- trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4’,8’- dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide. Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)- acyl derivative, N’-p-toluenesulfonylaminoacyl derivative, N’-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 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,N’- isopropylidenediamine, 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 derivative, N-diphenylborinic acid derivative, 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 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, but are not limited to, −R^aa, −N(R^bb)₂, −C(=O)SR^aa, −C(=O)R^aa, −CO2R^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, −SO2R^aa, −Si(R^aa)3, −P(R^cc)2, −P(R^cc)3, −P(=O)2R^aa, −P(=O)(R^aa)2, −P(=O)(OR^cc)2, −P(=O)₂N(R^bb)₂, and −P(=O)(NR^bb)₂, wherein 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. Exemplary oxygen protecting groups include, but are not limited to, methyl, 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, 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, α- 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, 3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl, 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, 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, α-naphthoate, nitrate, alkyl N,N,N’,N’- tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). Sulfur protecting groups include, but −P(=O)(NR^bb)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. As used herein, the term “salt” refers to any and all salts, and encompasses pharmaceutically acceptable salts. 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 this invention 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. 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. 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 H₂O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R⋅2 H₂O) and hexahydrates (R⋅6 H₂O)). The term “tautomers” or “tautomeric” refers to two or more interconvertable 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. It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”. 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. 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, Bundgard, H., Design of Prodrugs, pp.7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, 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. C_1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, C7-12 substituted aryl, and C7-C12 arylalkyl esters of the compounds described herein may be preferred. 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. “Disease,” “disorder,” and “condition” are used interchangeably herein. 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. 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). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence. 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, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health 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. 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 GCS. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating disease or disorder associated with GCS activity. A “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more signs or 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. BRIEF DESCRIPTION OF THE DRAWINGS FIGs.1A-1F show a high-throughput small molecule screen identifies inhibitors that block Shiga toxin binding to cell surface. FIG.1A shows a primary screen of 4,928 compounds. Human bladder epithelial 5637 cells were seeded into trans-bottom 384-well plates, and compounds from a library (shown as gray dots) were pin-transferred as 16.7 µg/mL. DMSO (0.33%, v/v, shown as blue circles) and PDMP (5 µM, shown as red circles) served as negative and positive controls, respectively. Two biological replicates were conducted in parallela. Following a 24-hour incubation, cells were exposed to 1.2 μg/mL Stx1 on ice for 60 min. Subsequently, the cells were washed, fixed, and subjected into immunostaining assay. Stx1 signal was detected using a polyclonal antibody. High- throughput imaging was employed to detect both cell number and the amount of cell surface- bound Stx1 for each compound. The average Z-scores for cell number and Stx1 binding were plotted as x-axis and y-axis, respectively. Compounds exhibiting Z-scores of cell number greater than -2 in both replicates and an average Z-score of Stx1 binding less than -2 were selected as hits. In total, 68 top hits (1.4%) met these criteria, and they were categorized into three groups: strong hits (shown as orange dots, with a Z-score of Stx1 binding less than - 2.5), medium hits (shown as purple dots, with a Z-score of Stx1 binding between -2.5 and - 2.25), and weak hits (shown as green dots, with a Z-score of Stx1 binding between -2.25 and -2). FIGs.1B-D. Through scaffold classification, the 68 top hits were categorized into 21 clusters. Following a secondary screen, 13 compounds from distinct clusters were selected (FIG.1B).5637 cells were pre-treated with PDMP or 13 selected compounds at various concentrations for 24h, and then subjected to the Stx1 cell surface binding assay. Among them, four lead compounds (TC5, TC7, TC10, and TC12) exhibited obvious dose-dependent inhibition (FIG.1C), and their half-maximal effective concentrations (EC₅₀) were calculated (FIG.1D). Error bars indicate mean ± s.d.; N = 3. FIGs.1E-1F show 5637 cells were pre- treated with PDMP (5 μM), TC5 (5 μM), TC7 (5 μM), TC10 (20 μM), TC12 (20 μM), or DMSO (Ctrl) for various durations and subsequently subjected to Stx1 or Ctx cell surface binding assay. Stx1 was detected using a polyclonal Stx1A antibody, CtxB was conjugated with Alexa-555 florescent dye. Nuclei were stained with DAPI. The percentage of Stx1 binding (FIG.1E) and CtxB binding (FIG.1F) were normalized to time-0 (before compounds pre-treatment). Error bars indicate mean ± s.d.; N = 3. FIGs.2A-2G show that GCS is identified as the cellular target of lead compounds. FIG.2A shows a schematic diagram of the representative biosynthetic pathway of glycolipids. FIGs.2B-2D show HeLa cells were pre-treated with PDMP, four lead compounds (5 μM or 20 μM), or DMSO (Ctrl) for 1 h and labeled with [14C]-serine for 16 h. The labeled lipids were extracted and analyzed by thin-layer chromatography (TLC). A representative radioactive image of the analyzed TLC plates is shown (FIG.2B), with distinct lipid species bands marked at the right. Band intensities were normalized and presented as bar-charts (FIG.2C-D). The treatment with compounds blocks the biosynthesis of GlcCer and downstream lipids, while having no effect on Cer amount. This observation suggests that these compounds target glucosylceramide synthase (GCS). Error bars indicate mean ± s.d.; N = 3; *, p < 0.05; **, p < 0.01 (Student’s t-test). FIGs.2E-G show HeLa cells were sonicated and the cell lysates were incubated with PDMP, four lead compounds (0.1, 1, 10, or 100 μM), or DMSO (Ctrl). Then 2 μM C6-NBD-Cer and 1 mM UDP-glucose (UDP-Glc) as substrates, and the reaction mixtures were incubated for 45 min at 37 °C. The lipids were extracted and analyzed by TLC, and the NBD-labeled lipides were visualized (FIG.2E). The proportion of NBD-GlcCer in total NBD-labeled lipids, which indicates the GCS activity, was quantified and normalized with Ctrl (FIG.2F). The EC₅₀ value were calculated in (FIG.2G). Error bars indicate mean ± s.d.; N = 3. FIGs.3A-3H show that screening close analogues of TC7 identified second- generation lead compounds. FIG.3A shows scaffold and substituent structures of TC7. FIGs. 3B-C show that 5637 cells were pre-treated with TC7, TC7.22, TC7.23, TC7.25, or TC7.26 at different concentrations for 24h, and then subjected to Stx1 cell surface binding assay. Four second-generation lead compounds were found to be more efficient (FIG.3B). Their substituent structures and EC50 values are shown (FIG.3C). Error bars indicate mean ± s.d.; N = 3. FIGs.3D-E show HeLa cells were pre-treated with 50 nM TC7.22, TC7.23, TC7.25, TC7.26, or DMSO (Ctrl) for 1 h and labeled with [14C]-serine for 16 h. The labeled lipids were extracted and analyzed by TLC. A representative radioactive image of the analyzed TLC plates is shown (FIG.3D), with distinct lipid species bands marked at the right. Band intensities were normalized and presented as bar-charts (FIG.3E). Error bars indicate mean ± s.d.; N = 3; **, p < 0.01 (Student’s t-test). FIGs.3F-H show HeLa cells were sonicated and the cell lysates were incubated with four second-generation lead compounds (0.001, 0.01, 0.03, 0.1, 0.3, 1, or 10 μM), or DMSO (Ctrl). Then C6-NBD-Cer and UDP-Glc were added as substrates, and the reaction mixtures were incubated for 45 min at 37 °C. The lipids were extracted and analyzed by TLC, and the NBD-labeled lipides were visualized (FIG.3F). The proportion of NBD-GlcCer in total NBD-labeled lipids, indicates the GCS activity, was quantified and normalized with Ctrl (FIG.3G). The EC50 value were calculated and shown (FIG.3H). Error bars indicate mean ± s.d.; N = 3. FIGs.4A-4E show SAR analysis for TC7.25. A panel of analogues of TC7.25 were selected for structure-activity relationship (SAR) analysis. Their dose-dependent inhibition on Stx1 cell surface binding is shown (FIG.4A-D), along with their substituent structures and EC50 values (FIG.4E). FIGs.5A-5G show that GCS-Y196 residue is critical for the species selectivity of TC7.25. FIGs.5A-B shows mouse embryonic fibroblast (MEF) cells were pre-treated with PDMP or TC7.25 (500, 50, or 5 nM) for four days and subjected to Ctx cell surface binding assay. Nuclei were labeled with DAPI (FIG.5A). Representative images were taken from one of three independent experiments. The toxin binding was quantified and normalized to Ctrl and plotted as a bar-chart (FIG.5B). The inhibition efficiency of TC7.25 is similar to PDMP. Scale bar, 200 μm; error bars indicate mean ± s.d.; N = 3; *, p < 0.05; **, p < 0.01 (Student’s t-test). FIGs.5C-D show human cell line HeLa, dog cell line MDCK, and mouse cell line Neuro2A were sonicated, and their cell lysates were incubated with TC7.25 (0.1 or 1 μM) or DMSO. Then C6-NBD-Cer and UDP-Glc were added as substrates, and the reaction mixtures were incubated for 45 min at 37 °C. The lipids were extracted and analyzed by TLC, and the NBD-labeled lipides were visualized (FIG.5C). The proportion of NBD-GlcCer in total NBD-labeled lipids, indicates the GCS activity, was quantified and normalized with Control (FIG.5D). The GCS inhibition of TC7.25 on human cells is more efficient than on dog and mouse cells. Error bars indicate mean ± s.d.; N = 3; **, p < 0.01 (Student’s t-test). FIG.5E shows the alignment of human, dog, and mouse GCS identifies several differential residues. There are only two differential residues (L20 and Y196) between human-GCS and dog-GCS. FIGs.5F-5G show overexpressing wild-type human GCS (hGCS-WT), its mutants (hGCS- Y196S, hGCS-L20V, and hGCS-Y196F), mouse GCS (mGCS-WT), or its mutants (mGCS- S196Y) in HeLa-GCS-KO cells by transient transfection. Then the cells were pre-treated with TC7.25 at different concentrations, and their Stx2 cell surface binding was detected by flow cytometry. The representative flow cytometry histograms are shown (FIG.5F), and the Stx2 binding was quantified by measuring relative mean fluorescence intensity (MFI) (FIG.5G). Error bars indicate mean ± s.d.; N = 3. FIGs.6A-6E shows comparisons with established drugs. FIG.6A shows chemical structures of miglustat, ibiglustat, and eliglustat. FIGs.6B-C show 5637 cells were pre- treated with TC7.25, TC7.25.33b, miglustat, ibiglustat, or eliglustat in different concentrations for 24 h, and subjected to Stx1 cell surface binding assay. Their dose- dependent curves (FIG.6B) and EC50 values are shown (FIG.6C). Error bars indicate mean ± s.d.; N = 3. FIGs.6D-E show TC7.25 (10 mg/kg) was IP injected into mice once per day for nine days. Stx2 (15 μg/kg) was then IP injected on the 5^th days, and the mice survival was monitored for another five days (FIG.6D). All mice injected with Stx2 (N = 22) died within 120 h. Three or five out of fifteen mice co-injected with TC7.25 at different doses survived (FIG.6E). FIGs.7A-7D show screening conditions and quality control. FIG.7A shows 5637 cells were pre-treated with PDMP (1 or 5 μM) or DMSO for 24 h and then subjected to Stx1 cell surface binding assay.5637-A4GALT-KO cells were used as positive control. Treatment with 5 μM PDMP efficiently blocked Stx1 cell binding and was selected as positive control for the following screen. Representative images were taken from one of three independent experiments. Bar, 100 μm. FIGs.5B-C show the screen results for two different biological replicates were plotted based on cell number (FIG.7B) or normalized Stx1 binding (FIG. 7C). These results indicate consistency between the two replicates, and the positive and negative controls (PDMP and DMSO, respectively) were effective. FIG.7D shows the screen results for 4,982 compounds were plotted by the average Z-score of Stx1 binding over cell number. Strong, medium, and weak hits have been described in FIG.1A are represented as orange, purple, and green dots, respectively. FIGs.8A-8F show validation of four lead compounds on multiple cell lines. FIG.8A shows that Human 5637, HT29, and green monkey Vero cells were pre-treated with PDMP (5 μM), TC5 (5 μM), TC7 (5 μM), TC10 (20 μM), TC12 (20 μM), or DMSO (Ctrl) for four days and then subjected to Stx1 or Ctx cell surface binding assays (FIG.8A, C, E). The percentages of Stx1 and CtxB binding were normalized and plotted as bar-charts (FIG.8B, 8D, 8F). Representative images were taken from one of three independent experiments. Scale bar, 100 μm, error bars indicate mean ± s.d.; N = 3; *, p < 0.05; **, p < 0.01 (Student’s t-test). FIGs.9A-9D show that four lead compounds reduce cytotoxicity of Stx1 and Stx2. Human 5637 and green monkey Vero cells were pre-treated with PDMP (5 μM), TC5 (5 μM), TC7 (5 μM), TC10 (20 μM), TC12 (20 μM), or DMSO (Ctrl) for four days and then challenged by Stx1 or Stx2. The relative cell viabilities were plotted over toxin concentrations. Error bars indicate mean ± s.d.; N = 3. FIGs.10A-10G show that four lead compounds reduce biosynthesis of glycosphingolipids. FIG.10A-B. HeLa (FIG.10A) or 5637 (FIG.10B) cells were pre-treated with PDMP(5 μM), TC5 (5 μM), TC7 (5 μM), TC10 (20 μM), TC12 (20 μM) or DMSO as control for 24h, then exposed to different concentrations of TcdB1.1 for another 24 h. The percentages of round-shaped cells were plotted over TcdB1.1 concentrations. There is no difference between control and treatments indicates that the reduction of GlcCer induced by the lead compounds is not caused by the inhibition of UDP-Glc. Error bars indicate mean ± s.d.; N = 3. FIG.10A. Adding extra UDP-Glc into 5637 cells cannot rescue the compounds- induced reduction of Stx1 cell surface binding. NS, not significant. FIG.10D-F. HeLa cells were pre-treated with PDMP, four lead compounds (5 μM or 20 μM), or DMSO (Ctrl) for 1 h and labeled with [¹⁴C]-galactose for 16 h. The labeled lipids were extracted and analyzed by HPTLC. A representative radioactive image of the analyzed HPTLC plates is shown (FIG. 10D), with distinct lipid species bands marked at the right. Band intensities were normalized and presented as bar-charts (FIG.10E-F). Error bars indicate mean ± s.d.; N = 3; *, p < 0.05; **, p < 0.01 (Student’s t-test). FIG.10G.5637 cells were pre-treated with PDMP, four lead compounds (5 μM or 20 μM), or DMSO (Ctrl) for four days, and the cells were harvested for mass spectrometry-based lipidomic analysis. A4GALT-KO cells were analyzed in parallela. The abundances of Cer, GlcCer, LacCer, and Gb3 were quantified and shown as relative amounts. Error bars indicate mean ± s.d.; N = 3; *, p < 0.05; **, p < 0.01 (Student’s t-test). FIGs.11A-11E shows the screening of analogues of TC7. FIG.11A. The substituent structures of close analogues of TC7 from the compound library. Their EC50 values in the Stx1 binding assay are also shown. FIG.3B-3E.5637 cells were pre-treated with PDMP, TC7, and its 31 analogues at various concentrations for 24 h and then subjected into Stx1 cell surface binding assay. Error bars indicate mean ± s.d.; N = 3. FIGs.12A-12F show validation of the second-generation lead compounds. FIGs. 12A-B.5637 cells were pre-treated with PDMP, TC7, TC7.22, TC7.23, TC7.25, TC7.26 at indicated concentrations, or DMSO (Ctrl) for four days and then subjected to Stx1 or Ctx cell surface binding assays. Stx1 was detected using a polyclonal Stx1A antibody, while CtxB was conjugated with Alexa-555 dye. Nuclei were labeled with DAPI (FIG.12A). The percentage of Stx and Ctx binding were normalized and plotted as bar-charts (FIG.12B). Representative images were taken from one of three independent experiments. Scale bar, 100 μm, error bars indicate mean ± s.d.; N = 3; *, p < 0.05; **, p < 0.01 (Student’s t-test). FIG. 12C-F. Human 5637 and green monkey Vero cells were pre-treated with TC7 (5 μM), TC7.22 (0.5 μM), TC7.23 (0.5 μM), TC7.25 (0.5 μM), TC7.26 (0.5 μM), or DMSO (Ctrl) for four days and then challenged with Stx1 or Stx2. The relative cell viabilities were plotted over toxin concentrations. Error bars indicate mean ± s.d.; N = 3. FIGs.13A-13B show that Second generation lead compounds inhibit GCS. FIGs. 13A-B. HeLa cells were pre-treated with 50 nM TC7.22, TC7.23, TC7.25, TC7.26, or DMSO (Ctrl) for 1 h and labeled with [¹⁴C]-galactose for 16 h. The labeled lipids were extracted and analyzed by HPTLC. A representative radioactive image of the analyzed HPTLC plates is shown (FIG.13A), with distinct lipid species bands marked at the right. Band intensities were normalized and shown as bar-charts (FIG.13B). Error bars indicate mean ± s.d.; N = 3; **, p < 0.01 (Student’s t-test). FIGs.14A-14D show validation of the SAR compounds of TC7.25. FIGs.14A-B. 5637 cells were pre-treated with TC7.25, TC7.25.23, TC7.25.31, TC7.25.33, TC7.25.33b, TC7.25.43, TC7.25.44, TC7.25.51, TC7.25.52 at indicated concentrations, or DMSO (Ctrl) for four days and then subjected to Stx1 or Ctx cell surface binding assays. Stx1 was detected using a polyclonal Stx1A antibody, while CtxB was conjugated with Alexa-555 dye. Nuclei were labeled with DAPI. FIGs.14C-D. The percentage of Stx and Ctx binding were normalized and plotted as bar-charts. Representative images were taken from one of three independent experiments. Scale bar, 100 μm (FIG.14A) or 200 μm (FIG.14B), error bars indicate mean ± s.d.; N = 3; *, p < 0.05; **, p < 0.01 (Student’s t-test). FIGs.15A-15G show species selectivity of lead compounds. FIGs.15A-B. Mouse MEF cells were pre-treated with PDMP (5 μM), TC5 (5 μM), TC7 (5 μM), TC10 (20 μM), TC12 (20 μM), or DMSO (Ctrl) for four days and then subjected to Ctx cell surface binding assay. Stx1 has no detectable binding on the surface of MEF cells. CtxB was conjugated with Alexa-555 dye, and nuclei were labeled with DAPI (FIG.15A). The percentage of Ctx binding were normalized and plotted as bar-charts (FIG.15B). Representative images were taken from one of three independent experiments. Scale bar, 100 μm, error bars indicate mean ± s.d.; N = 3; *, p < 0.05; **, p < 0.01 (Student’s t-test). FIGs.15C-D. Mouse MEF or BMDM cells were pre-treated with TC7.25.33b (500, 50, or 5 nM) or DMSO (Ctrl) for four days and then subjected to Ctx cell surface binding assay. CtxB was conjugated with Alexa- 555 dye, and nuclei were labeled with DAPI (FIG.15C). The percentage of Ctx binding were normalized and plotted as bar-charts (FIG.15D). Representative images were taken from one of three independent experiments. Scale bar, 200 μm, error bars indicate mean ± s.d.; N = 3. FIGs.15E-15F. The overexpression of human GCS (FIG.15E), mouse GCS (FIG.15F), along with their mutants, was validated by immunoblot assays to detect the fused HA tag. Tubulin served as a loading control. Representative blots are shown from two independent experiments. FIG.15G. Wild-type human GCS (hGCS-WT) or mouse GCS (mGCS-WT) was overexpressed in HeLa-GCS-KO cells by transient transfection. The cells were then pre- treated with TC7.25.33, TC7.25.33a, or TC7.25.33b at different concentrations, and their Stx2 cell surface binding was detected by flow cytometry. The Stx binding was quantified by measuring relative MFI. Error bars indicate mean ± s.d.; N = 3. FIGs.16A-16C show comparisons with three drugs miglustat, ibiglustat, and eliglustat. FIG.16A.5637 cells were pre-treated with PDMP, TC7.25, TC7.25.33b, or three drugs at indicated concentrations, or DMSO (Ctrl) for four days and then subjected to Stx1 or Ctx cell surface binding assays. Nuclei were labeled with DAPI. FIG.16B-C. The percentage of Stx1 and CtxB binding were normalized and plotted as bar-charts. Representative images were taken from one of three independent experiments. Scale bar, 200 μm, error bars indicate mean ± s.d.; N = 3; *, p < 0.05; **, p < 0.01 (Student’s t-test). FIGs.17A-17G show pharmacokinetic characterization of exemplary compounds in mouse models. FIG.18 shows safety evaluation of compound G1-1 (TC7.25) against 47 major host proteins. FIGs.19A-C show safety evaluation of compound G3-3B against 78 proteins in the SAFETYscan E/IC50 ELECT service of Eurofins DiscoverX. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS The present disclosure stems from the recognition that there are currently no treatment options for patients suffering from lysosomal storage disorders with neurological disorders. Furthermore, both eliglustat and miglustat mimic endogenous substrates, resulting in inhibition of other pathways that require these substrates. For example, miglustat will also inhibit protein glycosylation. These side effects limit the dose that can be utilized when administering these drugs. Accordingly, described herein are compounds of Formula (I), which are GCS inhibitors that are significantly more potent than known GCS inhibitors eliglustat, venglustat, and miglustat. Moreover, compounds of the disclosure enter the brain with good efficacy, are highly selective for inhibition of human GCS, have a clean safety profile with no toxicity in mice, have a long half-life upon exposure to mouse and human liver microsomes, and have high plasma protein binding, which limits its elimination in the hepatocytes and supports its long half-life in vivo. Thus, the compounds of the disclosure provide promising new compounds for the development of a new generation of brain-penetrating GCS inhibitors for treating lysosomal storage disorders (e.g., Gaucher disease, Fabry disease) as well as other diseases. Compounds In one aspect, the present disclosure provides compounds of Formula (I): and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein: R² is , , , , , , , _{, , or ;} each R³ is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR^A, -N(R^A)2, -SR^A, -CN, -SCN, -C(=NR^A)R^A, -C(=NR^A)OR^A, - C(=NR^A)N(R^A)₂, -C(=O)R^A, -C(=O)OR^A, -C(=O)N(R^A)₂, -C(=O)NR^AS(O)₂R^A, -NO₂, - NR^AC(=O)R^A, -NR^AC(=O)OR^A, -NR^AC(=O)N(R^A)₂, -NR^AC(=NR^A)N(R^A)₂, -OC(=O)R^A, - OC(=O)OR^A, -OC(=O)N(R^A)2, -NR^AS(O)2R^A, -OS(O)2R^A, -S(O)2NR^AC(O)R^A, - S(O)₂N(R^A)₂, -S(O)₂OR^A, or -S(O)₂R^A; n is 1, 2, or 3; and each occurrence of R^A is, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R^A groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring. In certain embodiments, the compound is not of the formula of any one or more of the following: , , or . In certain embodiments, the present disclosure provides a compound of Formula (I), or a tautomer or pharmaceutically acceptable salt thereof. In certain embodiments, the present disclosure provides a compound of Formula (I), or a tautomer thereof. In certain embodiments, the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof. R¹ A_{s described herein,} C(=O)OR^A. In certain embodiments, I_{n certain embodiments, embodiments, R1 is .} In certain embodiments, R¹ is -CH3. In certain embodiments, R¹ is -C(=O)OR^A. In certain embodiments, R¹ is -C(=O)OR^A, wherein R^A is hydrogen or substituted or unsubstituted alkyl. In certain embodiments, R¹ is -C(=O)OR^A, wherein R^A is hydrogen or substituted or unsubstituted C1-4alkyl. In certain embodiments, R¹ is -C(=O)OR^A, wherein R^A is hydrogen or unsubstituted C_1-4alkyl. In certain embodiments, R¹ is -C(=O)OR^A, wherein R^A is unsubstituted C1-4alkyl. In certain embodiments, R¹ is -C(=O)OH or -C(=O)OCH3. In certain embodiments, R¹ is -C(=O)OH. In certain embodiments, R¹ is -C(=O)OCH3. R² In certain embodiments, R² is . In certain embodiments, R² is certain embodiments, R² is . In certain embodiments, R² is embodiments, R² is . In certain embodiments, R² is . In certain embodiments, R² is . In certain embodiments, R² is . In certain embodiments, certain embodiments, R³ As described herein, each R³ is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR^A, -N(R^A)₂, -SR^A, -CN, -SCN, -C(=NR^A)R^A, -C(=NR^A)OR^A, -C(=NR^A)N(R^A)2, -C(=O)R^A, -C(=O)OR^A, -C(=O)N(R^A)2, - C(=O)NR^AS(O)2R^A, -NO2, -NR^AC(=O)R^A, -NR^AC(=O)OR^A, -NR^AC(=O)N(R^A)2, - NR^AC(=NR^A)N(R^A)₂, -OC(=O)R^A, -OC(=O)OR^A, -OC(=O)N(R^A)₂, -NR^AS(O)₂R^A, - OS(O)₂R^A, -S(O)₂NR^AC(O)R^A, -S(O)₂N(R^A)₂, -S(O)₂OR^A, or -S(O)₂R^A. In certain embodiments, R³ is halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR^A, -N(R^A)2, -SR^A, -CN, -SCN, -C(=NR^A)R^A, -C(=NR^A)OR^A, - C(=NR^A)N(R^A)₂, -C(=O)R^A, -C(=O)OR^A, -C(=O)N(R^A)₂, -C(=O)NR^AS(O)₂R^A, -NO₂, - NR^AC(=O)R^A, -NR^AC(=O)OR^A, -NR^AC(=O)N(R^A)2, -NR^AC(=NR^A)N(R^A)2, -OC(=O)R^A, - OC(=O)OR^A, -OC(=O)N(R^A)2, -NR^AS(O)2R^A, -OS(O)2R^A, -S(O)2NR^AC(O)R^A, - S(O)₂N(R^A)₂, -S(O)₂OR^A, or -S(O)₂R^A. In certain embodiments, each R³ is independently substituted or unsubstituted alkyl. In certain embodiments, each R³ is independently substituted or unsubstituted C1-4 alkyl. In certain embodiments, each R³ is independently unsubstituted alkyl. In certain embodiments, each R³ is independently unsubstituted C_1-4 alkyl. In certain embodiments, each R³ is independently unsubstituted C1-2 alkyl. In certain embodiments, each R³ is independently - CH3. In certain embodiments, at least one R³ is substituted or unsubstituted alkyl. In certain embodiments, at least one R³ is substituted or unsubstituted C1-4 alkyl. In certain embodiments, at least one R³ is unsubstituted alkyl. In certain embodiments, at least one R³ is unsubstituted C_1-4 alkyl. In certain embodiments, at least one R³ is unsubstituted C_1-2 alkyl. In certain embodiments, at least one R³ is -CH3. In certain embodiments, R³ is substituted or unsubstituted alkyl. In certain embodiments, R³ is substituted or unsubstituted C_1-4 alkyl. In certain embodiments, R³ is unsubstituted alkyl. In certain embodiments, R³ is unsubstituted C1-4 alkyl. In certain embodiments, R³ is unsubstituted C1-2 alkyl. In certain embodiments, R³ is -CH3. As described herein, n is 1, 2, or 3. In certain embodiments, n is 1 or 2. In certain embodiments, n is 1 or 3. In certain embodiments, n is 2 or 3. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. Embodiments of Formula (I) In certain embodiments, the compound of Formula (I) is a compound of Formula (I’): (I’), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein n, R¹, R² and R³ are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I’’): (I’’), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein n, R¹, R² and R³ are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I- or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R¹, R² and R³ are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I- (I-a’), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R¹, R² and R³ are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I- a’’): (I-a’’), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R¹, R² and R³ are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a- 1): (I-a-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R¹ and R² are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I- a’): (I-a-1’), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R¹ and R² are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-a- 1’’): (I-a-1’’), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R¹ and R² are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I- b): (I-b), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R¹ and R³ are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I- b’): (I-b’), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R¹ and R³ are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I- b’’): (I-b’’), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R¹ and R³ are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I- b-1): (I-b-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R¹ and R³ are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I- b-1’): (I-b-1’), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R¹ and R³ are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I- b-1’’): (I-b-1’’), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R¹ and R³ are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I- b-2): (I-b-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R¹ is as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I- b-2’): (I-b-2’), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R¹ is as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I- b-2’’): (I-b-2’’), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R¹ is as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I- or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R² and R³ are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I- c’): (I-c’), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R² and R³ are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I- or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R² and R³ are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-c- 1): (I-c-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R² and R³ are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-c- (I-c-1’), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R² and R³ are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-c- 1’’): or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R² and R³ are as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-c- 2): (I-c-2), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R² is as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-c- 2’): (I-c-2’), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R² is as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I-c- 2’’): (I-c-2’’), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R² is as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I- d): (I-d), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R³ is as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I- d’): (I-d’), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R³ is as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I- d’’): or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R³ is as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I- d-1): (I-d-1), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R³ is as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I- d-1’): (I-d-1’), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R³ is as defined herein. In certain embodiments, the compound of Formula (I) is a compound of Formula (I- d-1’’): or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, wherein R³ is as defined herein. In certain embodiments, the compound of Formula (I) is a compound of formula: (G2-4); (G2-5); (G2-6); (G3-1); (G3-2); (G3-3);/102 (G4-1); (G4-2); (G4-3); (G4-4); (G4-5); (G4-6);/102 (G5-1); or (G5-2); or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound of Formula (I) is a compound of formula: or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound of Formula (I) is a compound of formula: or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound of Formula (I) is a compound of formula: or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. In certain embodiments, the compound of Formula (I) is a compound of formula: or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof. Pharmaceutical Compositions, Kits, and Administration The present disclosure provides pharmaceutical compositions comprising a compound of the disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, co- crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound of the disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound of the disclosure (e.g., a compound of Formula (I)), or a tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition described herein comprises a compound of the disclosure (e.g., a compound of Formula (I)), or a tautomer thereof, and a pharmaceutically acceptable excipient. In certain embodiments, a compound of the disclosure (e.g., a compound of Formula (I)) 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. In certain embodiments, the effective amount is an amount effective for treating a disease or disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a disease or disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a disease or disorder is associated with glucosylceramide synthase (GCS) activity in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a disease or disorder is associated with glucosylceramide synthase (GCS) activity in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a neurological disease or disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a neurological disease or disorder in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating a lysosomal storage disorder, Parkinson’s Disease, a viral infection, or a bacterial infection. In certain embodiments, the effective amount is an amount effective for preventing a lysosomal storage disorder, Parkinson’s Disease, a viral infection, or a bacterial infection. In certain embodiments, the effective amount is an amount effective for treating Gaucher disease, Fabry disease, GM1 gangliosidosis, GM2 gangliosidosis, Tay-Sachs disease, or Sandhoff disease. In certain embodiments, the effective amount is an amount effective for preventing Gaucher disease, Fabry disease, GM1 gangliosidosis, GM2 gangliosidosis, Tay-Sachs disease, or Sandhoff disease. In certain embodiments, the effective amount is an amount effective for treating cancer in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing cancer in a subject in need thereof. In certain embodiments, the cancer is associated with KRAS (e.g., having a KRAS mutation). In certain embodiments, the cancer is non-small cell lung cancer, colorectal cancer, pancreatic ductal adenocarcinoma, choloangiocarcinoma, uterine endometrial carcinoma, testicular germ cell cancer, or cervical squamous cell carcinoma. In certain embodiments, the effective amount is an amount effective for inhibiting glucosylceramide synthase (GCS). In certain embodiments, the effective amount is an amount effective for inhibiting GCS in vitro. In certain embodiments, the effective amount is an amount effective for inhibiting GCS in vivo. Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the composition comprising a compound of the disclosure (e.g., a compound of Formula (I)) into association with a carrier 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. 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. As used herein, 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, for example, one-half or one-third of such a dosage. The compound 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, mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. 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, and/or in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve their ability to cross the blood- brain barrier, 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 exhibit a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.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. In certain embodiments, the additional pharmaceutical agent comprises an agent useful in the treatment of cancer. In certain embodiments, the additional pharmaceutical agent is an immune checkpoint inhibitor. In certain embodiments, the additional pharmaceutical agent is a PD-1 inhibitor, a PD-L1 inhibitor, or a CTLA-4 inhibitor. In certain embodiments, the additional pharmaceutical agent is a PD-1 inhibitor. In certain embodiments, the additional pharmaceutical agent is an anti PD-1 antibody, an anti PD-L1 antibody, or an anti CTLA-4 antibody. In certain embodiments, the additional pharmaceutical agent is an anti PD- 1 antibody. In certain embodiments, the additional pharmaceutical agent is ipilimumab, tremelimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab, or dostarlimab. In certain embodiments, the additional pharmaceutical agent is nivolumab, pembrolizumab, cemiplimab, or dostarlimab. 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 administered separately in different doses. 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. In certain embodiments, the subject is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject described herein is a human. In certain embodiments, the subject is a non-human animal. In certain embodiments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In certain embodiments, the subject is a fish or reptile. 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 one 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 neurological disease or disorder (e.g., lysosomal storage disorder, Parkinson’s Disease, a viral infection, or a bacterial infection) in a subject in need thereof. In certain embodiments, the kits are useful for preventing a neurological disease or disorder (e.g., lysosomal storage disorder, Parkinson’s Disease, a viral infection, or a bacterial infection) in a subject in need thereof. In certain embodiments, the kits are useful for reducing the risk of developing a neurological disease or disorder (e.g., lysosomal storage disorder, Parkinson’s Disease, a viral infection, or a bacterial infection) in a subject in need thereof. In certain embodiments, the kits are useful for for inhibiting glucosylceramide synthase (GCS). In certain embodiments, the kits are useful for inhibiting glucosylceramide synthase (GCS) in a subject and/or a cell. 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, a kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition. Methods of Treatment The present disclosure provides methods for treating a disease or disorder. In certain embodiments, the present disclosure provides a method for treating a disease or disorder associated with glucosylceramide synthase (GCS) activity. In certain embodiments, the present disclosure provides a method for treating cancer or a neurological disease or disorder. In certain embodiments, the present disclosure provides a method for treating a neurological disease or disorder. In certain embodiments, the present disclosure provides a method of treating a lysosomal storage disorder, Parkinson’s Disease, a viral infection, or a bacterial infection. In certain embodiments, the present disclosure provides a method of treating a lysosomal storage disorder. In certain embodiments, the present disclosure provides a method of treating Parkinson’s Disease. In certain embodiments, the present disclosure provides a method of treating a viral infection or a bacterial infection. In certain embodiments, the present disclosure provides a method of treating a viral infection. In certain embodiments, the present disclosure provides a method of treating a bacterial infection. In certain embodiments, the present disclosure provides a method of treating Gaucher disease, Fabry disease, GM1 gangliosidosis, GM2 gangliosidosis, Tay-Sachs disease, or Sandhoff disease. In certain embodiments, the present disclosure provides a method of treating Gaucher disease. In certain embodiments, the present disclosure provides a method of treating Fabry disease. In certain embodiments, the present disclosure provides a method of treating GM1 gangliosidosis. In certain embodiments, the present disclosure provides a method of treating GM2 gangliosidosis. In certain embodiments, the present disclosure provides a method of treating Tay-Sachs disease. In certain embodiments, the present disclosure provides a method of treating Sandhoff disease. In certain embodiments, the present disclosure provides a method of treating cancer. In certain embodiments, the present disclosure provides a method of treating a cancer associated with KRAS (e.g., having a KRAS mutation). In certain embodiments, the cancer is non-small cell lung cancer, colorectal cancer, pancreatic ductal adenocarcinoma, choloangiocarcinoma, uterine endometrial carcinoma, testicular germ cell cancer, or cervical squamous cell carcinoma. In certain embodiments, the present disclosure provides a method of inhibiting glucosylceramide synthase (GCS). In certain embodiments, the present disclosure provides a method of inhibiting glucosylceramide synthase (GCS) in vitro. In certain embodiments, the present disclosure provides a method of inhibiting glucosylceramide synthase (GCS) in vivo. In certain embodiments, the present disclosure provides a method of inhibiting glucosylceramide synthase (GCS), in a subject and/or a cell. In certain embodiments, the cell is a mammalian cell. In certain embodiments, the cell is a human cell. In certain embodiments, the cell is in a subject. In certain embodiments, the cell is in a mammal. In certain embodiments, the cell is in a human. In certain embodiments, the methods of the disclosure comprise administering to a subject an effective amount of a compound of the disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a prophylactically effective amount. In certain embodiments, the subject being treated is an animal. The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject is a mammal. In certain embodiments, the subject being treated is a human. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another embodiment, the subject is a research animal such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal. In certain embodiments, the animal is a fish or reptile. Certain methods described herein may comprise administering one or more additional pharmaceutical agent(s) in combination with the compounds described herein. The additional pharmaceutical agent(s) may be administered at the same time as a compound of the disclosure (e.g., a compound of Formula (I)), or at different times than a compound of the disclosure (e.g., a compound of Formula (I)). For example, a compound of the disclosure (e.g., a compound of Formula (I)) and any additional pharmaceutical agent(s) may be on the same dosing schedule or different dosing schedules. All or some doses of a compound of the disclosure (e.g., a compound of Formula (I)) may be administered before all or some doses of an additional pharmaceutical agent, after all or some does an additional pharmaceutical agent, within a dosing schedule of an additional pharmaceutical agent, or a combination thereof. The timing of administration of a compound of the disclosure (e.g., a compound of Formula (I)) and additional pharmaceutical agents may be different for different additional pharmaceutical agents. In certain embodiments, the additional pharmaceutical agent comprises an agent useful in the treatment of a disease or disorder associated with glucosylceramide synthase (GCS) activity. In certain embodiments, the additional pharmaceutical agent comprises an agent useful in the treatment of cancer or a neurological disease or disorder. In certain embodiments, the additional pharmaceutical agent comprises an agent useful in the treatment of a neurological disease or disorder. In certain embodiments, the additional pharmaceutical agent is useful in the treatment of a lysosomal storage disorder, Parkinson’s Disease, a viral infection, or a bacterial infection. In certain embodiments, the additional pharmaceutical agent is useful in the treatment of a lysosomal storage disorder. In certain embodiments, the additional pharmaceutical agent is useful in the treatment of Parkinson’s Disease. In certain embodiments, the additional pharmaceutical agent is useful in the treatment of Gaucher disease, Fabry disease, GM1 gangliosidosis, GM2 gangliosidosis, Tay-Sachs disease, or Sandhoff disease. In certain embodiments, the additional pharmaceutical agent is useful in the treatment of Gaucher disease. In certain embodiments, the additional pharmaceutical agent comprises an agent useful in the treatment of cancer. In certain embodiments, the additional pharmaceutical agent is an immune checkpoint inhibitor. In certain embodiments, the additional pharmaceutical agent is a PD-1 inhibitor, a PD-L1 inhibitor, or a CTLA-4 inhibitor. In certain embodiments, the additional pharmaceutical agent is a PD-1 inhibitor. In certain embodiments, the additional pharmaceutical agent is an anti PD-1 antibody, an anti PD-L1 antibody, or an anti CTLA-4 antibody. In certain embodiments, the additional pharmaceutical agent is an anti PD- 1 antibody. In certain embodiments, the additional pharmaceutical agent is ipilimumab, tremelimumab, nivolumab, pembrolizumab, atezolizumab, avelumab, durvalumab, cemiplimab, or dostarlimab. In certain embodiments, the additional pharmaceutical agent is nivolumab, pembrolizumab, cemiplimab, or dostarlimab.In another aspect, the present disclosure provides methods for inhibiting glucosylceramide synthase (GCS), the method comprising contacting GCS with a compound of the disclosure (e.g., a compound of Formula (I)), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof. In certain embodiments, the cell is in a cell. In certain embodiments, the cell is in a subject. In certain embodiments, the contacting is in a biological sample. In certain embodiments, the contacting results in a decrease of GCS activity by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95% as compared to baseline activity. In certain embodiments, the contacting is in vitro. In certain embodiments, the contacting is in vivo. In certain embodiments, the cell is a mammalian cell. In certain embodiments, the cell is a human cell. EXAMPLES 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 their scope. Compound Synthesis Compounds of Formula (I) were prepared following the synthetic schemes and procedures described in detail below. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope. Compounds of the disclosure that are not explicitly described in the following procedures may be prepared by analogous methods. Those having ordinary skill in the art would understand how to make such compounds from the disclosure provided herein and by means known in the art of organic synthesis. For example, those such as described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof are representative and instructive. Methods for optimizing reaction conditions, if necessary minimizing competing by products, are known in the art. Embodiments of this disclosure include methods of synthesizing compounds delineated herein using any of the compounds, reactants, and/or processes delineated herein. Compounds of Formula (I) described herein have been given compound identifiers as shown in the table below. At different locations throughout the present disclosure, the compounds may be referred to with one or the other identifier. Table 1. Exemplary compounds To a solution of 1-aminoguanidine;carbonic acid (5 g, 36.74 mmol, 1 eq) and TBAB (592.11 mg, 1.84 mmol, 0.05 eq) in dioxane (75 mL) was added 4-methylbenzoyl chloride (2.84 g, 18.37 mmol, 2.43 mL, 0.5 eq) at 0 °C. The reactions were carried out in parallel (8 batches). Then the reaction mixture was stirred at 0 ^oC for 0.8 hour. The reaction mixture was allowed to stir at 15 °C for 5.2 hours. The reaction mixture was quenched by addition 10% aq. NaOH (400 mL) at 20 °C, then it was filtered and the filter cake was dried under reduced pressure.1-[(4-Methylbenzoyl)amino]guanidine (40 g, crude) was obtained as a white solid and was used for next step without purification. A mixture of 1-[(4-methylbenzoyl)amino]guanidine (10 g, 52.02 mmol, 1 eq) in 10% aq. NaOH (100 mL) was stirred at 110 °C for 3 hr under N2 atmosphere (2 batches with the same scale). To the reaction mixture was added 0.1 M aq. HCl to adjust pH to 8. Then the reaction mixture was filtered and the filter cake was dried under reduced pressure.5-(p- Tolyl)-4H-1,2,4-triazol-3-amine (4) (11 g, 63.15 mmol, 60.69% yield) was obtained as a white solid and it was used for next step without further purification.¹H NMR (400 MHz, DMSO-d6) δ ppm 11.98 (s, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 7.2 Hz, 2H), 6.0 (br s, 2H), 2.31 (s, 3H). To a solution of 1-(4-methoxyphenyl)ethanone (2 g, 13.32 mmol, 1 eq) in EtOH (16 mL) and 10% aq. NaOH (8 mL) was added 2-fluorobenzaldehyde (1.65 g, 13.32 mmol, 1.39 mL, 1 eq) at 0 °C. The reaction mixture was stirred at 15 °C for 3 hours. The reaction mixture was filtered, the filter cake was washed by water (50 mL) and EtOH (50 mL). Then the filter cake was dried in vacuo. Compound (E)-3-(2-fluorophenyl)-1-(4-methoxyphenyl)prop-2-en- 1-one (3 g, 11.71 mmol, 87.90% yield) was obtained as a white solid.¹H NMR (400 MHz, CDCl3) δ ppm 8.06 (d, J = 8.4 Hz, 2H), 7.91-7.88 (m, 1H), 7.69-7.63 (m, 2H), 7.43-7.34 (m, 1H), 7.24-7.12 (m, 2H), 7.00 (d, J = 8.8 Hz, 2H), 3.91(s, 3H). To a solution of (E)-3-(2-fluorophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (1.8 g, 7.02 mmol, 1.2 eq) in toluene (18 mL) was added 3-(p-tolyl)-1H-1,2,4-triazol-5-amine (1.02 g, 5.85 mmol, 1 eq) and TsOH.H2O (3.34 g, 17.56 mmol, 3 eq). The mixture was stirred at 80 °C for 2 hr under N₂ atmosphere. The reaction mixture was adjusted pH to 7 by addition of sat. NaHCO3 and then diluted with H2O (20 mL). It was extracted with EtOAc (30 mL * 2). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to 5/1). Then the crude product was further purified by prep-HPLC (column: Phenomenex C18150*30mm* 5um;mobile phase: [water( NH₄HCO₃)-ACN];gradient:70%-100% B over 10 min) for three times. Compound 7-(2-fluorophenyl)-5-(4-methoxyphenyl)-2-(p-tolyl)-4,7-dihydro- [1,2,4]triazolo[1,5-a]pyrimidine (G2-2) (27 mg, 65 μmol, 95% purity) was obtained as a white solid.¹H NMR (400 MHz, DMSO-d6) δ ppm 10.07 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.8 Hz, 2H), 7.39-7.34 (m, 1H), 7.29-7.25(m, 1H), 7.22-7.19 (m, 4H), 6.97 (d, J = 8.8 Hz, 2H), 6.48 (d, J = 3.6 Hz, 1H), 5.11 (d, J = 3.2 Hz, 1H), 3.78 (s, 3H), 2.32 (s, 3H). To a solution of 1-(4-methoxyphenyl)ethanone (2 g, 13.32 mmol, 1 eq) in EtOH (16 mL) and 10% aq. NaOH (8 mL) was added 2-bromobenzaldehyde (2.46 g, 13.32 mmol, 1.54 mL, 1 eq) at 0 °C. The mixture was stirred at 15 °C for 3 hours. The suspension was filtered, the filter cake was washed with water (50 mL) and EtOH (50 mL). Then the filter cake was dried in vacuo. (E)-3-(2-bromophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (3 g, 9.27 mmol, 69.60% yield) was obtained as a white solid. To a solution of (E)-3-(2-bromophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (0.5 g, 1.58 mmol, 1 eq) in toluene (5 mL) was added TsOH.H₂O (899.58 mg, 4.73 mmol, 3 eq) and 3-(p-tolyl)-1H-1,2,4-triazol-5-amine (329.54 mg, 1.89 mmol, 1.2 eq). The mixture was stirred at 80 °C for 2 hours. The reaction mixture was adjusted pH to 7 by addition of sat. NaHCO3, and then it was diluted with H2O (20 mL) and extracted with EtOAc (30 mL * 2). The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=1/0 to 9/1) to give a yellow solid. The solid was purified by prep-HPLC (column: Waters xbridge 150*25mm 10um;mobile phase: [water( NH₄HCO₃)-ACN];gradient:65%-95% B over 10 min).7-(2-bromophenyl)-5-(4- methoxyphenyl)-2-(p-tolyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine (G2-3) (65 mg, 137.32 μmol, 93% purity) was obtained as a white solid.¹H NMR (400 MHz, DMSO-d6) δ ppm 10.15 (s, 1H), 7.95 (s, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.68-7.66 (m, 1H), 7.57-7.54 (m, 2H), 7.41-7.37 (m, 1H), 7.29-7.21 (m, 3H), 7.15-7.10 (m, 1H), 6.96 (d, J = 8.8 Hz, 2H), 6.55 (d, J = 3.6 Hz, 1H), 5.09-5.08 (d, J = 3.6 Hz, 1H), 3.78 (s, 3H), 2.32 (s, 3H). To a solution of 1-(4-methoxyphenyl)ethanone (2 g, 13.32 mmol, 1 eq) in EtOH (16 mL) and 10% aq.NaOH (8 mL) was added 2-(trifluoromethyl)benzaldehyde (2.32 g, 13.32 mmol, 1.76 mL, 1 eq) at 0 °C. The mixture was stirred at 15 °C for 3 hours. The reaction mixture was filtered. The filter cake was washed by water (50 mL) and EtOH (50 mL). Then the filter cake was dried in vacuo. (E)-1-(4-methoxyphenyl)-3-[2- (trifluoromethyl)phenyl]prop-2-en-1-one (3 g, 9.80 mmol, 73.55% yield) was obtained as a white solid. To a solution of (E)-1-(4-methoxyphenyl)-3-[2-(trifluoromethyl)phenyl]prop-2-en-1- one (2 g, 6.53 mmol, 1 eq) in toluene (10 mL) was added TsOH.H2O (3.73 g, 19.59 mmol, 3 eq) and 3-(p-tolyl)-1H-1,2,4-triazol-5-amine (1.37 g, 7.84 mmol, 1.2 eq). The mixture was stirred at 80 °C for 2 hours. The reaction mixture was adjusted pH to 7 by addition of sat. NaHCO3. Then it was diluted with H2O (20 mL) and extracted with EtOAc (30 mL * 2). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The crude product was triturated with (DMSO: ACN= 1:4, 20 mL) at 20 ^oC for 30 min. The mixture was filtered and the filter cake was dried under reduced pressure to give a residue.5-(4-methoxyphenyl)-2-(p-tolyl)-7- [2 (trifluoromethyl)phenyl]-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine (G2-4) (70 mg, 151.36 μmol, 92% purity) was obtained as a yellow solid.¹H NMR (400 MHz, DMSO-d6) δ ppm 10.21 (s, 1H), 7.80-7.76 (m, 3H), 7.68-7.65(m, 1H), 7.56-7.51 (m, 3H),7.23-7.21 (m, 3H), 6.96 (d, J = 8.8 Hz, 2H), 6.51 (d, J = 3.6 Hz, 1H), 5.01 (d, J = 3.6 Hz, 1H), 3.78 (s, 3H), 2.32(s, 3H). To a solution of 1-(4-methoxyphenyl)ethanone (2 g, 13.32 mmol, 1 eq) in EtOH (16 mL) was slowly added 10% NaOH (8 mL) dropwise at 0 ^oC. Then 2- (trifluoromethoxy)benzaldehyde (2.53 g, 13.32 mmol, 1 eq) was added into the solution dropwise at 0 °C. The solution was stirred at 15 °C for 3 hours. The reaction mixture was quenched by addition of H2O (10 mL) at 20 °C, and then filtered and the filter cake was dried under reduced pressure to give a residue. (E)-1-(4-methoxyphenyl)-3-[2- (trifluoromethoxy) phenyl] prop-2-en-1-one (2.5 g, 7.76 mmol, 58.25% yield) was obtained as a white solid. To a solution of (E)-1-(4-methoxyphenyl)-3-[2-(trifluoromethoxy)phenyl]prop-2-en- 1-one (3 g, 9.31 mmol, 1 eq) in Toltoluene (30 mL) was added TsOH.H₂O (5.31 g, 27.93 mmol, 3 eq) and3-(p-tolyl)-1H-1,2,4-triazol-5-amine (1.95 g, 11.17 mmol, 1.2 eq). The mixture was stirred at 100 °C for 2 hours. The reaction mixture was quenched by addition of sat. NaHCO3 (30 mL) at 20 °C. Then it was extracted with EtOAc (50 mL * 2). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Waters Xbridge BEH C18 150*25mm*5um;mobile phase: [water( NH4HCO3)-ACN];gradient:58%-88% B over 10 min) for 3 times.5-(4-methoxyphenyl)-2-(p-tolyl)-7-[2-(trifluoromethoxy)phenyl]-4,7-dihydro- [1,2,4]triazolo[1,5-a]pyrimidine (G2-6) (87 mg, 181.83 μmol, 97% purity) was obtained as a white solid.¹H NMR (400 MHz, DMSO-d6) δ ppm 10.12(s, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.57-7.55 (m, 2H), 7.50-7.45(m, 1H), 7.42-7.36 (m, 3H), 7.21 (d, J = 8.0 Hz, 2H), 6.99-6.97 (m, 2H), 6.50 (d, J = 3.6 Hz, 1H), 5.03-5.02 (d, J = 3.6 Hz, 1H), 3.79 (s, 3H), 2.32 (s, 3H). To a solution of 1-(4-methoxyphenyl)ethanone (1 g, 6.66 mmol, 1 eq) in EtOH (8 mL) and 10% aq.NaOH (4 mL) was added 4-chlorobenzaldehyde (936.03 mg, 6.66 mmol, 1 eq) at 0 °C. The mixture was stirred at 15 °C for 3 hours. The reaction mixture was filtered, the filter cake was washed with water (30 mL) and EtOH (30 mL), and then the filter cake was dried in vacuo. (E)-3-(4-chlorophenyl)-1-(4-methoxyphenyl) prop-2-en-1-one (1.2 g, 4.40 mmol, 66.08% yield) was obtained as a white solid.¹H NMR (400 MHz, CDCl₃) δ ppm 8.03 (d, J=11.6 Hz, 2H), 7.76-7.70 (m, 1H), 7.60-7.49 (m, 3H), 7.41-7.39 (m, 2H), 7.00 (d, J = 8.8 Hz, 2H), 3.91(s, 3H). To a solution of (E)-3-(4-chlorophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (0.5 g, 1.83 mmol, 1 eq) in toluene (5 mL) was added TsOH.H2O (1.05 g, 5.50 mmol, 3 eq) and 3- (p-tolyl)-1H-1,2,4-triazol-5-amine (383.25 mg, 2.20 mmol, 1.2 eq), 3-(p-tolyl)-1H-1,2,4- triazol-5-amine (383.25 mg, 2.20 mmol, 1.2 eq). The mixture was stirred at 100 °C for 2 hours. The reaction mixture was adjusted pH to 7 by addition of sat. NaHCO3, and then it was diluted with H2O (20 mL) and extracted with EtOAc (30 mL * 2). The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was dried under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to 8/1). The crude product was purified by prep-HPLC (column: Waters xbridge 150*25mm 10um;mobile phase: [water(NH4HCO3)-ACN];gradient:63%- 93% B over 10 min).7-(4-chlorophenyl)-5-(4-methoxyphenyl)-2-(p-tolyl)-4,7-dihydro- [1,2,4]triazolo[1,5-a]pyrimidine (G3-2) (35 mg, 81.60 μmol, 94% purity) was obtained as a white solid.¹H NMR (400 MHz, DMSO_d6) δ ppm 10.06 (s, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.4 Hz, 2H), 7.44 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 6.97 (d, J = 8.8 Hz, 2H), 6.27 (d, J = 4.0 Hz, 1H), 5.14-5.13 (m, 1H), 3.79 (s, 3H), 2.32 (s, 3H). To a solution of 2,5-dichlorobenzaldehyde (5 g, 28.57 mmol, 1 eq) in 10% aq. NaOH (30 mL) and EtOH (60 mL) was added 1-(4-methoxyphenyl) ethanone (4.29 g, 28.57 mmol, 1 eq) at 0 °C. The mixture was stirred at 15 °C for 3 hours. The reaction mixture was filtered, the filter cake was washed by water (100 mL) and EtOH (100 mL). Then the filter cake was dried in vacuo. (E)-3-(2,5-dichlorophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (5 g, 15.95 mmol, 55.84% yield, 98% purity) was obtained as a white solid. m/z (ES+) [M+H]+ = 306.8. ¹H NMR (400 MHz, DMSO-d6) δ ppm 8.38 (d, J=1.6 Hz, 1 H), 8.24-8.21 (m, 2 H), 8.12 (d, J=15.6 Hz, 1 H), 7.91 (d, J=15.6 Hz, 1 H), 7.60 (d, J=8.4 Hz, 1 H), 7.54-7.51 (m, 1 H), 7.12- 7.08 (m, 2 H), 3.88 (s, 3 H). To a solution of (E)-3-(2,5-dichlorophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (2 g, 6.51 mmol, 1 eq) in Tol. (10 mL) was added TsOH.H₂O (3.72 g, 19.53 mmol, 3 eq) and 3- (p-tolyl)-1H-1,2,4-triazol-5-amine (1.36 g, 7.81 mmol, 1.2 eq). The mixture was stirred at 100 °C for 2 hours. The reaction mixture was adjusted to pH 7 by addition of sat. NaHCO3, and then it was diluted with H₂O (20 mL) and extracted with EtOAc (30 mL * 2). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The crude product was triturated with the mixture solution (ACN:DMSO=4:1, 10 mL) at 20 °C for 30 min, then filtered. The filter cake was dried under reduced pressure to give the final product.7-(2,5-dichlorophenyl)-5-(4- methoxyphenyl)-2-(p-tolyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine (G3-3) (2 g, 4.14 mmol, 63.64% yield, 96% purity) was obtained as a white solid. m/z (ES⁺) [M+H]⁺ = 463.1. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.18 (s, 1H), 7.80 (d, J=8.0 Hz, 2H), 7.58-7.53 (m, 3H), 7.47-7.44 (m, 1H), 7.28-7.22 (m, 3H), 6.98 (d, J=8.8 Hz, 2H), 6.58 (d, J=3.6 Hz, 1H), 5.08 (d, J=3.6 Hz, 1H), 3.78 (s, 3H), 2.32 (s, 3H). Compound 7-(2,5-dichlorophenyl)-5-(4-methoxyphenyl)-2-(p-tolyl)-4,7-dihydro- [1,2,4]triazolo[1,5-a]pyrimidine (G3-3) (2 g, 4.14 mmol, 63.64% yield, 96% purity) was purified by prep-SFC(condition: column: (s,s) WHELK-O1 (250mm*30mm,10um);mobile phase: [CO₂-ACN/MeOH(0.1% NH₃ ^.H₂O)];B%:50%, isocratic elution mode). The fractions was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (basic condition;column: CD06-Waters Xbidge C18150*40*10um;mobile phase: [water(NH₃ ^.H₂O)-ACN];gradient:60%-90% B over 10 min). (7S)-7-(2,5-dichlorophenyl)-5- (4-methoxyphenyl)-2-(p-tolyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine (G3-3B) (200 mg, 401.42 μmol, 9.30% yield, 93% purity) was obtained as a white solid. m/z (ES⁺) [M+H]⁺ = 463.1.¹H NMR (400 MHz, DMSO-d6) δ ppm 10.16 (s, 1H), 7.79 (d, J=8.0 Hz, 2H), 7.58- 7.52 (m, 3H), 7.46-7.43 (m, 1H), 7.28-7.22 (m, 3H), 6.97 (d, J=8.8 Hz, 2H), 6.57 (d, J=3.6 Hz, 1H), 5.08 (d, J=3.6 Hz, 1H), 3.79 (s, 3H), 2.32 (s, 3H). The stereochemical assignment of compound (G3-3B) was verified by x-ray crystallographic analysis. (7R)-7-(2,5-dichlorophenyl)-5-(4-methoxyphenyl)-2-(p-tolyl)-4,7-dihydro- [1,2,4]triazolo[1,5-a]pyrimidine (G3-3A) was obtained as a white solid. m/z (ES⁺) [M+H]⁺ = 463.1.¹H NMR (400 MHz, DMSO-d₆) δ ppm 10.17 (s, 1H), 7.79 (d, J=8.4 Hz, 2H), 7.58-7.52 (m, 3H), 7.46-7.43 (m, 1H), 7.27-7.22 (m, 3H), 6.97 (d, J=8.4 Hz, 2H), 6.57 (d, J=3.60 Hz, 1H), 5.08 (d, J=3.60 Hz, 1H), 3.79 (s, 3H), 2.33 (s, 3H). To a solution of 1-(2-pyridyl)ethanone (2 g, 16.51 mmol, 1.85 mL, 1 eq) in MeOH (20 mL) and aq. NaOH (1 g, 25.00 mmol, 1.51 eq in H2O 10 mL) was added 2- chlorobenzaldehyde (2.32 g, 16.51 mmol,1.86 mL, 1 eq) at 0 °C. Then, the reaction mixture was stirred at 15 °C for 3 hours. The reaction mixture was filtered and the filter cake was dried under reduced pressure to give the desired compound. (E)-3-(2-chlorophenyl)-1-(2- pyridyl)prop-2-en-1-one (3.6 g, 14.77 mmol, 89.48% yield) was obtained as a white solid.¹H NMR (400 MHz, CDCl3) δ ppm 8.75 (d, J = 4.8 Hz, 1H), 8.40-8.36 (m, 2H), 8.32-8.28 (m, 1H), 7.90-7.83 (m, 2H), 7.52-7.49 (m, 1H), 7.47-7.46 (m, 1H),7.45-7.30 (m, 2H). To a solution of (E)-3-(2-chlorophenyl)-1-(2-pyridyl)prop-2-en-1-one (0.5 g, 2.05 mmol, 1.2 eq) in DMF (5 mL) was added 3-(p-tolyl)-1H-1,2,4-triazol-5-amine (297.86 mg, 1.71 mmol, 1 eq) and NaHCO₃ (861.83 mg, 10.26 mmol, 399.18 μL, 6 eq). The reaction mixture was stirred at 60 °C for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reversed- phase HPLC (column: Waters xbridge150*25mm 10um;mobile phase: [water( NH₄HCO₃)- ACN];gradient:59%-89% B over 10 min).7-(2-chlorophenyl)-2-(p-tolyl)-5-(2-pyridyl)-4,7- dihydro-[1,2,4]triazolo[1,5-a]pyrimidine (G4-1) (80 mg, 196.06 μmol, 11.47% yield, 99% purity) was obtained as a white solid.¹H NMR (400 MHz, MeOD) δ ppm 8.64 (d, J = 3.6 Hz, 1H), 7.84 (d, J = 8.0 Hz, 4H), 7.47-7.46 (m, 1H), 7.40 -7.39 (m, 1H), 7.32-7.30 (m, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.15-7.14 (m, 1H), 6.74 (d, J = 3.6 Hz, 1H), 5.82 (d, J = 3.6 Hz, 1H), 2.36 (s, 3H). To the mixture of 1-(3-pyridyl)ethanone (5 g, 41.28 mmol, 4.54 mL, 1 eq) and 2- chlorobenzaldehyde (5.80 g, 41.28 mmol, 4.65 mL, 1 eq) in MeCN (25 mL) was added 10% aq. NaOH (1 mL) dropwise at 0 °C, then the mixture was stirred at 0 °C for 3 hours. The reaction mixture was quenched by addition H₂O (30 mL) at 0 °C, Then the mixture was extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=5/1 to 3/1). Compound (E)-3-(2-chlorophenyl)-1-(3-pyridyl)prop-2-en-1- one (3 g, 12.31 mmol, 29.83% yield) was obtained as a light yellow solid. (E)-3-(2-chlorophenyl)-1-(3-pyridyl)prop-2-en-1-one (500 mg, 2.05 mmol, 1 eq), 3- (p-tolyl)-1H-1,2,4-triazol-5-amine (357.43 mg, 2.05 mmol, 1 eq) and K₃PO₄ (435.54 mg, 2.05 mmol, 1 eq) in DMF (3.5 mL) were taken up into a microwave tube. The sealed tube was heated at 60 °C for 60 min under microwave. The reaction mixture was quenched by addition H₂O (10 mL), and then extracted with EtOAc (20 mL * 3). The combined organic layers were washed with brine (10 mL * 2), dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=5/1 to 1/1).7-(2-chlorophenyl)-2-(p- tolyl)-5-(3-pyridyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine (G4-2) (60 mg, 142.84 μmol, 95% purity) was obtained as a white solid.¹H NMR (400 MHz, DMSO_d6) δ ppm 10.37 (s, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.59 (d, J = 1..2 Hz, 1H), 8.02-8.00 (m, 1H), 7.80- 7.78 (m, 2H), 7.49-7.47 (m, 2H), 7.38-7.36 (m, 2H), 7.24-7.22 (m, 3H), 6.65 (d, J = 3.6 Hz, 1H), 5.33-5.31 (m, 1H), 2.33 (s, 3H). To the mixture of 1-(4-pyridyl)ethanone (5 g, 41.28 mmol, 4.57 mL, 1 eq) and 2- chlorobenzaldehyde (5.80 g, 41.28 mmol, 4.65 mL, 1 eq) in MeCN (25 mL) was added 10% aq. NaOH (1 mL) dropwise at 0 ^oC, and then the mixture was stirred at 0 °C for 3 hours. The reaction mixture was quenched by addition H2O (10 mL) at 0 °C. Then the mixture was extracted with DCM (30 mL * 3). The combined organic layers were washed with brine (30 mL), dried over Na₂SO₄, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=5/1 to 3/1). (E)-3-(2-chlorophenyl)-1-(4-pyridyl)prop-2-en-1-one (800 mg, 3.28 mmol) was obtained as a light yellow solid. (E)-3-(2-chlorophenyl)-1-(4-pyridyl)prop-2-en-1-one (400 mg, 1.64 mmol, 1 eq), 3- (ptolyl)-1H-1,2,4-triazol-5-amine (285.94 mg, 1.64 mmol, 1 eq) and K3PO4 (348.43 mg,1.64 mmol, 1 eq) in DMF (3 mL) were taken up into a microwave tube. The sealed tube was heated at 60 °C for 60 min under microwave. The reaction mixture was quenched by addition H2O (10 mL), then extracted with EtOAc (20 mL * 2). The combined organic layers were washed with brine (10 mL * 3). The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=5/1 to 1/1).7-(2- chlorophenyl)-2-(p-tolyl)-5-(4-pyridyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine (G4-3) (65 mg, 162.55 μmol, 98% purity) was obtained as a white solid.¹H NMR (400 MHz, DMSO_d6) δ ppm 10.40 (s, 1H), 8.62 (d, J = 6.4 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.66-7.65 (m, 2H), 7.50-7.48 (m, 1H), 7.38-7.36 (m, 2H), 7.23 (d, J = 8.0 Hz, 3H), 6.66 (d, J = 3.6 Hz , 1H), 5.53-5.52 (m, 1H), 2.33 (s, 3H). To a solution of 1-(triphenyl-phosphanylidene)propan-2-one (5.00 g, 15.71 mmol, 1 eq) in EtOH (50 mL) was added the solution of NaOH (2.5 g, 62.50 mmol, 3.98 eq) in H2O (25 mL) and 2-chlorobenzaldehyde (2.21 g, 15.71 mmol, 1.77 mL, 1 eq) at 15 °C. The mixture was stirred at 15 °C for 3 hours. The reaction mixture was filtered and the filter cake was dried under reduced pressure to give a residue. (E)-4-(2-chlorophenyl)but-3-en-2-one (3 g, crude) was obtained as a white solid.¹H NMR (400 MHz, MeOD) δ ppm 7.98 (d, J = 16.4 Hz, 1H), 7.78-7.77 (m, 1H), 7.46-7.45 (m, 1H), 7.39-7.35 (m, 2H), 6.81 (d, J = 16.4 Hz, 1H), 2.39 (s, 3H). To a solution of (E)-4-(2-chlorophenyl)but-3-en-2-one (0.3 g, 1.66 mmol, 1 eq) in DMF (3 mL) was added 3-(p-tolyl)-1H-1,2,4-triazol-5-amine (347.19 mg, 1.99 mmol, 1.2 eq). The mixture was stirred at 140 °C for 1 hour. The reaction mixture was diluted with H₂O (10 mL) and extracted with EtOAc (20 mL * 2). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by reversed- phase HPLC (column: Waters xbridge150*25mm 10um;mobile phase: [water ( NH₄HCO₃)- ACN]; gradient:52%-82% B over 10 min).7-(2-chlorophenyl)-5-methyl-2-(p-tolyl) -4,7- dihydro-[1,2,4]triazolo[1,5-a]pyrimidine (G4-4) (52 mg, 154.39 μmol, 9.30% yield, 96% purity) was obtained as a white solid.¹H NMR (400 MHz, DMSO_d6) δ ppm 9.80 (s, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.46-7.45 (m, 1H), 7.33-7.30 (m, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.00-6.99 (m, 1H), 6.40-6.39 (m, 1H), 4.60-4.59 (m, 1H), 2.31 (s, 3H), 1.86 (s, 3H). To a solution of 2-oxopropanoic acid (1 g, 11.36 mmol, 800.00 μL, 1 eq) in EtOH (10 mL) and NaOH (227.10 mg, 5.68 mmol, 0.5 eq) in H2O (5 mL) was added 2- chlorobenzaldehyde (1.44 g, 10.22 mmol, 1.15 mL, 0.9 eq) at 0 °C. The mixture was stirred at 20 °C for 3 hours. The reaction mixture was filtered and the filter cake was dried under reduced pressure to get the desired product. (E)-4-(2-chlorophenyl)-2-oxo-but-3-enoic acid (1 g, 4.75 mmol, 41.81% yield) was obtained as a yellow solid. To a solution of (E)-4-(2-chlorophenyl)-2-oxo-but-3-enoic acid (500.00 mg, 2.37 mmol, 1.2 eq) in DMF (5 mL) was added 3-(p-tolyl)-1H-1,2,4-triazol-5-amine (344.63 mg, 1.98 mmol, 1 eq). The mixture was stirred at 140 °C for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC(column: Phenomenex C18 150*25mm*10um;mobile phase: [water( NH4HCO3)-ACN];gradient:17%-47% B over 10 min) and by reversed-phase HPLC(column: Waters xbridge 150*25mm 10um;mobile phase: [water( NH₄HCO₃)-ACN];gradient:18%-48% B over 14 min).7-(2-chlorophenyl)-2-(p-tolyl)- 4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine-5-carboxylic acid (G4-6) (300 mg, 817.86 μmol, 34% yield, 99% purity) was obtained as a white solid.¹H NMR (400 MHz, DMSO_d6) δ ppm 9.67 (s, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.51-7.49 (m, 1H), 7.36-7.34 (m, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.05-7.04 (m, 1H), 6.61 (d, J = 4.0 Hz, 1H), 5.66 (d, J = 3.6 Hz, 1H), 2.31 (s, 3H). To a solution of 7-(2-chlorophenyl)-2-(p-tolyl)-4,7-dihydro-[1,2,4]triazolo[1,5- a]pyrimidine-5-carboxylic acid (0.2 g, 545.26 μmol, 1 eq) in MeOH (2 mL) was added SOCl₂ (194.61 mg, 1.64 mmol, 118.81 μL, 3 eq) dropwise at 0 ^oC. The mixture was stirred at 60 °C for 12 hours. The reaction mixture was quenched by addition of sat. NaHCO3 (10 mL) and extracted with EtOAc (10 mL * 2). The combined organic layers were concentrated under reduced pressure to give a residue. The residue was purified by reversed-phase HPLC(column: Phenomenex C18150*25mm*10um;mobile phase: [water( NH4HCO3)- ACN];gradient:45%-75% B over 10 min). methyl 7-(2-chlorophenyl)-2-(p-tolyl)-4,7-dihydro- [1,2,4]triazolo[1,5-a]pyrimidine-5-carboxylate (G4-5) (80 mg, 210.07 μmol, 38.5% yield, 99% purity) was obtained as a white solid.¹H NMR (400 MHz, DMSO_d6) δ ppm 10.30 (s, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.51-7.49 (m, 1H), 7.37-7.35 (m, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.13-7.11 (m, 1H), 6.65 (d, J = 3.6 Hz, 1H), 5.80 (d, J = 2.8 Hz, 1H), 3.78 (s, 3H), 2.31 (s, 3H). To a solution of 1-(4-methoxyphenyl)ethanone (5 g, 33.29 mmol, 1 eq), NaOH (2.66 g, 66.59 mmol, 2 eq) in EtOH (40 mL) and H2O (10 mL) was added 3-chlorobenzaldehyde (4.68 g, 33.29 mmol, 3.79 mL, 1 eq) at 0 °C. The resulting mixture was stirred at 25 °C for 3 hours. The reaction mixture was poured into water and filtered. The precipitate was washed with water and dried under reduced pressure to provide the product. (E)-3-(3- chlorophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (7 g, 25.67 mmol, 77.09% yield) was obtained as a white solid. A mixture of (E)-3-(3-chlorophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (1 g, 3.67 mmol, 1 eq), 3-(p-tolyl)-1H-1,2,4-triazol-5-amine (766.49 mg, 4.40 mmol, 1.2 eq), KOH (411.48 mg, 7.33 mmol, 2 eq) in DMF (10 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 60 °C for 12 hours under N2 atmosphere. The reaction mixture was partitioned between H2O (100 mL) and EtOAc (80 mL * 3). The organic phase was separated, dried over anhydrous Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=1/0 to 0/1). Then the crude product (100 mg) was purified by flash silica gel chromatography (column: YMC-Pack CN 150*30mm*5um;mobile phase: [Heptane-EtOH];gradient:5%-95% B over 10.0 min).7-(3-chlorophenyl)-5-(4- methoxyphenyl)-2-(p-tolyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine (G3-1) (8.5 mg, 17.64 μmol, 3.78% yield, 89% purity) was obtained as a yellow solid.¹H NMR (400 MHz, DMSO) δ ppm 10.08 (s, 1H), 7.78 (d, J = 8 Hz, 2H), 7.59 (d, J = 8.8 Hz, 2H), 7.45-7.36 (m, 3H), 7.30-7.20 (m, 3H), 6.98 (d, J = 8.8 Hz, 2H), 6.28 (d, J = 3.6 Hz, 1H), 5.19-5.14 (m, 1H), 3.79 (s, 3 H), 2.32 (s, 3 H). To a solution of 1-(4-methoxyphenyl)ethanone (5 g, 33.29 mmol, 1 eq), NaOH (2.66 g, 66.59 mmol, 100 mL, 2 eq) in EtOH (40 mL) and H2O (10 mL) was added 2- chlorobenzaldehyde (4.68 g, 33.29 mmol, 3.75 mL, 1 eq) at 0 °C. The resulting mixture was stirred at 25 °C for 3 hours. The reaction mixture was poured into water and filtered. The solid was washed with water and dried to get the product. (E)-3-(3-chlorophenyl)-1-(4- methoxyphenyl)prop-2-en-1-one (7 g, 25.67 mmol, 77.09% yield) was obtained as a white solid. A mixture of (E)-3-(2-chlorophenyl)-1-(4-methoxyphenyl)prop-2-en-1-one (1 g, 3.67 mmol, 1.2 eq) , 3-(p-tolyl)-1H-1,2,4-triazol-5-amine (532.29 mg, 3.06 mmol, 1 eq), TsOH.H₂O (1.74 g, 9.17 mmol, 3 eq) in Tol. (10 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 100 °C for 4 hours under N₂ atmosphere. The mixture was concentrated in vacuum to get a residue. The residue was purified by p- HPLC (column: YMC-Pack CN 150*30mm*5um;mobile phase: [Heptane- EtOH];gradient:5%-95% B over 10.0 min, twice).7-(2-chlorophenyl)-5-(4-methoxyphenyl)- 2-(p-tolyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine (G1-1) (100 mg, 233.15 μmol, 6.36% yield) was obtained as a white solid.¹H NMR (400 MHz, DMSO) δ ppm 10.13 (s, 1H), 7.78 (d, J = 8 Hz, 2H), 7.58-7.52 (m, 2H), 7.51-7.45 (m, 1H), 7.38-7.31 (m, 2H), 7.22 (d, J = 8 Hz, 2H), 7.18-7.12 (m, 1H), 6.96 (d, J = 8.8 Hz, 2H), 6.58 (d, J = 3.6 Hz, 1H), 5.11- 5.05 (m, 1H), 3.78 (s, 3H), 2.32 (s, 3H). NaOH (201.26 mg, 5.03 mmol, 1.10 eq) was dissolved H₂O (25 mL). Then, acetone (3.97 g, 68.44 mmol, 5.03 mL, 14.97 eq) and 2,5-dichlorobenzaldehyde (800 mg, 4.57 mmol, 1 eq) were added. The mixture was stirred at 25 °C for 1 hour. The reaction mixture was concentrated to give a residue. The residue was diluted with H₂O (60 mL) and extracted with EtOAc (15 mL × 5). The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate=0/1 to 1/0). (E)-4-(2,5- dichlorophenyl)but-3-en-2-one (650 mg, 2.97 mmol, 64.87% yield, 98.12% purity) was obtained as a white solid.¹H NMR (400 MHz, CDCl₃) δ ppm 7.84 (d, J=16.4 Hz, 1H), 7.61 (d, J=2.4 Hz, 1H), 7.41-7.35(m, 1 H), 7.33-7.28 (m, 1H), 6.67 (d, J=16.0 Hz, 1H), 2.43 (s, 3 H). To a solution of (E)-4-(2,5-dichlorophenyl)but-3-en-2-one (500 mg, 2.37 mmol, 1 eq) in DMF (5 mL) was added 3-(p-tolyl)-1H-1,2,4-triazol-5-amine (412.59 mg, 2.37 mmol, 1 eq). The mixture was stirred at 140 °C for 1 hour. The reaction mixture was purified by prep-HPLC (Neutral condition; column: Waters Xbridge BEH C18250*50mm*10um;mobile phase: [water( NH4HCO3)-ACN];gradient:48%-78% B over 10 min) directly.7-(2,5- dichlorophenyl)-5-methyl-2-(p-tolyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine (G5-1) (54 mg, 154.90 μmol, 6.24% yield, 95.85% purity) was obtained as a white solid. m/z (ES⁺) [M+H]⁺ = 371.0.¹H NMR (400 MHz, DMSO-d6) δ ppm 9.86 (s, 1 H), 7.75 (d, J=8.0 Hz, 2H), 7.52 (d, J=8.4 Hz, 1H), 7.44-7.39 (m, 1H), 7.21 (d, J=8.00 Hz, 2H), 7.08 (d, J=1.60 Hz, 1H), 6.38 (d, J=1.60 Hz, 1H), 4.58 (s, 1H), 2.31 (s, 3H), 1.87 (s, 3H). To a mixture of 2,5-dichlorobenzaldehyde (1 g, 5.71 mmol, 1 eq) and 1-(4- pyridyl)ethanone (346 mg, 2.86 mmol, 0.5 eq) in MeCN (10 mL) was added 10% aq. NaOH (1 mL) dropwise at 0 °C, and then the mixture was stirred at 0 °C for 1.5 hours. The reaction mixture was concentrated to give a residue. The residue was diluted with H2O (50 mL) and extracted with EtOAc (30 mL × 3). The combined organic layers were dried over Na₂SO₄, filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether/Ethyl acetate=5/1 to 3/1). (E)-3-(2,5- dichlorophenyl)-1-(4-pyridyl)prop-2-en-1-one (400 mg, 1.31 mmol, 22.87% yield) was obtained as a yellow solid. m/z (ES⁺) [M+H]⁺ = 278.1. (E)-3-(2,5-dichlorophenyl)-1-(4-pyridyl)prop-2-en-1-one (400 mg, 1.44 mmol, 1 eq), 3-(p-tolyl)-1H-1,2,4-triazol-5-amine (250.53 mg, 1.44 mmol, 1 eq) and K3PO4 (305.28 mg, 1.44 mmol, 1 eq), DMF (5 mL) were taken up into a microwave tube. The sealed tube was heated at 60 °C for 1 hour. The reaction mixture was purified by prep-HPLC (Neutral condition; column: Daisogel SP ODS RPS 150*25mm*5um;mobile phase: [water(NH₄HCO₃)-ACN];gradient:50%-80% B over 10 min) directly.7-(2,5- dichlorophenyl)-2-(p-tolyl)-5-(4-pyridyl)-4,7-dihydro-[1,2,4]triazolo[1,5-a]pyrimidine (60 mg, 143.85 μmol, 5.10% yield, 95.64% purity) (G5-2) was obtained as white solid. m/z (ES⁺) [M+H]⁺ = 434.1.¹H NMR (400 MHz, DMSO_d6) δ ppm 10.43 (s, 1 H), 8.62 (d, J=6.00 Hz, 2 H), 7.79 (d, J=8.00 Hz, 2 H), 7.65 (d, J=6.4 Hz, 2 H), 7.48-7.47 (m, 1H), 7.37 (s, 1 H) ,7.23 (d, J=8.00 Hz, 2 H), 6.64 (d, J=3.6 Hz, 1 H), 5.51 (d, J=3.2 Hz, 1 H), 2.32 (s, 3 H). X-ray crystallographic analysis of compound (G3-3B) The crystal was a colorless block with the following dimensions: 0.20 × 0.20 × 0.20 mm3. The symmetry of the crystal structure was assigned the orthorhombic space group C2221 with the following parameters: a = 15.72120(10) Å, b = 24.13950(10) Å, c = 24.9596(2) Å, α = 90°, β = 90°, γ = 90°, V = 9472.22(10) Å3, Z = 4, Dc = 1.359 g/cm³, F(000) = 4008.0, μ(CuKα) = 3.189 mm-1, and T = 149.99(10) K. The absolute configuration structure is judged by the value of Flack parameter, and the structure of the tested crystal is as follows: Absolute configuration structure ORTEP structure Description of Equipment and Data Collection Rigaku Oxford Diffraction XtaLAB Synergy-S equipped with a HyPix-6000HE area detector Cryogenic system: Oxford Cryostream 800 Cu: λ=1.54184 Å, 50W Distance from the crystal to the CCD detector: d = 35 mm Tube Voltage: 50 kV; Tube Current: 1 mA A total of 68695 reflections were collected in the 2θ range from 6.71 to 133.196. The limiting indices were: -18 ≤ h ≤ 18, -28 ≤ k ≤ 28, -29 ≤ l ≤ 29; which yielded 8378 unique reflections (Rint = 0.0376). The structure was solved using SHELXT (Sheldrick, G. M.2015. Acta Cryst. A71, 3-8) and refined using SHELXL (against F²) (Sheldrick, G. M.2015. Acta Cryst. C71, 3-8). The total number of refined parameters was 600, compared with 8378 data. All reflections were included in the refinement. The goodness of fit on F² was 1.027 with a final R value for [I >= 2σ (I)] R1 = 0.0434 and wR2 = 0.1122. The largest differential peak and hole were 1.31 and -1.17 eÅ^-3. Description of Crystal Preparation 50mg (G3-3B) was dissolved in 2 mL dichloromethane/methanol (1:1) and kept in a 4 mL vial. The solution evaporated at room temperature and single crystals were obtained. Table 2: Summary of X-ray Crystallographic Data Crystal size/mm³ 0.20 × 0.20 × 0.20 Radiation Type Cu Kα (λ = 1.54184) Crystal system orthorhombic Space group C2221 a/Å 15.72120(10) b/Å 24.13950(10) c/Å 24.9596(2) α/° 90 β/° 90 γ/° 90 Cell Volume/ų 9472.22(10) Cell Formula Units Z 4 Crystal Density calc g/cm³ 1.359 Crystal F(000) 4008.0 Absorption Coefficient μ/mm^-1 3.189 Index ranges -18 ≤ h ≤ 18, -28 ≤ k ≤ 28, -29 ≤ l ≤ 29 Cell Measurement Temperature/K 149.99(10) 2θ range for data collection/° 6.71 to 133.196 Goodness-of-fit on F2 1.027 Final R indexes [I>=2σ (I)] R1= 0.0434, wR2= 0.1122 Final R indexes [all data] R₁= 0.0444, wR₂= 0.1133 Largest diff. peak/hole/e Å^-3 1.31/-1.17 Reflections collected/unique 68695/8378 [R_int= 0.0376] Flack parameter -0.003(3) Assay Protocol UDP-glucose ceramide glucosyltransferase (UGCG) is the enzyme that catalyzes the transfer of glucose from UDP-glucose to ceramide to produce glucosylceramide/GlcCer. Since GlcCer is the core component of glycosphingolipids and their derivatives, blocking UGCG will significantly decrease their production. GM1 and Gb3 are two gangliosides synthesized from glucosylceramide. At the same time, GM1 was the receptor for the Cholera toxin while Gb3 was the receptor for the Shiga toxin. Small molecular inhibitors that target UGCG will reduce the cellular levels of these two gangliosides, thereby reducing the cell surface binding of the toxin. This assay measures the EC50 for the UGCG small molecular inhibitors. Cell line: 5637 cell line (ATCC Cat. #HTB-9), cultured with DMEM+10% FBS+1% PS, 37 degree 5% CO2 Day 1 1) Sterilize the cover glass with flame and put it into 24 well plates. 2) Seed 5637 cells at 2.5×10^5 cells per well in growth medium (DMEM + 10% iFBS+ 1% PS) in prepared 24 well plates. 3) Incubate cells overnight (37 °C, 5% CO2). The cells should be 40-50 % confluent. Day 2 4) Replace the medium with the fresh medium containing small molecules. To calculate EC 50, all the small molecules should be serial dilution, and use 10uM Eliglustat as the positive control. For Shiga toxin binding assay, the cells were incubated with small molecules for 24h, while for Cholera toxin the cells were incubated with small molecules for 36h first, then replace the medium with fresh small molecular for another 36h. Day 3 5) Dilute the Shiga toxin or fluorescence-labeled Cholera toxin with PBS (1:500 dilution, working concentration, Shiga toxin=2.4 ug/ml, Cholera toxin=2 ng/ml). Remove all the medium and incubate the cell with toxin at 4 degrees for 1h. Wash the cell with fresh PBS three times and fix the cells with formalin at room temperature for 20 mins, then wash with PBS three times. 6) In the Cholera toxin binding assay, carefully take the cover glass and put it on glass slides with one drop of mounting medium (containing 1ug/ml DAPI). Capture images with the microscope. 7) In the Shiga toxin binding assay, incubate the fixed cells with 1% goat serum at room temperature for 1h to block non-specific binding. 8) Remove the goat serum and incubate the cells with anti-Shiga toxin rabbit primary antibody (1:500 dilute with goat serum) at room temperature for 1h. Wash three times with PBS. 9) Incubate the cells with goat anti-rabbit Alexa Fluor™ 488 secondary antibody (1:500 dilute with goat serum) at room temperature for 1h. Wash three times with PBS. 10) Carefully take the cover glass and put it on glass slides with one drop of mounting medium (containing 1ug/ml DAPI). Capture images with the microscope. Data analysis For each group, at least three fluorescence pictures were taken, the signal strength was quantitated, and the EC50 was calculated. Table 3. EC50 data for exemplary compounds Pharmacokinetic Studies of G3-3B Pharmacokinetics were tested in male C57Bl-6 mice using intravenous injection of the tail vein and oral gavage. Triplicate mice were dosed and a micro-sampling technique was used, collecting 20 µL blood in heparin coated in capillary hematocrit tubes at multiple time points (0, 5, 15, 30, 60, 120, 240, 360 and 480 minutes). Microsampling reduces the total blood taken from the mouse and allows a single mouse to be used for the entire time course and the health of the mouse is maintained. Plasma was generated by standard centrifugation techniques resulting in approximately 10 µL of plasma which was immediately frozen. Drug levels were determined by mass spectrometry using an ABSciex 5500 mass spectrometer and multiple reaction monitoring analytical methods. Pharmacokinetic parameters were calculated using a non-compartmental model (Phoenix WinNonlin, Pharsight Inc.). The data is summarized in Table 4 below. Table 4. Pharmacokinetic data for exemplary compound G3-3B Tissue (brain) distribution of G3-3B Compound was dosed at 10 mg/kg intraperitoneally in six C57Bl-6 mice. Blood and brain were collected from three mice after 30 and 60 minutes. The plasma and brain were mixed with acetonitrile (1:5 v:v or 1:5 w:v, respectively). The brain sample was disrupted with a probe tip sonicator. Samples were centrifuged at 16,000 x g and the drug level in the supernatant was determined. Separate standard curves were prepared in blank plasma and brain matrix. Analysis was as described in the pharmacokinetics section. Brain concentration was calculated as drug per mg tissue and converted to molarity assuming a density of 1 (1 g tissue equals 1 ml). The data is summarized in Table 5 below. Table 5. Tissue distribution data for G3-3B Hepatic microsomal stability Microsome stability was evaluated by incubating 1 µM test compound with 1 mg/mL hepatic microsomes in 100 mM KPi, pH 7.4. The reaction was initiated by adding NADPH (1 mM final concentration). Aliquots were removed at 0, 5, 10, 20, 40, and 60 minutes and added to acetonitrile (5X, v:v) to stop the reaction and precipitate the protein. NADPH dependence of the reaction was evaluated by setting up incubations without NADPH. At the end of the assay, the samples were centrifuged through a Millipore Multiscreen Solvinter 0.45 micron low binding PTFE hydrophilic filter plate and analyzed by LC-MS/MS. Data were log-transformed and represented as half-life. The data is summarized in Table 6 below. Table 6. Hepatic microsomal stability of exemplary compounds Solubility and plasma protein binding assays . Plasma protein binding was determined using equilibrium dialysis. All samples were tested in triplicate using the RED Rapid Equilibrium Dialysis Device (Thermo Scientific). The initial drug concentration in the plasma chamber was 2 µM, and phosphate buffered saline was added to the receiver chamber. The plate was covered and allowed to shake in a 37⁰C incubator for 6 hours.25 µL was sampled from the plasma and PBS chambers, which were then diluted with either blank PBS or plasma to achieve a 1:1 ratio or plasma:PBS for all samples. The concentration of the drug in the plasma and PBS chambers was determined by LC-MS/MS. The fraction bound was calculated as ([plasma] – [PBS]) / [plasma]. The data is summarized in Table 7. Kinetic solubility was tested from a 10 mM DMSO stock solution by spiking into pre- warmed pH 7.4 phosphate buffered saline in a 96-well plate. The final concentration was 100 µM (1% DMSO). The plate was maintained at ambient temperature for 24 hours on an orbital shaker. Samples were centrifuged through a Millipore Multiscreen Solvinter 0.45 micron low binding PTFE hydrophilic filter plate and were analyzed by HPLC or LC-MS/MS if additional sensitivity was required. Peak area was compared to standards of known concentration. Table 7. Solubility and plasma protein binding of exemplary compounds EQUIVALENTS AND SCOPE 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 invention 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 invention 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. Furthermore, the 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 invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention 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 invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. 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 invention 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 invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art. 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 invention, as defined in the following claims.

Claims

CLAIMS What is claimed is: 1. A compound of Formula (I): (I), or a tautomer or pharmaceutically acceptable salt thereof, wherein: each R³ is independently halogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, -OR^A, -N(R^A)₂, -SR^A, -CN, -SCN, -C(=NR^A)R^A, -C(=NR^A)OR^A, - C(=NR^A)N(R^A)2, -C(=O)R^A, -C(=O)OR^A, -C(=O)N(R^A)2, -C(=O)NR^AS(O)2R^A, -NO2, - NR^AC(=O)R^A, -NR^AC(=O)OR^A, -NR^AC(=O)N(R^A)₂, -NR^AC(=NR^A)N(R^A)₂, -OC(=O)R^A, - OC(=O)OR^A, -OC(=O)N(R^A)₂, -NR^AS(O)₂R^A, -OS(O)₂R^A, -S(O)₂NR^AC(O)R^A, - S(O)2N(R^A)2, -S(O)2OR^A, or -S(O)2R^A; n is 1, 2, or 3; and each occurrence of R^A is, independently, hydrogen, substituted or unsubstituted acyl, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaliphatic, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, or a sulfur protecting group when attached to a sulfur atom, or two R^A groups are joined to form a substituted or unsubstituted heterocyclyl ring, or a substituted or unsubstituted heteroaryl ring; provided that the compound is not of formula: .

2. The compound of claim 1, or a tautomer or pharmaceutically acceptable salt thereof, wherein

3. The compound of claim 1, or a tautomer or pharmaceutically acceptable salt thereof, _wherein

4. The compound of claim 1, or a tautomer or pharmaceutically acceptable salt thereof, _wherein

5. The compound of claim 1, or a tautomer or pharmaceutically acceptable salt thereof, wherein R¹ is -CH3.

6. The compound of any one of claims 1-5, or a tautomer or pharmaceutically acceptable .

7. The compound of any one of claims 1-6, or a tautomer or pharmaceutically acceptable _{salt thereof, wherein}

8. The compound of any one of claims 1-7, or a tautomer or pharmaceutically acceptable salt thereof, wherein

9. The compound of any one of claims 1-8, or a tautomer or pharmaceutically acceptable salt thereof, wherein at least one R³ is substituted or unsubstituted alkyl.

10. The compound of any one of claims 1-9, or a tautomer or pharmaceutically acceptable salt thereof, wherein at least one R³ is unsubstituted alkyl.

11. The compound of any one of claims 1-10, or a tautomer or pharmaceutically acceptable salt thereof, wherein at least one R³ is unsubstituted C_1-4 alkyl.

12. The compound of any one of claims 1-11, or a tautomer or pharmaceutically acceptable salt thereof, wherein at least one R³ is unsubstituted C_1-2 alkyl.

13. The compound of any one of claims 1-12, or a tautomer or pharmaceutically acceptable salt thereof, wherein at least one R³ is -CH3.

14. The compound of any one of claims 1-13, or a tautomer or pharmaceutically acceptable salt thereof, wherein n is 1.

15. The compound of claim 1, wherein the compound is of Formula (I-a): or a tautomer or pharmaceutically acceptable salt or tautomer thereof.

16. The compound of claim 1, wherein the compound is of Formula (I-b): or a tautomer or pharmaceutically acceptable salt or tautomer thereof.

17. The compound of claim 1, wherein the compound is of Formula (I-b-1): or a tautomer or pharmaceutically acceptable salt thereof.

18. The compound of claim 1, wherein the compound is of Formula (I-c): or a tautomer or pharmaceutically acceptable salt thereof.

19. The compound of claim 1, wherein the compound is of Formula (I-c-1): or a tautomer or pharmaceutically acceptable salt thereof.

20. The compound of claim 1, wherein the compound is of Formula (I-c-2): or a tautomer or pharmaceutically acceptable salt thereof.

21. The compound of claim 1, wherein the compound is of Formula (I-d): or a tautomer or pharmaceutically acceptable salt thereof.

22. The compound of claim 1, wherein the compound is of Formula (I-d-1): or a tautomer or pharmaceutically acceptable salt thereof.

23. The compound of claim 1, wherein the compound is of Formula (I-d-2): or a tautomer or pharmaceutically acceptable salt thereof.

24. The compound of claim 1, wherein the compound is of Formula (I-e): or a tautomer or pharmaceutically acceptable salt thereof.

25. The compound of claim 1, wherein the compound is of Formula (I-e-1): or a tautomer or pharmaceutically acceptable salt thereof.

26. The compound of claim 1, wherein the compound is of formula: (G1-1B); (G2-1); (G2-2); (G2-3); (G2-4); (G2-5);/102 (G2-6); (G3-1); (G3-2); (G3-3); (G4-1); (G4-2);/102 (G4-3); (G4-4); (G4-5); (G4-6); (G5-1); or (G5-2); or a tautomer or pharmaceutically acceptable salt thereof.

27. The compound of claim 1, wherein the compound is of formula: (G3-3), or a tautomer or pharmaceutically acceptable salt thereof.

28. The compound of claim 1, wherein the compound is of formula: or a tautomer or pharmaceutically acceptable salt thereof.

29. The compound of claim 1, wherein the compound is of formula: or a tautomer or pharmaceutically acceptable salt thereof.

30. A pharmaceutical composition comprising a compound of any one of claims 1-29, or a tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

31. A kit comprising a compound of any one of claims 1-29, or a pharmaceutically acceptable salt thereof, or a tautomer or pharmaceutical composition of claim 30, and instructions for administering the compound or pharmaceutical composition to a subject in need thereof.

32. A method of treating a disease or disorder, the method comprising administering an effective amount of a compound of any one of claims 1-29, or a tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 30, to a subject in need thereof.

33. The method of claim 32, wherein the disease or disorder is associated with glucosylceramide synthase (GCS) activity.

34. The method of claim 32 or 33, wherein the disease or disorder is cancer or a neurological disease or disorder.

35. The method of any of claims 32-34, wherein the disease or disorder is a lysosomal storage disorder, Parkinson’s Disease, a viral infection, or a bacterial infection.

36. The method of any of claims 32-34, wherein the disease or disorder is Gaucher disease, Fabry disease, GM1 gangliosidosis, GM2 gangliosidosis, Tay-Sachs disease, or Sandhoff disease.

37. A method of inhibiting glucosylceramide synthase (GCS), the method comprising contacting GCS with an effective amount of a compound of any one of claims 1-29, or a tautomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 30.

38. The method of claim 37, wherein the contacting is in vitro.

39. The method of claim 37, wherein the contacting is in vivo.