Broad spectrum antiviral compounds

Abstract

Provided herein are antiviral compounds including compounds of Formulae (I), (II'), (II), and (III), and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof. The compounds provided herein are useful for the treatment and / or prevention of infectious diseases (e.g., viral infections including COVID-19). In other aspects, provided herein are kits comprising compounds and pharmaceutical compositions described herein, methods of synthesizing the compounds provided herein, and intermediates useful in the synthesis of compounds provided herein. Formula (II):

Description

[0001] BROAD SPECTRUM ANTIVIRAL COMPOUNDS RELATED APPLICATIONS

[0001] This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application, U.S.S.N.63 / 555,854, filed February 20, 2024, the entire contents of which is incorporated herein by reference. GOVERNMENT SUPPORT

[0002] This invention was made with government support under HR0011-20-2-0040 awarded by U.S. Department of Defense / Defense Advanced Research Projects Agency (DOD / DARPA) and under HL141797 awarded by National Institutes of Health (NIH). The government has certain rights in this invention. BACKGROUND OF THE INVENTION

[0003] Infectious diseases are a continuing threat to human health. There is a need for new small molecule therapeutics that can treat and / or prevent infectious diseases, including viral infections. In particular, in response to the COVID-19 pandemic there is a need for new antiviral drugs that can inhibit the replication of the SARS-CoV-2 virus and variants thereof. SUMMARY

[0004] Provided herein are compounds (e.g., of Formulae (I), (IIʹ), (II), and (III)), and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. Compounds provided herein have antiviral properties and can be used in the treatment and / or prevention of infectious diseases (e.g., viral infections) in a subject. In certain embodiments, the compounds provided herein inhibit the replication of a coronavirus (e.g., a SARS coronavirus). In certain embodiments, the compounds provided herein inhibit the replication of a SARS-CoV-2 virus, or variant thereof, and can therefore be used to treat and / or prevent COVID-19 in a subject.

[0005] In one aspect, provided herein are compounds of Formula (II): and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein Ring A, RA, RB, R2a, R2b, R2c, Y1, R3a, R3b, R3c, m, and w are as defined herein.

[0006] In another aspect, provided herein are compounds of Formula (III): and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein Ring A, RA, R2a, R2b, R2c, Y1, R3a, R3b, R3c, X4, X5, X6, X7, m, and w are as defined herein.

[0007] In one aspect, provided herein are compounds of Formula (I): and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein RA, R2a, R2b, X1, X2, X3, Y1, R3a, R3b, R3c, and m are as defined herein.

[0008] In certain embodiments, for example, a compound provided herein is selected from those in Tables I-III, and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.

[0009] In another aspect, provided herein are pharmaceutical compositions comprising a compound provided herein (e.g., a compound of Formula (I), (IIʹ), (II), or (III), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof) and a pharmaceutically acceptable carrier. In certain embodiments, the pharmaceutical composition described herein includes a therapeutically and / or prophylactically effective amount of a compound provided herein (e.g., a compound of Formula (I), (IIʹ), (II), or (III), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof). The pharmaceutical compositions described herein are useful for treating and / or preventing diseases or conditions in a subject (e.g., infectious diseases, such as viral infections).

[0010] In another aspect, provided herein are methods of the using the compounds and pharmaceutical compositions provided herein. Methods provided herein include, but are not limited to, the following: (i) methods for treating and / or preventing an infectious disease (e.g., viral infection) in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof; (ii) methods for treating and / or preventing COVID-19 in a subject comprising administering to the subject a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof; and (iii) methods of inhibiting the replication of a virus in a cell comprising contacting the cell with a compound disclosed herein, or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof.

[0011] In certain embodiments, the infectious disease is a viral infection (e.g., a coronavirus infection, e.g., an infection with a SARS-CoV-2 virus or variant thereof, e.g., COVID-19). In certain embodiments, the virus is a coronavirus (e.g., a SARS-CoV-2 virus or a variant thereof).

[0012] In certain embodiments, the compound or pharmaceutically acceptable salt thereof does not inhibit AXL receptor tyrosine kinase.

[0013] Also provided here are compounds (e.g., compounds of Formulae (I), (IIʹ), (II), and (III), and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof), and pharmaceutical compositions thereof, for use in any of the methods described herein. Additionally, provided herein are uses of compounds provided herein (e.g., compounds of Formulae (I), (IIʹ), (II), and (III), and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof), and pharmaceutical compositions thereof, for the manufacture of medicaments.

[0014] In certain embodiments, a compound provided herein is capable of inhibiting viral replication in a cell without significantly inhibiting AXL receptor kinase activity.

[0015] In another aspect, provided herein are methods of preparing the compounds provided herein (e.g., compounds of Formulae (I), (IIʹ), (II), and (III), and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof). Also provided herein are intermediates useful in the preparation of the compounds described herein.

[0016] Another aspect of the present disclosure relates to kits comprising a compound (e.g., a compound of Formula (I), (IIʹ), (II), or (III), or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co- crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof), or pharmaceutical composition thereof, described herein. The kits described herein may include a single dose or multiple doses of the compound or composition. The provided kits may be useful in a method of the disclosure (e.g., a method of treating and / or preventing an infectious disease, e.g., a viral infection). A kit provided herein may further include instructions for using the kit.

[0017] The details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the invention will be apparent from the Definitions, Examples, and Claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments of the disclosure and together with the description, provide non-limiting examples.

[0019] FIG.1. The Spike (S) protein homotrimer facilitates membrane fusion. (FIG.1A) Homology model of the S protein homotrimer in its metastable pre-fusion state. Host protease cleavage sites are indicated along with the fusion peptide (red), S1(blue), and S2 (orange) subunits. (FIG.1B) (left) A single S1 and S2 subunit with the mapping (right) of results from an evolutionary conservation analysis showing evolutionary variation is predominantly found in the vicinity of the receptor-binding domain of the S1 subunit. (FIG.1C) A schematic of the S protein transformation during the viral membrane fusion process as it is thought to proceed (from left to right). The S protein starts in a metastable state and binds to ACE2 proteins on the cell surface. The viral particle is endocytosed while host proteases on the cell surface and the endosome cleave the S protein to generate the fusion peptide and S2 subunit. The S1 units are liberated from the S2 units, and the decreasing pH of the endosome causes the internal rearrangement of S2 structures. As the S2 structures rearrange, the fusion peptides are embedded in the host cell membrane. The S2 structure continues to rearrange to generate a highly stable coiled-coil motif facilitated by heptad repeats found within the S2 structure. The formation of this stable motif drives the trimer into its highly stable post-fusion structural formation, which is irreversible and eventually pulls the viral envelope into contact with the host cell membrane, causing the two lipid bilayers to fuse.

[0020] FIG.2. Targeting Spike protein fusion dynamics for Broad Spectrum efficacy against SARS-CoV2. (FIG.2A) Conformations of the S protein subunit taken from a simulation of the homotrimer with pulling forces applied to the ACE2 binding domain. Showing the displacement of the TNFTISVTT peptide from within a conserved region of the S2 domain and the unpacking of the fusion peptide. (FIG.2B) The region of the S2 subunit that is targeted during in silico docking screens. (FIG.2C) Poses of bemcentinib were generated using AI-based blind docking using DiffDock across conformations of the S protein during the same pulling simulation in (FIG.2A). The structure of bemcentinib is shown at the bottom.

[0021] FIG.3. Compound EC50 values on pseudotyped SARS-CoV-2 viral infection in ACE2-expressing HEK293 cells or on pseudotyped MERS viral entry in DPP4-expressing HELA cells.

[0022] FIG 4. Bemcentinib and novel analogs inhibit infection in vitro. (FIG.4A) Effects of bemcentinib against SARS-CoV-2_GFP infected ACE2-expressing A549 cells and BA.2 omicron SARS-CoV-2pp infected ACE2-expressing HEK293 cells. (FIG.4B) The structure of Compound 1 with the region modified in bemcentinib is highlighted. (FIG.4C) The structure of Compound 37. (FIG.4D) Bemcentinib, Compound 1, and Compound 37 docked in the target region. The binding affinity and RMSD analysis of the top 9 poses docked with the S protein conformation shown and scored with smina. (FIG.4E) Effects of compounds on pseudotyped SARS-CoV-2 viral entry in ACE2-expressing HEK293 cells. The plot shows the inhibitory effects of bemcentinib, Compound 1, and Compound 37 on ACE2- expressing HEK293 cells infected with SARS-CoV-2pp for 48 hours. The number of pseudoparticles in the infected cells was quantified by measuring luciferase activity; viral entry in untreated cells was set as 100%.

[0023] FIG.5. (FIG.5A) in vivo antiviral activity in SARS-CoV2-infected mice that overexpress human ACE2. Activity assessed by prophylactic administration at 24 hours and then 2 hours before intranasal administration of SARS-CoV2 virus. After three days, viral load was determined in lung homogenates. (FIG.5B) Bemcentinib dosed at 100 mg / kg p.o.. (FIG.5C) Compound 1 dosed at 100 mg / kg p.o.. (FIG. 5D) Compound 37, dosed at 30 mg / kg p.o. to match the overall exposure of Compound 1.

[0024] FIG.6. Pharmacokinetics of test articles in C57Bl / 6 mice.

[0025] FIG.7. Location of defining mutations within the S protein for WHO designated variants of concern. Alpha ( B.1.1.7), Beta ( B.1.351), Gamma (P.1), Delta (B.1.617.2), Omicron (B.1.1.529).

[0026] FIG.8. Effects of compounds on AXL kinase activity. The AXL kinase activity in the absence of compound was set as 100%.

[0027] FIG.9. EC50 values for bemcentinib and Compound 1 in: (1) SARS-CoV-2=GFP infected A549- hACE2 cells; (2) BA.2 omicron SARS-CoV-2pp infected HEK-293-hACE2 cells; and (3) AXL kinase enzyme assay. Values are means ± SD of data.

[0028] FIG.10. A549 cell vacuolization. Cells were incubated with DMSO (vehicle) or 5 µM of bemcentinib or Compound 1 for 24 hours. Phase-contrast images were captured with Echo Revolve. The figure shows representative pictures of at least three independent experiments.

[0029] FIG.11. A549 cell phospholipidosis. Cells were incubated with DMSO (vehicle), bemcentinib, or Compound 1 for 24 hours. Fluorescence intensities of NBD-PE and Hoechst33342 were measured at wavelengths of 485 / 538 or 355 / 460 (Ex / Em), respectively. Normalized values were calculated by dividing of the NBD-PE value by the Hoechst33342 value and normalized to 10 µM of amiodarone (100%). Representative concentration curves are shown of three independent experiments. Each data point is the mean ± SD from three replicates.

[0030] FIG.12. IC50 values for bemcentinib, Compound 1, and Compound 37 on cell viability in ACE2- expressing A549 cells, in ACE2-expressing HEK293 cells, or in DPP4-expressing HELA cells. DEFINITIONSChemical Definitions

[0031] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rdEdition, Cambridge University Press, Cambridge, 1987.

[0032] 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.

[0033] 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 of19F with18F, or the replacement of12C with13C or14C are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

[0034] When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example, “C1-6 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.

[0035] The term “aliphatic” refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

[0036] The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1- 5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In some 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 C1-10alkyl (such as unsubstituted C1-6alkyl, 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 (i-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 C1-10alkyl (such as substituted C1-6alkyl, e.g., −CF3, Bn).

[0037] 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 some embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1-8haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1-4haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3haloalkyl”). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2haloalkyl”). Examples of haloalkyl groups include –CHF2, −CH2F, −CF3, −CH2CF3, −CF2CF3, −CF2CF2CF3, −CCl3, −CFCl2, −CF2Cl, and the like.

[0038] 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 some embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-9 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-7 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-6 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC1-5 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC1-4 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-3 alkyl”). In some 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 some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“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 heteroC1-10alkyl.

[0039] 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 some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C2-9alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2- butenyl) or terminal (such as in 1-butenyl). Examples of C2-4alkenyl groups include ethenyl (C2), 1- propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6alkenyl groups include the aforementioned C2-4alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently 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 C2-10 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.

[0040] 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 (“heteroC2-10 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-4 alkenyl”). In some 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 some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 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 heteroC2-10 alkenyl.

[0041] 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) (“C2-10alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C2alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 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.

[0042] 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 some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-7 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-4alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC2-3alkynyl”). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6alkynyl”). 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 heteroC2-10alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-10alkynyl.

[0043] The term “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C3-14carbocyclyl”) and zero heteroatoms in the non- aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6carbocyclyl”). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10carbocyclyl”). Exemplary C3-6carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 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.

[0044] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10cycloalkyl”). Examples of C5-6cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6cycloalkyl groups include the aforementioned C5-6cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8cycloalkyl groups include the aforementioned C3-6cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14cycloalkyl.

[0045] 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.

[0046] In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

[0047] Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, aziridinyl, 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 3 heteroatoms include, without limitation, triazinyl. 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.

[0048] 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 (“C6-14 aryl”). In some embodiments, an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms (“C14 aryl”; e.g., anthracenyl). “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 C6-14 aryl. In certain embodiments, the aryl group is a substituted C6-14 aryl.

[0049] 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).

[0050] In some embodiments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. 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.

[0051] 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.

[0052] The term “unsaturated bond” refers to a double or triple bond. The term “unsaturated” or “partially unsaturated” refers to a moiety that includes at least one double or triple bond. The term “saturated” refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.

[0053] 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.

[0054] 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.

[0055] Exemplary carbon atom substituents include, but are not limited to, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORaa, −ON(Rbb)2, −N(Rbb)2, −N(Rbb)3+X−, −N(ORcc)Rbb, −SH, −SRaa, −SSRcc, −C(=O)Raa, −CO2H, −CHO, −C(ORcc)3, −CO2Raa, −OC(=O)Raa, −OCO2Raa, −C(=O)N(Rbb)2, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −OC(=NRbb)Raa, −OC(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −OC(=NRbb)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −C(=O)NRbbSO2Raa, −NRbbSO2Raa, −SO2N(Rbb)2, −SO2Raa, −SO2ORaa, −OSO2Raa, −S(=O)Raa, −OS(=O)Raa, −Si(Raa)3, −OSi(Raa)3−C(=S)N(Rbb)2, −C(=O)SRaa, −C(=S)SRaa, −SC(=S)SRaa, −SC(=O)SRaa, −OC(=O)SRaa, −SC(=O)ORaa, −SC(=O)Raa, −P(=O)(Raa)2, −P(=O)(ORcc)2, −OP(=O)(Raa)2, −OP(=O)(ORcc)2, −P(=O)(N(Rbb)2)2, −OP(=O)(N(Rbb)2)2, −NRbbP(=O)(Raa)2, −NRbbP(=O)(ORcc)2, −NRbbP(=O)(N(Rbb)2)2, −P(Rcc)2, −P(ORcc)2, −P(Rcc)3+X−, −P(ORcc)3+X−, −P(Rcc)4, −P(ORcc)4, −OP(Rcc)2, −OP(Rcc)3+X−, −OP(ORcc)2, −OP(ORcc)3+X−, −OP(Rcc)4, −OP(ORcc)4, −B(Raa)2, −B(ORcc)2, −BRaa(ORcc), C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2- 10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; wherein X−is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; each instance of Raais, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raagroups 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 Rddgroups; each instance of Rbbis, independently, selected from hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)(N(Rcc)2)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rbbgroups 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 Rddgroups; wherein X−is a counterion; each instance of Rccis, independently, selected from hydrogen, C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rddgroups; each instance of Rddis, independently, selected from halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORee, −ON(Rff)2, −N(Rff)2, −N(Rff)3+X−, −N(ORee)Rff, −SH, −SRee, −SSRee, −C(=O)Ree, −CO2H, −CO2Ree, −OC(=O)Ree, −OCO2Ree, −C(=O)N(Rff)2, −OC(=O)N(Rff)2, −NRffC(=O)Ree, −NRffCO2Ree, −NRffC(=O)N(Rff)2, −C(=NRff)ORee, −OC(=NRff)Ree, −OC(=NRff)ORee, −C(=NRff)N(Rff)2, −OC(=NRff)N(Rff)2, −NRffC(=NRff)N(Rff)2, −NRffSO2Ree, −SO2N(Rff)2, −SO2Ree, −SO2ORee, −OSO2Ree, −S(=O)Ree, −Si(Ree)3, −OSi(Ree)3, −C(=S)N(Rff)2, −C(=O)SRee, −C(=S)SRee, −SC(=S)SRee, −P(=O)(ORee)2, −P(=O)(Ree)2, −OP(=O)(Ree)2, −OP(=O)(ORee)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 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 Rgggroups, or two geminal Rddsubstituents can be joined to form =O or =S; wherein X−is a counterion; each instance of Reeis, independently, selected from C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6 alkenyl, 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 Rgggroups; each instance of Rffis, independently, selected from hydrogen, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3- 10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, or two Rffgroups 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 Rgggroups; and each instance of Rggis, independently, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −OC1-6 alkyl, −ON(C1-6 alkyl)2, −N(C1-6 alkyl)2, −N(C1-6 alkyl)3+X−, −NH(C1-6 alkyl)2+X−, −NH2(C1-6alkyl)+X−, −NH3+X−, −N(OC1-6alkyl)(C1-6alkyl), −N(OH)(C1-6alkyl), −NH(OH), −SH, −SC1-6alkyl, −SS(C1-6alkyl), −C(=O)(C1-6alkyl), −CO2H, −CO2(C1-6alkyl), −OC(=O)(C1-6alkyl), −OCO2(C1-6 alkyl), −C(=O)NH2, −C(=O)N(C1-6 alkyl)2, −OC(=O)NH(C1-6 alkyl), −NHC(=O)(C1-6 alkyl), −N(C1-6alkyl)C(=O)( C1-6alkyl), −NHCO2(C1-6alkyl), −NHC(=O)N(C1-6alkyl)2, −NHC(=O)NH(C1-6alkyl), −NHC(=O)NH2, −C(=NH)O(C1-6alkyl), −OC(=NH)(C1-6alkyl), −OC(=NH)OC1-6alkyl, −C(=NH)N(C1-6alkyl)2, −C(=NH)NH(C1-6alkyl), −C(=NH)NH2, −OC(=NH)N(C1-6alkyl)2, −OC(=NH)NH(C1-6alkyl), −OC(=NH)NH2, −NHC(=NH)N(C1-6 alkyl)2, −NHC(=NH)NH2, −NHSO2(C1-6alkyl), −SO2N(C1-6alkyl)2, −SO2NH(C1-6alkyl), −SO2NH2, −SO2(C1-6alkyl), −SO2O(C1-6alkyl), −OSO2(C1-6alkyl), −SO(C1-6alkyl), −Si(C1-6alkyl)3, −OSi(C1-6alkyl)3−C(=S)N(C1-6alkyl)2, C(=S)NH(C1-6alkyl), C(=S)NH2, −C(=O)S(C1-6alkyl), −C(=S)SC1-6alkyl, −SC(=S)SC1-6alkyl, −P(=O)(OC1-6alkyl)2, −P(=O)(C1-6alkyl)2, −OP(=O)(C1-6alkyl)2, −OP(=O)(OC1-6alkyl)2, C1-6alkyl, C1-6perhaloalkyl, C2-6alkenyl, C2-6alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10carbocyclyl, C6-10aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rggsubstituents can be joined to form =O or =S; wherein X−is a counterion.

[0056] In certain embodiments, exemplary substituents include, but are not limited to, halogen, −CN, −NO2, −N3, −SO2H, −SO3H, −OH, −ORaa, −N(Rbb)2, −N(Rbb)3+X−, −SH, −SRaa, −C(=O)Raa, −CO2H, −CHO, −CO2Raa, −OC(=O)Raa, −OCO2Raa, −C(=O)N(Rbb)2, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −NRbbSO2Raa, −SO2N(Rbb)2, −SO2Raa, −SO2ORaa, −OSO2Raa, −S(=O)Raa, −OS(=O)Raa, −Si(Raa)3, −OSi(Raa)3, −P(=O)(Raa)2, −P(=O)(ORcc)2, −OP(=O)(Raa)2, −OP(=O)(ORcc)2, −P(=O)(N(Rbb)2)2, −OP(=O)(N(Rbb)2)2, −NRbbP(=O)(Raa)2, −NRbbP(=O)(ORcc)2, −NRbbP(=O)(N(Rbb)2)2, −B(Raa)2, −B(ORcc)2, −BRaa(ORcc), C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl; wherein X−is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(Rbb)2, =NNRbbC(=O)Raa, =NNRbbC(=O)ORaa, =NNRbbS(=O)2Raa, =NRbb, or =NORcc; each instance of Raais, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; each instance of Rbbis, independently, selected from hydrogen, −OH, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −P(=O)(Raa)2, −P(=O)(ORcc)2, −P(=O)(N(Rcc)2)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rbbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring; and each instance of Rccis, independently, selected from hydrogen, C1-10 alkyl, C1-10 perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring.

[0057] In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, – NO2, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −OC(=O)Raa, −OCO2Raa, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, or −NRbbC(=O)N(Rbb)2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, –NO2, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −OC(=O)Raa, −OCO2Raa, −OC(=O)N(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, or −NRbbC(=O)N(Rbb)2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts). In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1-6 alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, or –NO2. In certain embodiments, each carbon atom substituent is independently halogen, substituted (e.g., substituted with one or more halogen moieties) or unsubstituted C1–10 alkyl, −ORaa, −SRaa, −N(Rbb)2, –CN, –SCN, or –NO2, wherein Raais hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, an oxygen protecting group (e.g., silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl) when attached to an oxygen atom, or a sulfur protecting group (e.g., acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur atom; and each Rbbis independently hydrogen, substituted (e.g., substituted with one or more halogen) or unsubstituted C1–10 alkyl, or a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, acetyl, or Ts).

[0058] In certain embodiments, the molecular weight of a carbon atom substituent is lower than 250, lower than 200, lower than 150, lower than 100, or lower than 50 g / mol. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, nitrogen, and / or silicon atoms. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, iodine, oxygen, sulfur, and / or nitrogen atoms. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, chlorine, bromine, and / or iodine atoms. In certain embodiments, a carbon atom substituent consists of carbon, hydrogen, fluorine, and / or chlorine atoms.

[0059] The term “halo” or “halogen” refers to fluorine (fluoro, −F), chlorine (chloro, −Cl), bromine (bromo, −Br), or iodine (iodo, −I).

[0060] 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 wherein X−, Raa, Rbb, and Rccare as defined herein.

[0061] 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.

[0062] 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(Rbb), −NHC(=O)Raa, −NHCO2Raa, −NHC(=O)N(Rbb)2, −NHC(=NRbb)N(Rbb)2, −NHSO2Raa, −NHP(=O)(ORcc)2, and −NHP(=O)(N(Rbb)2)2, wherein Raa, Rbband Rccare as defined herein, and wherein Rbbof the group −NH(Rbb) is not hydrogen.

[0063] 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(Rbb)2, −NRbbC(=O)Raa, −NRbbCO2Raa, −NRbbC(=O)N(Rbb)2, −NRbbC(=NRbb)N(Rbb)2, −NRbbSO2Raa, −NRbbP(=O)(ORcc)2, and −NRbbP(=O)(N(Rbb)2)2, wherein Raa, Rbb, and Rccare as defined herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.

[0064] 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(Rbb)3 and −N(Rbb)3+X−, wherein Rbband X−are as defined herein.

[0065] The term “sulfonyl” refers to a group selected from –SO2N(Rbb)2, –SO2Raa, and –SO2ORaa, wherein Raaand Rbbare as defined herein.

[0066] The term “sulfinyl” refers to the group –S(=O)Raa, wherein Raais as defined herein.

[0067] The term “acyl” refers to a group having the general formula −C(=O)Raa, −C(=O)ORaa, −C(=O)−O−C(=O)Raa, −C(=O)SRaa, −C(=O)N(Rbb)2, −C(=S)Raa, −C(=S)N(Rbb)2, and −C(=S)S(Raa), −C(=NRbb)Raa, −C(=NRbb)ORaa, −C(=NRbb)SRaa, and −C(=NRbb)N(Rbb)2, wherein Raaand Rbbare as defined herein. Exemplary acyl groups include aldehydes (−CHO), carboxylic acids (−CO2H), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas.

[0068] The term “carbonyl” refers a group wherein the carbon directly attached to the parent molecule is sp2hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (e.g., –C(=O)Raa), carboxylic acids (e.g., –CO2H), aldehydes (–CHO), esters (e.g., –CO2Raa, – C(=O)SRaa, –C(=S)SRaa), amides (e.g., –C(=O)N(Rbb)2, –C(=O)NRbbSO2Raa, −C(=S)N(Rbb)2), and imines (e.g., –C(=NRbb)Raa, –C(=NRbb)ORaa), –C(=NRbb)N(Rbb)2), wherein Raaand Rbbare as defined herein.

[0069] The term “silyl” refers to the group –Si(Raa)3, wherein Raais as defined herein.

[0070] The term “oxo” refers to the group =O, and the term “thiooxo” refers to the group =S.

[0071] 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, −ORaa, −N(Rcc)2, −CN, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRbb)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, −P(=O)(ORcc)2, −P(=O)(Raa)2, −P(=O)(N(Rcc)2)2, C1-10alkyl, C1-10perhaloalkyl, C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10carbocyclyl, 3-14 membered heterocyclyl, C6-14aryl, and 5-14 membered heteroaryl, or two Rccgroups 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 Rddgroups, and wherein Raa, Rbb, Rccand Rddare as defined above.

[0072] In certain embodiments, the substituent present on the nitrogen atom is a nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include, but are not limited to, −OH, −ORaa, −N(Rcc)2, −C(=O)Raa, −C(=O)N(Rcc)2, −CO2Raa, −SO2Raa, −C(=NRcc)Raa, −C(=NRcc)ORaa, −C(=NRcc)N(Rcc)2, −SO2N(Rcc)2, −SO2Rcc, −SO2ORcc, −SORaa, −C(=S)N(Rcc)2, −C(=O)SRcc, −C(=S)SRcc, C1-10alkyl (e.g., aralkyl, heteroaralkyl), C2-10alkenyl, C2-10alkynyl, heteroC1-10alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 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 Rddgroups, and wherein Raa, Rbb, Rccand Rddare 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, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0073] For example, nitrogen protecting groups such as amide groups (e.g., −C(=O)Raa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitrophenylacetamide, 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.

[0074] Nitrogen protecting groups such as carbamate groups (e.g., −C(=O)ORaa) include, but are not limited to, methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9-(2- sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10- dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and 4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p- nitrobenzyl 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.

[0075] Nitrogen protecting groups such as sulfonamide groups (e.g., −S(=O)2Raa) 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.

[0076] 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, a nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9- flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p- methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2- trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).

[0077] 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, −Raa, −N(Rbb)2, −C(=O)SRaa, −C(=O)Raa, −CO2Raa, −C(=O)N(Rbb)2, −C(=NRbb)Raa, −C(=NRbb)ORaa, −C(=NRbb)N(Rbb)2, −S(=O)Raa, −SO2Raa, −Si(Raa)3, −P(Rcc)2, −P(Rcc)3+X−, −P(ORcc)2, −P(ORcc)3+X−, −P(=O)(Raa)2, −P(=O)(ORcc)2, and −P(=O)(N(Rbb) 2)2, wherein X−, Raa, Rbb, and Rccare 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, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

[0078] 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, an oxygen protecting group is silyl. In certain embodiments, an oxygen protecting group is t-butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethylsilyl (TMS), triisopropylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-trimethylsilylethyl carbonate, methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methyoxy-2- propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2-trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THF), p-methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), dimethoxytrityl (DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).

[0079] 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 are not limited to, −Raa, 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, 3rdedition, John Wiley & Sons, 1999, incorporated herein by reference. In certain embodiments, a sulfur protecting group is acetamidomethyl, t- Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.

[0080] A “counterion” or “anionic counterion” is a negatively charged group associated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (i.e., including one formal negative charge). An anionic counterion may also be multivalent (i.e., including more than one formal negative charge), such as divalent or trivalent. Exemplary counterions include halide ions (e.g., F–, Cl–, Br–, I–), NO3–, ClO4–, OH–, H2PO4–, HCO3−, HSO4–, sulfonate ions (e.g., methansulfonate, trifluoromethanesulfonate, p–toluenesulfonate, benzenesulfonate, 10–camphor sulfonate, naphthalene–2–sulfonate, naphthalene–1–sulfonic acid–5–sulfonate, ethan–1–sulfonic acid–2– sulfonate, and the like), carboxylate ions (e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate, glycolate, gluconate, and the like), BF4−, PF4–, PF6–, AsF6–, SbF6–, B[3,5-(CF3)2C6H3]4]–, B(C6F5)4−, BPh4–, Al(OC(CF3)3)4–, and carborane anions (e.g., CB11H12–or (HCB11Me5Br6)–). Exemplary counterions which may be multivalent include CO32−, HPO42−, PO43−, B4O72−, SO42−, S2O32−, carboxylate anions (e.g., tartrate, citrate, fumarate, maleate, malate, malonate, gluconate, succinate, glutarate, adipate, pimelate, suberate, azelate, sebacate, salicylate, phthalates, aspartate, glutamate, and the like), and carboranes.

[0081] As used herein, use of the phrase “at least one instance” refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive. Other Definitions

[0082] The following definitions are more general terms used throughout the present application.

[0083] 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+(C1-4 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.

[0084] 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.

[0085] 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)).

[0086] The term “tautomers” or “tautomeric” refers to two or more interconvertible compounds resulting from at least one formal migration of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the tautomers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to- enol, amide-to-imide, lactam-to-lactim, enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.

[0087] 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”.

[0088] 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”.

[0089] 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.

[0090] 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. C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C12 substituted aryl, and C7-C12arylalkyl esters of the compounds described herein may be preferred.

[0091] The terms “composition” and “formulation” are used interchangeably.

[0092] A “subject” to which administration is contemplated refers to a human (i.e., male or female of any age group, e.g., pediatric subject (e.g., infant, child, or adolescent) or adult subject (e.g., young adult, middle-aged adult, or senior adult)) or non-human animal. In certain embodiments, the non-human animal is a mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey), commercially relevant mammal (e.g., cattle, pig, horse, sheep, goat, cat, or dog), or bird (e.g., commercially relevant bird, such as chicken, duck, goose, or turkey)). In certain embodiments, the non-human animal is a fish, reptile, or amphibian. The non-human animal may be a male or female at any stage of development. The non-human animal may be a transgenic animal or genetically engineered animal. The term “patient” may refer to a human subject in need of treatment of a disease. In certain embodiments, the subject or patient is a human. In certain embodiments, the subject or patient is a non-human mammal. In certain embodiments, the subject or patient is a dog.

[0093] The term “biological sample” refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and separating the components thereof by centrifugation or otherwise). Other examples of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, saliva, swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.

[0094] 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.

[0095] The terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a pathogen). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

[0096] The terms “condition,” “disease,” and “disorder” are used interchangeably.

[0097] 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.

[0098] 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 effective to treat an infectious disease (e.g., viral infection). In certain embodiments, a therapeutically effective amount is an amount effective to inhibit viral replication in a cell.

[0099] A “prophylactically effective amount” of a compound described herein is an amount sufficient to prevent a condition, or one or more symptoms associated with the condition or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent. In certain embodiments, a prophylactically effective amount is an amount effective to prevent an infectious disease (e.g., viral infection). In certain embodiments, a prophylactically effective amount is an amount effective to inhibit viral replication in a cell.

[0100] An “infectious disease” refers to any disease caused by a pathogen (i.e., pathogenic microorganisms). An infectious disease may be caused by bacteria, viruses, parasites, or fungi. An infectious disease can be a microbial infection. A “microbial infection” refers to an infection with a microorganism, such as a fungus, bacteria, or virus. In certain embodiments, the microbial infection is an infection with a fungus, i.e., a fungal infection. In certain embodiments, the microbial infection is an infection with a bacteria, i.e., a bacterial infection. In certain embodiments, the microbial infection is an infection with a virus, i.e., a viral infection. In certain embodiments, the infectious disease is a viral infection. Viral infections include, but are not limited to, common cold, influenza (e.g., influenza A, B, C, D), respiratory tract infections (e.g., upper respiratory tract infections, lower respiratory tract infections, viral sinusitis, viral bronchitis, viral pneumonia, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), respiratory syncytial virus (RSV), coronavirus disease 2019 (COVID-19)), herpes, chickenpox, shingles, mumps, infection with human papillomavirus (HPV), measles, rubella, infection with human immunodeficiency virus (HIV / AIDS), viral gastroenteritis (e.g., stomach flu caused by rotavirus or norovirus), viral hepatitis (e.g., hepatitis A, B, C), mononucleosis, viral conjunctivitis, molluscum contagiosum, Ebola, and Zika. Viral infections also include, but are not limited to, infection with any of the viruses listed below. Examples of viruses include, but are not limited to, Adeno-associated virus, Aichi virus, Australian bat lyssavirus, BK polyomavirus, Banna virus, Barmah forest virus, Bunyamwera virus, Bunyavirus La Crosse, Bunyavirus snowshoe hare, Cercopithecine herpesvirus, Chandipura virus, Chikungunya virus, Cosavirus A, Cowpox virus, Coxsackievirus, Crimean-Congo hemorrhagic fever virus, Dengue virus, Dhori virus, Dugbe virus, Duvenhage virus, Eastern equine encephalitis virus, Ebolavirus, Echovirus, Encephalomyocarditis virus, Epstein-Barr virus, European bat lyssavirus, GB virus C / Hepatitis G virus, Hantaan virus, Hendra virus, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, Hepatitis E virus, Hepatitis delta virus, Horsepox virus, Human adenovirus, Human astrovirus, Human coronavirus, Human cytomegalovirus, Human enterovirus 68 or 70, Human herpesvirus 1, Human herpesvirus 2, Human herpesvirus 6, Human herpesvirus 7, Human herpesvirus 8, Human immunodeficiency virus (HIV), Human papillomavirus 1, Human papillomavirus 2, Human papillomavirus 16 or 18, Human parainfluenza, Human parvovirus B19, Human respiratory syncytial virus, Human rhinovirus, Human SARS coronavirus, Human spumaretrovirus, Human T-lymphotropic virus, Human torovirus, Influenza A virus, Influenza B virus, Influenza C virus, Isfahan virus, JC polyomavirus, Japanese encephalitis virus, Junin arenavirus, KI Polyomavirus, Kunjin virus, Lagos bat virus, Lake Victoria marburgvirus, Langat virus, Lassa virus, Lordsdale virus, Louping ill virus, Lymphocytic choriomeningitis virus, Machupo virus, Mayaro virus, MERS coronavirus, Measles virus, Mengo encephalomyocarditis virus, Merkel cell polyomavirus, Mokola virus, Molluscum contagiosum virus, Monkeypox virus, Mumps virus, Murray valley encephalitis virus, New York virus, Nipah virus, Norwalk virus, O'nyong-nyong virus, Orf virus, Oropouche virus, Pichinde virus, Poliovirus, Punta toro phlebovirus, Puumala virus, Rabies virus, Rift valley fever virus, Rosavirus A, Ross river virus, Rotavirus A, Rotavirus B, Rotavirus C, Rubella virus, Sagiyama virus, Salivirus A, Sandfly fever sicilian virus, Sapporo virus, SARS coronavirus 2, Semliki forest virus, Seoul virus, Simian foamy virus, Simian virus 5, Sindbis virus, Southampton virus, St. Louis encephalitis virus, Tick-borne powassan virus, Torque teno virus, Toscana virus, Uukuniemi virus, Vaccinia virus, Varicella-zoster virus, Variola virus, Venezuelan equine encephalitis virus, Vesicular stomatitis virus, Western equine encephalitis virus, WU polyomavirus, West Nile virus, Yaba monkey tumor virus, Yaba-like disease virus, Yellow fever virus, and Zika virus.

[0101] In certain embodiments, the virus is a coronavirus. In certain embodiments, the virus is a SARS coronavirus. In certain embodiments, the virus is SARS-CoV-2 or a variant thereof. The SARS-CoV-2 variant may be an existing variant (e.g., Alpha variant, Beta variant, Delta variant, Gamma variant, Omicron variant), subvariant, or a future variant. In certain embodiments, the SARS-CoV-2 variant is an Omicron subvariant (e.g., BA.2, BA.2.12, BA.2.12.1, BA.3, BA.4, BA.5).

[0102] As used herein the term “inhibit” or “inhibition” in the context of viral replication, for example, refers to the reduction in the rate of viral replication (e.g., relative to a reference). In some embodiments, the term refers to a reduction in the rate of viral replication to a level that is statistically significantly lower than an initial level or reference level. In some embodiments, the term refers to a reduction in the rate of viral replication that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a reference level of viral replication. DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS

[0103] Provided herein are antiviral compounds and uses thereof. In one aspect, provided herein are compounds (e.g., of Formulae (I), (IIʹ), (II), and (III), and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof. The compounds are useful for the treatment and / or prevention of infectious diseases (e.g., viral infections including COVID-19). In other aspects, provided herein are kits comprising compounds and pharmaceutical compositions described herein, methods of synthesizing compounds provided herein, and intermediates useful in the synthesis of compounds provided herein. Compounds Compounds of Formula (IIʹ) and (II)

[0104] Provided herein are compounds of Formula (IIʹ): or a pharmaceutically acceptable salt thereof, wherein: Ring A is a C6-10 aryl or 5-10 membered heteroaryl ring; RBis optionally substituted alkyl, halogen, or optionally substituted haloalkyl; Y1is –N(RN2)–, –O–, –S–, or –C(=O)–; YAis a bond, –C(RC)2– or –C(=O)–, wherein each instance of RCis independently hydrogen, halogen, or optionally substituted alkyl; each instance of RA, R2a, R2b, R3a, and R3bis independently hydrogen, halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; each instance of R2cand R3cis independently halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; or wherein R2aand an atom in the group RAare joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl; or wherein any two instances of R3a, R3b, and R3care joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl; each instance of RNand RN2is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, optionally substituted sulfonyl, or a nitrogen protecting group; or wherein two RNor RN1bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of ROis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; each instance of RSis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; w is 0, 1, 2, 3, or 4, as valency permits; and m is 0, 1, 2, or 3.

[0105] In certain embodiments, provided herein are compounds of Formula (II): and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein: Ring A is a C6-10aryl or 5-10 membered heteroaryl ring; RBis optionally substituted alkyl, halogen, or optionally substituted haloalkyl; Y1is –N(RN2)–, –O–, –S–, or –C(=O)–; each instance of RA, R2a, R2b, R3a, and R3bis independently hydrogen, halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; each instance of R2cand R3cis independently halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; or wherein R2aand an atom in the group RAare joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl; or wherein any two instances of R3a, R3b, and R3care joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl; each instance of RNand RN2is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, optionally substituted sulfonyl, or a nitrogen protecting group; or wherein two RNor RN1bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of ROis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; each instance of RSis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; w is 0, 1, 2, 3, or 4, as valency permits; and m is 0, 1, 2, or 3.

[0106] In certain embodiments, a compound of Formula (II) is of Formula (II-a): or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0107] In certain embodiments, a compound of Formula (II) is of Formula (II-b): or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0108] In certain embodiments, a compound of Formula (II) is of the formula: , or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: G1is N or CR1a; G2, G3, G4, and G5are each independently N or CR1b; and each instance of R1aand R1bis independently hydrogen, halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; or wherein R1aand R2aare joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl.

[0109] In certain embodiments, a compound of Formula (II) is of the formula: , or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein n is 0, 1, 2, 3, or 4.

[0110] In other embodiments, a compound of Formula (II) is of the formula: , or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Y2is optionally substituted C1-4alkylene or optionally substituted C1-4heteroalkylene.

[0111] In certain embodiments, a compound of Formula (II) is of the formula: , or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: s is 0, 1, 2, or 3; p is 1, 2, 3, or 4; each instance of R6is independently hydrogen, optionally substituted alkyl, halogen, –CN, –ORO, –N(RN3)2, or –SRS; optionally wherein two R6on the same carbon atom are taken together to form =O; and each instance of RN3is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, optionally substituted sulfonyl, or a nitrogen protecting group; optionally wherein two RN3bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl.

[0112] In other embodiments, a compound of Formula (II) is of the formula: , or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0113] In certain embodiments, a compound of Formula (II) is of the formula: , or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0114] In certain embodiments, for example, a compound of Formula (II) is selected from those in Table II, and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. Table II

[0115] In certain embodiments, the compound is a compound of Formula (II) or any subgeneric formula or species thereof (e.g., a compound in Table II), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (II) or any subgeneric formula or species thereof (e.g., a compound in Table II), in free base form. Compounds of Formula (III)

[0116] Provided herein are compounds of Formula (III): or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: X4, X5, X6, and X7are independently selected from N and CRX; Ring A is a C6-10 aryl or 5-10 membered heteroaryl ring; RBis optionally substituted alkyl, halogen, or optionally substituted haloalkyl; Y1is –N(RN2)–, –O–, –S–, or –C(=O)–; each instance of RA, R2a, R2b, R3a, R3b, and RXis independently hydrogen, halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; each instance of R2cand R3cis independently halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; or wherein R2aand an atom in the group RAare joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl; or wherein any two instances of R3a, R3b, and R3care joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl; each instance of RNand RN2is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, optionally substituted sulfonyl, or a nitrogen protecting group; or wherein two RNor RN1bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of ROis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; each instance of RSis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; w is 0, 1, 2, 3, or 4, as valency permits; and m is 0, 1, 2, or 3.

[0117] In certain embodiments, a compound of Formula (III) is of Formula (III-a): or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0118] In certain embodiments, a compound of Formula (III) is of Formula (III-b): or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0119] In certain embodiments, a compound of Formula (III) is of the formula: , or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: G1is N or CR1a; G2, G3, G4, and G5are each independently N or CR1b; and each instance of R1aand R1bis independently hydrogen, halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; or wherein R1aand R2aare joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl.

[0120] In certain embodiments, a compound of Formula (III) is of the formula: , or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein n is 0, 1, 2, 3, or 4.

[0121] In certain embodiments, a compound of Formula (III) is of the formula: , or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Y2is optionally substituted C1-4alkylene or optionally substituted C1-4 heteroalkylene.

[0122] In certain embodiments, a compound of Formula (III) is of the formula: , or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: or a pharmaceutically acceptable salt thereof, wherein: s is 0, 1, 2, or 3; p is 1, 2, 3, or 4; each instance of R6is independently hydrogen, optionally substituted alkyl, halogen, –CN, –ORO, –N(RN3)2, or –SRS; optionally wherein two R6on the same carbon atom are taken together to form =O; and each instance of RN3is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, optionally substituted sulfonyl, or a nitrogen protecting group; optionally wherein two RN3bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl.

[0123] In certain embodiments, a compound of Formula (III) is of the formula: , or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0124] In certain embodiments, a compound of Formula (III) is of the formula: , or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0125] In certain embodiments, for example, a compound of Formula (III) is selected from those in Table III, and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. Table

[0126] In certain embodiments, the compound is a compound of Formula (III) or any subgeneric formula or species thereof (e.g., a compound in Table III), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (III) or any subgeneric formula or species thereof (e.g., a compound in Table III), in free base form. Compounds of Formula (I)

[0127] Provided herein are compounds of Formula (I): and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, wherein: X1, X2, and X3are each independently N, NRN1, O, S, or CR4; Y1is –N(RN2)–, –O–, –S–, or –C(=O)–; RAis hydrogen, halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; each instance of R2a, R2b, R3a, R3b, R3c, and R4is independently hydrogen, halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; or wherein R2aand an atom in ring RAare joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl; or wherein any two instances of R3a, R3b, or R3care joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl; each instance of RN, RN1, and RN2is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, optionally substituted sulfonyl, or a nitrogen protecting group; or wherein two RNbonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of ROis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; each instance of RSis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; and m is 0, 1, 2, or 3; provided that when RAis hydrogen or halogen, then X1is not O or S; or X3is not N.

[0128] As defined herein, when RAis hydrogen or halogen, then X1is not O or S; or X3is not N. In certain embodiments, when RAis hydrogen or halogen, then X1is not O or S. In certain embodiments, when RAis hydrogen or halogen, then X3is not N. In certain embodiments, when RAis hydrogen or halogen, then X1is not O or S; and X3is not N.

[0129] In certain embodiments, when RAis hydrogen or halogen, then X1is N and / or X3is O. In certain embodiments, when RAis hydrogen or halogen, then X1is N. In certain embodiments, when RAis hydrogen or halogen, then X3is O. In certain embodiments, when RAis hydrogen or halogen, then X1is N; X2is N; and X3is O.

[0130] In certain embodiments, RAis a ring selected from optionally substituted aryl or optionally substituted 6-10 membered heteroaryl.

[0131] In certain embodiments, a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0132] In certain embodiments, a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0133] In certain embodiments, a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0134] In certain embodiments, a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0135] In certain embodiments, a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: G1is N or CR1a; G2, G3, G4, and G5are each independently N or CR1b; and each instance of R1aand R1bis independently hydrogen, halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; or wherein R1aand R2aare joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl.

[0136] In certain embodiments, a compound of Formula (I) is of one of the following formulae: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0137] In certain embodiments, a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein n is 0, 1, 2, 3, or 4.

[0138] In certain embodiments, a compound of Formula (I) is of one of the following formulae: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0139] In certain embodiments, a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein Y2is optionally substituted C1-4alkylene or optionally substituted C1-4heteroalkylene.

[0140] In certain embodiments, a compound of Formula (I) is of one of the following formulae: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0141] In certain embodiments, a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein: s is 0, 1, 2, or 3; p is 1, 2, 3, or 4; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, as valency permits; each instance of R6is independently hydrogen, optionally substituted alkyl, halogen, –CN, –ORO, –N(RN3)2, or –SRS; or wherein two R6on the same carbon atom are taken together to form =O; and each instance of RN3is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, optionally substituted sulfonyl, or a nitrogen protecting group; or wherein two RN3bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl.

[0142] In certain embodiments, a compound of Formula (I) is of one of the following formulae: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0143] In certain embodiments, a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0144] In certain embodiments, a compound of Formula (I) is of one of the following formulae: or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0145] In certain embodiments, a compound of Formula (I) is of the formula: , or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof.

[0146] In certain embodiments, for example, a compound of Formula (I) is selected from those in Table I, and pharmaceutically acceptable salts, hydrates, solvates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof. Table I

[0147] In certain embodiments, the compound is a compound of Formula (I) or any subgeneric formula or species thereof (e.g., a compound in Table I), or a pharmaceutically acceptable salt thereof. In certain embodiments, the compound is a compound of Formula (I) or any subgeneric formula or species thereof (e.g., a compound in Table I), in free base form.

[0148] References to compounds provided herein, including references to compounds of Formula (I), are intended to include compounds of all generic and subgeneric formulae recited herein, as well as all specific compounds recited herein.

[0149] References to compounds provided herein, including references to compounds of Formula (II), are intended to include compounds of all generic and subgeneric formulae recited herein, as well as all specific compounds recited herein.

[0150] References to compounds provided herein, including references to compounds of Formula (III), are intended to include compounds of all generic and subgeneric formulae recited herein, as well as all specific compounds recited herein.

[0151] The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0152] The following chemical group definitions and embodiments apply to all generic and subgeneric formulae (e.g., Formula (I), (II), and (III), and subgeneric formulae thereof) recited herein. Ring A

[0153] As defined herein, Ring A is a C6-10 aryl or 5-10 membered heteroaryl ring. In certain embodiments, Ring A is a C6-10 aryl ring. In certain embodiments, Ring A is a 5-10 membered heteroaryl ring. In certain embodiments, Ring A is a 5-10 membered heteroaryl ring having 1, 2, or 3 ring heteroatoms independently selected from O, N, and S.

[0154] In certain embodiments, Ring A is 6-membered heteroaryl ring. In certain embodiments, Ring A is 6-membered heteroaryl ring having 1 or 2 ring heteroatoms independently selected from O, N, and S. In certain embodiments, Ring A is 6-membered heteroaryl ring having 1 or 2 ring nitrogen atoms. In certain embodiments, Ring A is a pyridine ring. In certain embodiments, Ring A is a pyridazine ring. In certain embodiments, Ring A is a pyrimidine ring. In certain embodiments, Ring A is a pyrazine ring.

[0155] In certain embodiments, the group of the formula: the formula: .

[0156] In certain embodiments, the group of the formula: embodiments, the group of the formula:

[0157] In certain embodiments, the group of the formula: one of the following formulae: formulae: Group RB

[0159] As defined herein, RBis optionally substituted alkyl, halogen, or optionally substituted haloalkyl.

[0160] In certain embodiments, RBis optionally substituted haloalkyl. In certain embodiments, RBis unsubstituted C1-3 haloalkyl. In certain embodiments, RBis unsubstituted C1 haloalkyl. In certain embodiments, RBis -CF3.

[0161] In certain embodiments, RBis optionally substituted C1-6 alkyl. In certain embodiments, RBis optionally substituted C1-3 alkyl. In certain embodiments, RBis unsubstituted C1-3 alkyl. In certain embodiments, RBis methyl. X1, X2, X3, and X4

[0162] As defined herein, X1is N, NRN1, O, S, or CR4. In certain embodiments, X1is N. In certain embodiments, X1is NRN1. In certain embodiments, X1is NH. In certain embodiments, X1is O. In certain embodiments, X1is S. In certain embodiments, X1is CR4. In certain embodiments, X1is CH. In certain embodiments, X1is O, N, or CR4. In certain embodiments, X1is O, N, or CH.

[0163] As defined herein, X2is N, NRN1, O, S, or CR4. In certain embodiments, X2is N. In certain embodiments, X2is NRN1. In certain embodiments, X2is NH. In certain embodiments, X2is O. In certain embodiments, X2is S. In certain embodiments, X2is CR4. In certain embodiments, X2is CH. In certain embodiments, X2is N or O.

[0164] As defined herein, X3is N, NRN1, O, S, or CR4. In certain embodiments, X3is N. In certain embodiments, X3is NRN1. In certain embodiments, X3is NH. In certain embodiments, X3is O. In certain embodiments, X3is S. In certain embodiments, X3is CR4. In certain embodiments, X3is CH. In certain embodiments, X3is CR4, O, or S. In certain embodiments, X3is CH, O, or S. In certain embodiments, X3is N, CR4, O, or S. In certain embodiments, X3is N, CH, O, or S.

[0165] As defined herein, X4is N or CRX. In certain embodiments, X4is N. In certain embodiments, X4is CRX. In certain embodiments, X4is CH.

[0166] In certain embodiments, X1, X2, X3, and X4are each independently CRX.

[0167] In some embodiments, X1, X2, X3, and X4are each CH.

[0168] In some embodiments, X1, X3, and X4are each independently CRX; and X2is N.

[0169] In some embodiments, X1, X3, and X4are each CH; and X2is N.

[0170] In certain embodiments, X1is O; X2is N; and X3is CR4. In certain embodiments, X1is O; X2is N; and X3is CH.

[0171] In certain embodiments, X1is N; X2is N; and X3is O.

[0172] In certain embodiments, X1is CR4; X2is N; and X3is S. In certain embodiments, X1is CH; X2is N; and X3is S.

[0173] In certain embodiments, X1is CR4; X2is N; and X3is O. In certain embodiments, X1is CH; X2is N; and X3is O.

[0174] In certain embodiments, X1is O; X2is N; and X3is N.

[0175] In certain embodiments, X1is N; X2is O; and X3is N. X4, X5, X6, and X7

[0176] As defined herein, X4, X5, X6, and X7are independently selected from N and CRX.

[0177] In certain embodiments, X4is CRX. In certain embodiments, X4is CH. In certain embodiments, X4is N.

[0178] In certain embodiments, X5is CRX. In certain embodiments, X5is CH. In certain embodiments, X5is N.

[0179] In certain embodiments, X6is CRX. In certain embodiments, X6is CH. In certain embodiments, X6is N.

[0180] In certain embodiments, X7is CRX. In certain embodiments, X7is CH. In certain embodiments, X7is N.

[0181] In certain embodiments, wherein X4, X5, X6, and X7are each independently CRX. In certain embodiments, X4, X5, X6, and X7are each CH.

[0182] In certain embodiments, X4, X6, and X7are each independently CRX; and X5is N. in certain embodiments, X4, X6, and X7are each CH; and X5is N. Y1, Y2, and s

[0183] As defined herein, Y1is –N(RN2)–, –O–, –S–, or –C(=O)–. In certain embodiments, Y1is –N(RN2)–. In certain embodiments, Y1is –NH–. In certain embodiments, Y1is –O–. In certain embodiments, Y1is –S–. In certain embodiments, Y1is –C(=O)–. In certain embodiments, Y1is –CH2–.

[0184] As defined herein, Y2is optionally substituted C1-4alkylene or optionally substituted C1-4heteroalkylene. In certain embodiments, Y2is optionally substituted C1-4heteroalkylene. In certain embodiments, Y2is optionally substituted C1-4alkylene. In certain embodiments, Y2is unsubstituted C1-4alkylene (i.e., , wherein s is 0, 1, 2, or 3). In certain embodiments, Y2is optionally substituted C3 alkylene. In certain embodiments, Y2is unsubstituted C3alkylene (i.e.,

[0185] As defined herein, s is 0, 1, 2, or 3. In certain embodiments, s is 0. In certain embodiments, s is 1. In certain embodiments, s is 2. In certain embodiments, s is 3. RA, G1, G2, G3, G4, and G5

[0186] As defined herein, RAis hydrogen, halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl. In certain embodiments, RAis hydrogen. In certain embodiments, RAis halogen. In certain embodiments, RAis –CN. In certain embodiments, RAis –NO2. In certain embodiments, RAis –N3. In certain embodiments, RAis –SCN. In certain embodiments, RAis –ORO. In certain embodiments, RAis – N(RN)2. In certain embodiments, RAis –SRS. In certain embodiments, RAis optionally substituted alkyl. In certain embodiments, RAis optionally substituted alkenyl. In certain embodiments, RAis optionally substituted alkynyl. In certain embodiments, RAis optionally substituted carbocyclyl. In certain embodiments, RAis optionally substituted heterocyclyl. In certain embodiments, RAis optionally substituted aryl. In certain embodiments, RAis optionally substituted heteroaryl. In certain embodiments, RAis optionally substituted acyl. In certain embodiments, RAis optionally substituted sulfinyl. In certain embodiments, RAis optionally substituted sulfonyl.

[0187] In certain embodiments, RAis a ring selected from optionally substituted aryl or optionally substituted 6-10 membered heteroaryl. In certain embodiments, RAis optionally substituted 5-membered heteroaryl. In certain embodiments, RAis optionally substituted 6-membered heteroaryl. In certain embodiments, RAis optionally substituted aryl. In certain embodiments, RAis optionally substituted C6 aryl (i.e., optionally substituted phenyl). In certain embodiments, RAis optionally substituted C10 aryl (i.e., optionally substituted naphthyl).

[0188] In certain embodiments, RAis a ring of the formula: .

[0189] As defined herein, G1is N or CR1a. In certain embodiments, G1is N. In certain embodiments, G1is CR1a. In certain embodiments, G1is CH.

[0190] As defined herein, G2is N or CR1b. In certain embodiments, G2is N. In certain embodiments, G2is CR1b. In certain embodiments, G2is CH.

[0191] As defined herein, G3is N or CR1b. In certain embodiments, G3is N. In certain embodiments, G3is CR1b. In certain embodiments, G3is CH.

[0192] As defined herein, G4is N or CR1b. In certain embodiments, G4is N. In certain embodiments, G4is CR1b. In certain embodiments, G4is CH.

[0193] As defined herein, G5is N or CR1b. In certain embodiments, G5is N. In certain embodiments, G5is CR1b. In certain embodiments, G5is CH.

[0194] In certain embodiments, G1is CR1a; and G2, G3, G4, and G5are CR1b. In certain embodiments, G1is CR1a; and G2, G3, G4, and G5are CH.

[0195] In certain embodiments, RAis a ring of the formula: .

[0196] In certain embodiments, R2aand an atom in ring RAare joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl. In certain embodiments, R2aand an atom in ring RAare joined together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, R2aand an atom in ring RAare joined together with the intervening atoms to form optionally substituted carbocyclyl. In certain embodiments, R2aand an atom in ring RAare joined together with the intervening atoms to form optionally substituted C6-8carbocyclyl. In certain embodiments, R2aand an atom in ring RAare joined together with the intervening atoms to form optionally substituted C7carbocyclyl.

[0197] In certain embodiments, RAis one of the following: R1a, R1b, R2a, R2b, and n

[0198] As defined herein, R1ais hydrogen, halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl. In certain embodiments, R1ais hydrogen. In certain embodiments, R1ais halogen. In certain embodiments, R1ais –CN. In certain embodiments, R1ais –NO2. In certain embodiments, R1ais –N3. In certain embodiments, R1ais –SCN. In certain embodiments, R1ais –ORO. In certain embodiments, R1ais – N(RN)2. In certain embodiments, R1ais –SRS. In certain embodiments, R1ais optionally substituted alkyl. In certain embodiments, R1ais optionally substituted C1-6 alkyl. In certain embodiments, R1ais unsubstituted C1-6 alkyl. In certain embodiments, R1ais optionally substituted alkenyl. In certain embodiments, R1ais optionally substituted alkynyl. In certain embodiments, R1ais optionally substituted carbocyclyl. In certain embodiments, R1ais optionally substituted heterocyclyl. In certain embodiments, R1ais optionally substituted aryl. In certain embodiments, R1ais optionally substituted heteroaryl. In certain embodiments, R1ais optionally substituted acyl. In certain embodiments, R1ais optionally substituted sulfinyl. In certain embodiments, R1ais optionally substituted sulfonyl.

[0199] As defined herein, R2ais hydrogen, halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl. In certain embodiments, R2ais hydrogen. In certain embodiments, R2ais halogen. In certain embodiments, R2ais –CN. In certain embodiments, R2ais –NO2. In certain embodiments, R2ais –N3. In certain embodiments, R2ais –SCN. In certain embodiments, R2ais –ORO. In certain embodiments, R2ais – N(RN)2. In certain embodiments, R2ais –SRS. In certain embodiments, R2ais optionally substituted alkyl. In certain embodiments, R2ais optionally substituted C1-6alkyl. In certain embodiments, R2ais unsubstituted C1-6alkyl. In certain embodiments, R2ais optionally substituted alkenyl. In certain embodiments, R2ais optionally substituted alkynyl. In certain embodiments, R2ais optionally substituted carbocyclyl. In certain embodiments, R2ais optionally substituted heterocyclyl. In certain embodiments, R2ais optionally substituted aryl. In certain embodiments, R2ais optionally substituted heteroaryl. In certain embodiments, R2ais optionally substituted acyl. In certain embodiments, R2ais optionally substituted sulfinyl. In certain embodiments, R2ais optionally substituted sulfonyl.

[0200] In certain embodiments, R2ais optionally substituted phenyl. In certain embodiments, R2ais unsubstituted phenyl.

[0201] In certain embodiments, R1aand R2aare joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl. In certain embodiments, R1aand R2aare joined together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, R1aand R2aare joined together with the intervening atoms to form optionally substituted carbocyclyl. In certain embodiments, R1aand R2aare joined together with the intervening atoms to form optionally substituted C6-8carbocyclyl. In certain embodiments, R1aand R2aare joined together with the intervening atoms to form optionally substituted C7 carbocyclyl.

[0202] As defined herein, each instance of R1bis independently hydrogen, halogen, –CN, –NO2, –N3, – SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl. In certain embodiments, at least one instance of R1bis hydrogen. In certain embodiments, at least one instance of R1bis halogen. In certain embodiments, at least one instance of R1bis –CN. In certain embodiments, at least one instance of R1bis –NO2. In certain embodiments, at least one instance of R1bis –N3. In certain embodiments, at least one instance of R1bis – SCN. In certain embodiments, at least one instance of R1bis –ORO. In certain embodiments, at least one instance of R1bis –N(RN)2. In certain embodiments, at least one instance of R1bis –SRS. In certain embodiments, at least one instance of R1bis optionally substituted alkyl. In certain embodiments, at least one instance of R1bis optionally substituted alkenyl. In certain embodiments, at least one instance of R1bis optionally substituted alkynyl. In certain embodiments, at least one instance of R1bis optionally substituted carbocyclyl. In certain embodiments, at least one instance of R1bis optionally substituted heterocyclyl. In certain embodiments, at least one instance of R1bis optionally substituted aryl. In certain embodiments, at least one instance of R1bis optionally substituted heteroaryl. In certain embodiments, at least one instance of R1bis optionally substituted acyl. In certain embodiments, at least one instance of R1bis optionally substituted sulfinyl. In certain embodiments, at least one instance of R1bis optionally substituted sulfonyl.

[0203] In certain embodiments, at least one instance of R1bis: .

[0204] In certain embodiments, at least one instance of R1bcomprises a Michael acceptor (e.g., a moiety comprising, embodiments, at least one instance of R1bis: . In certain embodiments, at least one instance of R1bis: .

[0205] As defined herein, n is 0, 1, 2, 3, or 4. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4.

[0206] As defined herein, R2bis hydrogen, halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl. In certain embodiments, R2bis hydrogen. In certain embodiments, R2bis halogen. In certain embodiments, R2bis –CN. In certain embodiments, R2bis –NO2. In certain embodiments, R2bis –N3. In certain embodiments, R2bis –SCN. In certain embodiments, R2bis –ORO. In certain embodiments, R2bis – N(RN)2. In certain embodiments, R2bis –SRS. In certain embodiments, R2bis optionally substituted alkyl. In certain embodiments, R2bis optionally substituted C1-6alkyl. In certain embodiments, R2bis unsubstituted C1-6alkyl. In certain embodiments, R2bis optionally substituted alkenyl. In certain embodiments, R2bis optionally substituted alkynyl. In certain embodiments, R2bis optionally substituted carbocyclyl. In certain embodiments, R2bis optionally substituted heterocyclyl. In certain embodiments, R2bis optionally substituted aryl. In certain embodiments, R2bis optionally substituted heteroaryl. In certain embodiments, R2bis optionally substituted acyl. In certain embodiments, R2bis optionally substituted sulfinyl. In certain embodiments, R2bis optionally substituted sulfonyl.

[0207] In certain embodiments, R2bis optionally subsituted phenyl. In certain embodiments, R2bis unsubstituted phenyl. R3a, R3b, R3c, RX, m, p, w, v1, and v2

[0208] As defined herein, R3ais hydrogen, halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl. In certain embodiments, R3ais hydrogen. In certain embodiments, R3ais halogen. In certain embodiments, R3ais –CN. In certain embodiments, R3ais –NO2. In certain embodiments, R3ais –N3. In certain embodiments, R3ais –SCN. In certain embodiments, R3ais –ORO. In certain embodiments, R3ais – N(RN)2. In certain embodiments, R3ais –SRS. In certain embodiments, R3ais optionally substituted alkyl. In certain embodiments, R3ais optionally substituted C1-6alkyl. In certain embodiments, R3ais unsubstituted C1-6 alkyl. In certain embodiments, R3ais optionally substituted alkenyl. In certain embodiments, R3ais optionally substituted alkynyl. In certain embodiments, R3ais optionally substituted carbocyclyl. In certain embodiments, R3ais optionally substituted heterocyclyl. In certain embodiments, R3ais optionally substituted aryl. In certain embodiments, R3ais optionally substituted heteroaryl. In certain embodiments, R3ais optionally substituted acyl. In certain embodiments, R3ais optionally substituted sulfinyl. In certain embodiments, R3ais optionally substituted sulfonyl.

[0209] As defined herein, R3bis hydrogen, halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl. In certain embodiments, R3bis hydrogen. In certain embodiments, R3ais halogen. In certain embodiments, R3bis –CN. In certain embodiments, R3bis –NO2. In certain embodiments, R3bis – N3. In certain embodiments, R3bis –SCN. In certain embodiments, R3bis –ORO. In certain embodiments, R3bis –N(RN)2. In certain embodiments, R3bis –SRS. In certain embodiments, R3bis optionally substituted alkyl. In certain embodiments, R3bis optionally substituted C1-6 alkyl. In certain embodiments, R3bis unsubstituted C1-6 alkyl. In certain embodiments, R3bis optionally substituted alkenyl. In certain embodiments, R3bis optionally substituted alkynyl. In certain embodiments, R3bis optionally substituted carbocyclyl. In certain embodiments, R3bis optionally substituted heterocyclyl. In certain embodiments, R3bis optionally substituted aryl. In certain embodiments, R3bis optionally substituted heteroaryl. In certain embodiments, R3bis optionally substituted acyl. In certain embodiments, R3bis optionally substituted sulfinyl. In certain embodiments, R3bis optionally substituted sulfonyl.

[0210] In certain embodiments, any two instances of R3a, R3b, or R3care joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl. In certain embodiments, any two instances of R3a, R3b, or R3care joined together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, any two instances of R3a, R3b, or R3care joined together with the intervening atoms to form optionally substituted carbocyclyl.

[0211] In certain embodiments, any two instances of R3a, R3b, or R3care joined together with the intervening atoms to form optionally substituted carbocyclyl substituted with at least one instance of R6. In certain embodiments, any two instances of R3a, R3b, or R3care joined together with the intervening atoms to form optionally substituted carbocyclyl substituted with at least one instance of –N(RN3)2. In certain embodiments, any two instances of R3a, R3b, or R3care joined together with the intervening atoms to form optionally substituted C5-8 carbocyclyl substituted with at least one instance of R6. In certain embodiments, any two instances of R3a, R3b, or R3care joined together with the intervening atoms to form optionally substituted C5-8 carbocyclyl substituted with at least one instance of –N(RN3)2. In certain embodiments, any two instances of R3a, R3b, or R3care joined together with the intervening atoms to form optionally substituted C7carbocyclyl substituted with at least one instance of R6. In certain embodiments, any two instances of R3a, R3b, or R3care joined together with the intervening atoms to form optionally substituted C7carbocyclyl substituted with at least one instance of –N(RN3)2.

[0212] In certain embodiments, any two instances of R3a, R3b, or R3care joined together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, any two instances of R3a, R3b, or R3care joined together with the intervening atoms to form optionally substituted 6- or 7- membered heterocyclyl comprising 1 or 2 ring heteroatoms selected from N, O, and S. In certain embodiments, any two instances of R3a, R3b, or R3care joined together with the intervening atoms to form optionally substituted 6- or 7-membered heterocyclyl comprising 1 ring heteroatoms selected from N, O, and S. In certain embodiments, any two instances of R3a, R3b, or R3care joined together with the intervening atoms to form optionally substituted 6- or 7-membered heterocyclyl comprising 1 ring N atom.

[0213] In certain embodiments, R3aand R3bare joined together with the intervening atoms to form optionally substituted carbocyclyl substituted with at least one instance of R6. In certain embodiments, R3aand R3bare joined together with the intervening atoms to form optionally substituted carbocyclyl substituted with at least one instance of –N(RN3)2. In certain embodiments, R3aand R3bare joined together with the intervening atoms to form optionally substituted C5-8carbocyclyl substituted with at least one instance of R6. In certain embodiments, R3aand R3bare joined together with the intervening atoms to form optionally substituted C5-8 carbocyclyl substituted with at least one instance of –N(RN3)2. In certain embodiments, a R3aand R3bare joined together with the intervening atoms to form optionally substituted C7 carbocyclyl substituted with at least one instance of R6. In certain embodiments, R3aand R3bare joined together with the intervening atoms to form optionally substituted C7 carbocyclyl substituted with at least one instance of –N(RN3)2.

[0214] In certain embodiments, R3aand R3bare joined together with the intervening atoms to form: certain embodiments, R3aand R3bare joined together with the intervening atoms to form: certain embodiments, R3aand R3bare joined together with the intervening atoms to form: certain embodiments, R3aand R3bare joined together with the intervening atoms to form:

[0215] In certain embodiments, R3aand R3bare joined together with the intervening atoms to form: , g

[0216] In certain embodiments, R3aand R3bare joined together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, R3aand R3bare joined together with the intervening atoms to form optionally substituted 6- or 7-membered heterocyclyl comprising 1 or 2 ring heteroatoms selected from N, O, and S. In certain embodiments, R3aand R3bare joined together with the intervening atoms to form optionally substituted 6- or 7-membered heterocyclyl comprising 1 ring heteroatoms selected from N, O, and S. In certain embodiments, R3aand R3bare joined together with the intervening atoms to form optionally substituted 6- or 7-membered heterocyclyl comprising 1 ring N atom. In certain embodiments, R3aand R3bare joined together with the intervening atoms to form:

[0217] In certain embodiments, R3ais optionally substituted –O-C1-6 alkyl-R6. In certain embodiments, R3ais –O-(CH2)1-6-R6. In certain embodiments, R3ais –O-(CH2)1-6-N(RN3)2. In certain embodiments, R3ais – O-(CH2)1-3-R6. In certain embodiments, R3ais –O-(CH2)1-3-N(RN3)2. In certain embodiments, R3ais: o .

[0218] In certain embodiments, R3bis optionally substituted –O-C1-6alkyl-R6. In certain embodiments, R3bis –O-(CH2)1-6-R6. In certain embodiments, R3bis –O-(CH2)1-6-N(RN3)2. In certain embodiments, R3bis – O-(CH2)1-3-R6. In certain embodiments, R3bis –O-(CH2)1-3-N(RN3)2. In certain embodiments, R3bis:

[0219] As defined herein, each instance of R3cis independently hydrogen, halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl. In certain embodiments, at least one instance of R3cis hydrogen. In certain embodiments, at least one instance of R3cis halogen. In certain embodiments, at least one instance of R3cis –CN. In certain embodiments, at least one instance of R3cis –NO2. In certain embodiments, at least one instance of R3cis –N3. In certain embodiments, at least one instance of R3cis – SCN. In certain embodiments, at least one instance of R3cis –ORO. In certain embodiments, at least one instance of R3cis –N(RN)2. In certain embodiments, at least one instance of R3cis –SRS. In certain embodiments, at least one instance of R3cis optionally substituted alkyl. In certain embodiments, at least one instance of R3cis optionally substituted alkenyl. In certain embodiments, at least one instance of R3cis optionally substituted alkynyl. In certain embodiments, at least one instance of R3cis optionally substituted carbocyclyl. In certain embodiments, at least one instance of R3cis optionally substituted heterocyclyl. In certain embodiments, at least one instance of R3cis optionally substituted aryl. In certain embodiments, at least one instance of R3cis optionally substituted heteroaryl. In certain embodiments, at least one instance of R3cis optionally substituted acyl. In certain embodiments, at least one instance of R3cis optionally substituted sulfinyl. In certain embodiments, at least one instance of R3cis optionally substituted sulfonyl.

[0220] In certain embodiments, at least one instance of R3cis optionally substituted –O-C1-6alkyl-R6. In certain embodiments, at least one instance of R3cis –O-(CH2)1-6-R6. In certain embodiments, at least one instance of R3cis –O-(CH2)1-6-N(RN3)2. In certain embodiments, at least one instance of R3cis –O-(CH2)1-3- R6. In certain embodiments, at least one instance of R3cis –O-(CH2)1-3-N(RN3)2. In certain embodiments, at least one instance of R3cis:

[0221] As defined herein, RXis hydrogen, halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl. In certain embodiments, RXis hydrogen. In certain embodiments, RXis halogen. In certain embodiments, RXis –CN. In certain embodiments, RXis –NO2. In certain embodiments, RXis –N3. In certain embodiments, RXis –SCN. In certain embodiments, RXis –ORO. In certain embodiments, RXis – N(RN)2. In certain embodiments, RXis –SRS. In certain embodiments, RXis optionally substituted alkyl. In certain embodiments, RXis optionally substituted C1-6alkyl. In certain embodiments, RXis unsubstituted C1-6alkyl. In certain embodiments, RXis optionally substituted alkenyl. In certain embodiments, RXis optionally substituted alkynyl. In certain embodiments, RXis optionally substituted carbocyclyl. In certain embodiments, RXis optionally substituted heterocyclyl. In certain embodiments, RXis optionally substituted aryl. In certain embodiments, RXis optionally substituted heteroaryl. In certain embodiments, RXis optionally substituted acyl. In certain embodiments, RXis optionally substituted sulfinyl. In certain embodiments, RXis optionally substituted sulfonyl.

[0222] As defined herein, m is 0, 1, 2, or 3. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2. In certain embodiments, m is 3. 4.

[0223] As defined herein, p is 1, 2, 3, or 4. In certain embodiments, p is 1. In certain embodiments, p is 2. In certain embodiments, p is 3. In certain embodiments, p is 4.

[0224] As defined herein, w is 1, 2, 3, or 4. In certain embodiments, w is 1. In certain embodiments, w is 2. In certain embodiments, w is 3. In certain embodiments, w is 4

[0225] As defined herein, v1 is 0 or 1. In certain embodiments, v1 is 0. In certain embodiments, v1 is 1. As defined herein, v2 is 0 or 1. In certain embodiments, v2 is 0. In certain embodiments, v2 is 1. R4, R6, and r

[0226] As defined herein, each instance of R4is independently hydrogen, halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl. In certain embodiments, at least one instance of R4is hydrogen. In certain embodiments, each instance of R4is hydrogen. In certain embodiments, at least one instance of R4is halogen. In certain embodiments, at least one instance of R4is –CN. In certain embodiments, at least one instance of R4is –NO2. In certain embodiments, at least one instance of R4is – N3. In certain embodiments, at least one instance of R4is –SCN. In certain embodiments, at least one instance of R4is –ORO. In certain embodiments, at least one instance of R4is –SRS. In certain embodiments, at least one instance of R4is optionally substituted alkyl. In certain embodiments, at least one instance of R4is optionally substituted alkenyl. In certain embodiments, at least one instance of R4is optionally substituted alkynyl. In certain embodiments, at least one instance of R4is optionally substituted carbocyclyl. In certain embodiments, at least one instance of R4is optionally substituted heterocyclyl. In certain embodiments, at least one instance of R4is optionally substituted aryl. In certain embodiments, at least one instance of R4is optionally substituted heteroaryl. In certain embodiments, at least one instance of R4is optionally substituted acyl. In certain embodiments, at least one instance of R4is optionally substituted sulfinyl. In certain embodiments, at least one instance of R4is optionally substituted sulfonyl.

[0227] In certain embodiments, at least one instance of R4is –N(RN)2. In certain embodiments, at least one instance of R4is –NH2.

[0228] As defined herein, each instance of R6is independently hydrogen, optionally substituted alkyl, halogen, –CN, –ORO, –N(RN3)2, or –SRS; or wherein two R6on the same carbon atom are taken together to form =O. In certain embodiments, at least one instance of R6is hydrogen. In certain embodiments, at least one instance of R6is optionally substituted alkyl. In certain embodiments, at least one instance of R6is halogen. In certain embodiments, at least one instance of R6is –CN. In certain embodiments, at least one instance of R6is –ORO. In certain embodiments, at least one instance of R6is or –SRS. In certain embodiments, two R6on the same carbon atom are taken together to form =O. In certain embodiments, at least one instance of R6is –N(RN3)2. In certain embodiments, at least one instance of R6is: . In certain embodiments, one instance of R6is –N(RN3)2. In certain embodiments, one instance of R6is: . In certain embodiments, at least one instance of R6is: . In certain embodiments, one instance of R6is: .

[0229] As defined herein, r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, as valency permits. In certain embodiments, r is 0. In certain embodiments, r is 1. In certain embodiments, r is 2. In certain embodiments, r is 3. In certain embodiments, r is 4. In certain embodiments, r is 5. In certain embodiments, r is 6. In certain embodiments, r is 7. In certain embodiments, r is 8. In certain embodiments, r is 8. In certain embodiments, r is 10. In certain embodiments, r is 11. In certain embodiments, r is 12. RN, RN1, RN2, RN3, RO, and RS

[0230] As defined herein, each instance of RNis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, optionally substituted sulfonyl, or a nitrogen protecting group; or two RNbonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl. In certain embodiments, at least one instance of RNis hydrogen. In certain embodiments, at least one instance of RNis optionally substituted alkyl. In certain embodiments, at least one instance of RNis optionally substituted alkenyl. In certain embodiments, at least one instance of RNis optionally substituted alkynyl. In certain embodiments, at least one instance of RNis optionally substituted carbocyclyl. In certain embodiments, at least one instance of RNis optionally substituted heterocyclyl. In certain embodiments, at least one instance of RNis optionally substituted aryl. In certain embodiments, at least one instance of RNis optionally substituted heteroaryl. In certain embodiments, at least one instance of RNis optionally substituted acyl. In certain embodiments, at least one instance of RNis optionally substituted sulfinyl. In certain embodiments, at least one instance of RNis optionally substituted sulfonyl. In certain embodiments, at least one instance of RNis a nitrogen protecting group. In certain embodiments, two RNbonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, two RNbonded to the same nitrogen atom are joined together with the intervening atoms to form or optionally substituted heteroaryl.

[0231] As defined herein, each instance of RN1is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, optionally substituted sulfonyl, or a nitrogen protecting group. In certain embodiments, at least one instance of RN1is hydrogen. In certain embodiments, at least one instance of RN1is optionally substituted alkyl. In certain embodiments, at least one instance of RN1is optionally substituted alkenyl. In certain embodiments, at least one instance of RN1is optionally substituted alkynyl. In certain embodiments, at least one instance of RN1is optionally substituted carbocyclyl. In certain embodiments, at least one instance of RN1is optionally substituted heterocyclyl. In certain embodiments, at least one instance of RN1is optionally substituted aryl. In certain embodiments, at least one instance of RN1is optionally substituted heteroaryl. In certain embodiments, at least one instance of RN1is optionally substituted acyl. In certain embodiments, at least one instance of RN1is optionally substituted sulfinyl. In certain embodiments, at least one instance of RN1is optionally substituted sulfonyl. In certain embodiments, at least one instance of RN1is a nitrogen protecting group.

[0232] As defined herein, RN2is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, optionally substituted sulfonyl, or a nitrogen protecting group. In certain embodiments, RN2is hydrogen. In certain embodiments, RN2is optionally substituted alkyl. In certain embodiments, RN2is optionally substituted alkenyl. In certain embodiments, RN2is optionally substituted alkynyl. In certain embodiments, RN2is optionally substituted carbocyclyl. In certain embodiments, RN2is optionally substituted heterocyclyl. In certain embodiments, RN2is optionally substituted aryl. In certain embodiments, RN2is optionally substituted heteroaryl. In certain embodiments, RN2is optionally substituted acyl. In certain embodiments, RN2is optionally substituted sulfinyl. In certain embodiments, RN2is optionally substituted sulfonyl. In certain embodiments, RN2is a nitrogen protecting group.

[0233] As defined herein, each instance of RN3is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, optionally substituted sulfonyl, or a nitrogen protecting group; or two RN3bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl. In certain embodiments, at least one instance of RN3is hydrogen. In certain embodiments, at least one instance of RN3is optionally substituted alkyl. In certain embodiments, at least one instance of RN3is optionally substituted C1-6alkyl. In certain embodiments, at least one instance of RN3is optionally substituted alkenyl. In certain embodiments, at least one instance of RN3is optionally substituted alkynyl. In certain embodiments, at least one instance of RN3is optionally substituted carbocyclyl. In certain embodiments, at least one instance of RN3is optionally substituted heterocyclyl. In certain embodiments, at least one instance of RN3is optionally substituted aryl. In certain embodiments, at least one instance of RN3is optionally substituted heteroaryl. In certain embodiments, at least one instance of RN3is optionally substituted acyl. In certain embodiments, at least one instance of RN3is optionally substituted sulfinyl. In certain embodiments, at least one instance of RN3is optionally substituted sulfonyl. In certain embodiments, at least one instance of RN3is a nitrogen protecting group. In certain embodiments, two RN3bonded to the same nitrogen atom are joined together with the intervening atoms to form or optionally substituted heteroaryl.

[0234] In certain embodiments, at least one instance of RN3is optionally substituted C1-6 alkyl. In certain embodiments, at least one instance of RN3is unsubstituted C1-6 alkyl. In certain embodiments, at least one instance of RN3is methyl, ethyl, n-propyl, iso-propyl, iso-butyl, sec-butyl, or tert-butyl. In certain embodiments, at least one instance of RN3is hydrogen, methyl, or iso-propyl. In certain embodiments, each instance of RN3is methyl.

[0235] In certain embodiments, two RN3bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl. In certain embodiments, two RN3bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted 5- or 6-membered heterocyclyl. In certain embodiments, two RN3bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted 5- or 6-membered heterocyclyl containing 1 or 2 heteroatoms selected from O and N. In certain embodiments, two RN3bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted 5- membered heterocyclyl containing 1 or 2 heteroatoms selected from O and N. In certain embodiments, two RN3bonded to the same nitrogen atom are joined together with the intervening atoms to form: .

[0236] As defined herein, each instance of ROis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, at least one instance of ROis hydrogen. In certain embodiments, at least one instance of ROis optionally substituted alkyl. In certain embodiments, at least one instance of ROis optionally substituted alkenyl. In certain embodiments, at least one instance of ROis optionally substituted alkynyl. In certain embodiments, at least one instance of ROis optionally substituted carbocyclyl. In certain embodiments, at least one instance of ROis optionally substituted heterocyclyl. In certain embodiments, at least one instance of ROis optionally substituted aryl. In certain embodiments, at least one instance of ROis optionally substituted heteroaryl. In certain embodiments, at least one instance of ROis optionally substituted acyl. In certain embodiments, at least one instance of ROis an oxygen protecting group.

[0237] As defined herein, each instance of RSis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group. In certain embodiments, at least one instance of RSis hydrogen. In certain embodiments, at least one instance of RSis optionally substituted alkyl. In certain embodiments, at least one instance of RSis optionally substituted alkenyl. In certain embodiments, at least one instance of RSis optionally substituted alkynyl. In certain embodiments, at least one instance of RSis optionally substituted carbocyclyl. In certain embodiments, at least one instance of RSis optionally substituted heterocyclyl. In certain embodiments, at least one instance of RSis optionally substituted aryl. In certain embodiments, at least one instance of RSis optionally substituted heteroaryl. In certain embodiments, at least one instance of RSis optionally substituted acyl. In certain embodiments, at least one instance of RSis a sulfur protecting group. Pharmaceutical Compositions, Kits, and Administration

[0238] The present disclosure provides pharmaceutical compositions comprising a compound described herein (e.g., a compound of Formula (I), (IIʹ), (II), or (III), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof), and a pharmaceutically acceptable carrier or excipient. In certain embodiments, the compound described herein is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the effective amount is a prophylactically effective amount.

[0239] Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include bringing the compound described herein (i.e., the “active ingredient”) into association with a carrier or excipient, and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping, and / or packaging the product into a desired single- or multi-dose unit.

[0240] Pharmaceutical compositions can be prepared, packaged, and / or sold in bulk, as a single unit dose, and / or as a plurality of single unit doses. A “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and / or a convenient fraction of such a dosage, such as one-half or one-third of such a dosage.

[0241] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and / or any additional ingredients in a pharmaceutical composition described herein will vary, depending upon the identity, size, and / or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w / w) active ingredient.

[0242] Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and / or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

[0243] Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

[0244] Exemplary granulating and / or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross- linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

[0245] Exemplary surface active agents and / or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween®20), polyoxyethylene sorbitan (Tween®60), polyoxyethylene sorbitan monooleate (Tween®80), sorbitan monopalmitate (Span®40), sorbitan monostearate (Span®60), sorbitan tristearate (Span®65), glyceryl monooleate, sorbitan monooleate (Span®80), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj®45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol®), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor®), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij®30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic®F-68, poloxamer P-188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and / or mixtures thereof.

[0246] Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum®), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and / or mixtures thereof.

[0247] Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, antiprotozoan preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

[0248] Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

[0249] Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

[0250] Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

[0251] Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

[0252] Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

[0253] Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant®Plus, Phenonip®, methylparaben, Germall®115, Germaben®II, Neolone®, Kathon®, and Euxyl®.

[0254] Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer’s solution, ethyl alcohol, and mixtures thereof.

[0255] Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

[0256] Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

[0257] Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates described herein are mixed with solubilizing agents such as Cremophor®, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

[0258] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension, or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P., and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0259] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0260] In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution, which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the drug in an oil vehicle.

[0261] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate, (h) absorbents such as kaolin and bentonite clay, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets, and pills, the dosage form may include a buffering agent.

[0262] Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmacology. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

[0263] The active ingredient can be in a micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating agents which can be used include polymeric substances and waxes.

[0264] Dosage forms for topical and / or transdermal administration of a compound described herein may include ointments, pastes, creams, lotions, gels, foams, powders, solutions, sprays, inhalants, and / or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and / or any needed preservatives and / or buffers as can be required. Additionally, the present disclosure contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and / or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and / or by dispersing the active ingredient in a polymer matrix and / or gel.

[0265] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid formulations to the dermis via a liquid jet injector and / or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable. Ballistic powder / particle delivery devices which use compressed gas to accelerate the compound in powder form through the outer layers of the skin to the dermis are suitable.

[0266] Formulations suitable for topical administration include, but are not limited to, liquid and / or semi- liquid preparations such as liniments, lotions, oil-in-water and / or water-in-oil emulsions such as creams, ointments, and / or pastes, and / or solutions and / or suspensions. A formulation suitable for topical administration may be in the form of a gel or foam. Topically administrable formulations may, for example, comprise from about 1% to about 10% (w / w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

[0267] A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and / or using a self-propelling solvent / powder dispensing container such as a device comprising the active ingredient dissolved and / or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[0268] Low boiling propellants generally include liquid propellants having a boiling point of below 65 °F at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w / w) of the composition, and the active ingredient may constitute 0.1 to 20% (w / w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and / or solid anionic surfactant and / or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

[0269] Pharmaceutical compositions described herein formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and / or suspension. Such formulations can be prepared, packaged, and / or sold as aqueous and / or dilute alcoholic solutions and / or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and / or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and / or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

[0270] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition described herein. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder held close to the nares.

[0271] Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w / w) to as much as 100% (w / w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation for buccal administration. Such formulations may, for example, be in the form of tablets and / or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w / w) active ingredient, the balance comprising an orally dissolvable and / or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations for buccal administration may comprise a powder and / or an aerosolized and / or atomized solution and / or suspension comprising the active ingredient. Such powdered, aerosolized, and / or aerosolized formulations, when dispersed, may have an average particle and / or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

[0272] A pharmaceutical composition described herein can be prepared, packaged, and / or sold in a formulation for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1-1.0% (w / w) solution and / or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient. Such drops may further comprise buffering agents, salts, and / or one or more other of the additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and / or in a liposomal preparation. Ear drops and / or eye drops are also contemplated as being within the scope of this disclosure.

[0273] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates described herein with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

[0274] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and / or perform such modification with ordinary experimentation.

[0275] Compounds and compositions provided herein are typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions described herein will be decided by a physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject or organism will depend upon a variety of factors including the disease being treated and the severity of the disorder; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex, and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

[0276] The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, intradermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and / or drops), ocular, mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and / or inhalation; and / or as an oral spray, nasal spray, and / or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and / or lymph supply, and / or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and / or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).

[0277] The exact amount of a compound or composition required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell.

[0278] In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 µg and 1 µg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.

[0279] Dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

[0280] A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents (e.g., therapeutically and / or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their activity (e.g., activity (e.g., potency and / or efficacy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, in reducing the risk to develop a disease in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and / or modify metabolism, inhibit excretion, and / or modify distribution in a subject or cell. It will also be appreciated that the therapy employed may achieve a desired effect for the same disorder, and / or it may achieve different effects. In certain embodiments, a pharmaceutical composition described herein including a compound described herein and an additional pharmaceutical agent shows a synergistic effect that is absent in a pharmaceutical composition including one of the compounds and the additional pharmaceutical agent, but not both.

[0281] The compound or pharmaceutical composition thereof 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.

[0282] In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and / or preventing a disease or condition. 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.

[0283] The additional pharmaceutical agents include, but are not limited to, anti-proliferative agents, anti- cancer agents, anti-angiogenesis agents, anti-inflammatory agents, immunosuppressants, anti-bacterial agents, anti-viral agents, cardiovascular agents, cholesterol-lowering agents, anti-diabetic agents, anti- allergic agents, contraceptive agents, and pain-relieving agents.

[0284] Also encompassed by the disclosure are kits (e.g., pharmaceutical packs). The kits provided may comprise a compound or pharmaceutical composition 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 disease or condition (e.g., viral infection) in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease or condition (e.g., viral infection) in a subject.

[0285] 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. A kit described herein may include one or more additional pharmaceutical agents described herein as a separate composition. Methods of Treatment and Uses

[0286] Provided herein are methods of treating and / or preventing an infectious disease (e.g., a viral infection) in a subject comprising administering to the subject 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 thereof. Also provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in treating and / or preventing an infectious disease (e.g., a viral infection) in a subject. Also provided herein are uses of compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for treating and / or preventing an infectious disease (e.g., a viral infection) in a subject.

[0287] Provided herein are methods of treating and / or preventing an infectious disease (e.g., a viral infection) in a subject comprising administering to the subject an effective amount of a compound of Formula (IIʹ) or (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. Also provided herein are compounds of Formula (IIʹ) or (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in treating and / or preventing an infectious disease (e.g., a viral infection) in a subject. Also provided herein are uses of compounds of Formula (IIʹ) or (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for treating and / or preventing an infectious disease (e.g., a viral infection) in a subject.

[0288] Provided herein are methods of treating and / or preventing an infectious disease (e.g., a viral infection) in a subject comprising administering to the subject an effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. Also provided herein are compounds of Formula (III), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in treating and / or preventing an infectious disease (e.g., a viral infection) in a subject. Also provided herein are uses of compounds of Formula (III), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for treating and / or preventing an infectious disease (e.g., a viral infection) in a subject.

[0289] In certain embodiments, the infectious disease is a viral infection. Viral infections include, but are not limited to, infections with any of the viruses described herein. In certain embodiments, the viral infection is caused by a coronavirus. In certain embodiments, the viral infection is caused by a SARS coronavirus. In certain embodiments, the viral infection is caused by a SARS-CoV-2 virus or variant thereof. In certain embodiments, the viral infection is COVID-19. The SARS-CoV-2 variant may be an existing variant (e.g., Alpha variant, Beta variant, Delta variant, Gamma variant, Omicron variant), subvariant, or future variant. In certain embodiments, the SARS-CoV-2 variant is an Omicron subvariant (e.g., BA.2, BA.2.12, BA.2.12.1, BA.3, BA.4, BA.5).

[0290] Provided herein are methods of treating and / or preventing COVID-19 in a subject, the methods comprising administering to the subject 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 thereof. Also provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in treating and / or preventing COVID-19 in a subject. Also provided herein are uses of compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for treating and / or preventing COVID-19.

[0291] Provided herein are methods of treating and / or preventing COVID-19 in a subject, the methods comprising administering to the subject an effective amount of a compound of Formula (IIʹ) or (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. Also provided herein are compounds of Formula (IIʹ) or (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in treating and / or preventing COVID-19 in a subject. Also provided herein are uses of compounds of Formula (IIʹ) or (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for treating and / or preventing COVID-19.

[0292] Provided herein are methods of treating and / or preventing COVID-19 in a subject, the methods comprising administering to the subject an effective amount of a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. Also provided herein are compounds of Formula (III), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in treating and / or preventing COVID-19 in a subject. Also provided herein are uses of compounds of Formula (III), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for the manufacture of medicaments for treating and / or preventing COVID-19.

[0293] Also provided herein are methods for inhibiting viral replication in a cell comprising contacting the cell with 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 thereof. Also provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in inhibiting viral replication in a cell. Also provided herein are uses of compounds of Formula (I), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for the manufacture of a medicament capable of inhibiting viral replication in a cell.

[0294] Also provided herein are methods for inhibiting viral replication in a cell comprising contacting the cell with a compound of Formula (IIʹ) or (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. Also provided herein are compounds of Formula (IIʹ) or (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in inhibiting viral replication in a cell. Also provided herein are uses of compounds of Formula (IIʹ) or (II), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for the manufacture of a medicament capable of inhibiting viral replication in a cell.

[0295] Also provided herein are methods for inhibiting viral replication in a cell comprising contacting the cell with a compound of Formula (III), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, or a pharmaceutical composition thereof. Also provided herein are compounds of Formula (III), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for use in inhibiting viral replication in a cell. Also provided herein are uses of compounds of Formula (III), and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof, and pharmaceutical compositions thereof, for the manufacture of a medicament capable of inhibiting viral replication in a cell.

[0296] In certain embodiments, the inhibiting occurs in vivo in a subject (i.e., the cell is contacted in vivo). In certain embodiments, the inhibiting occurs in vitro (e.g., in an assay, cell line, or biological sample). The virus may be any virus described herein. In certain embodiments, the virus is a coronavirus. In certain embodiments, the virus is a SARS coronavirus. In certain embodiments, the virus is a SARS-CoV-2 virus or variant thereof. The SARS-CoV-2 variant may be an existing variant (e.g., Alpha variant, Beta variant, Delta variant, Gamma variant, Omicron variant) or a future variant. In certain embodiments, the SARS- CoV-2 variant is an Omicron subvariant (e.g., BA.2, BA.2.12, BA.2.12.1, BA.3, BA.4, BA.5).

[0297] In certain embodiments, a compound provided herein is capable of inhibiting viral replication in a cell without significantly inhibiting AXL receptor kinase activity. In certain embodiments, a compound provided herein does not inhibit AXL receptor tyrosine kinase activity. In certain embodiments, a compound provided herein shows reduced inhibition of AXL receptor tyrosine kinase activity compared to bemcentinib. For example, in certain embodiments, a compound provided herein shows a reduction in inhibition of AXL receptor tyrosine kinase activity by about 10% or more, about 20% or more, about 30% or more, about 40% or more, about 50% or more, about 60% or more, about 70% or more, about 80% or more, about 90% or more, about 95% or more, about 98% or more, or about 99% or more, compared to bemcentinib. EXAMPLESExample 1: Synthesis of Compounds

[0298] As used herein the following terms have the meanings given: “DMF” refers to N,N - dimethylformamide; “EtOAc” refers to ethyl acetate; “DCM” refers to dichloromethane; “DMSO” refers to dimethylsulfoxide; “THF” refers to tetrahydrofuran; “2-MeTHF” refers to 2-methyltetrahydrofuran; “MeOH” refers to methanol; “EtOH” refers to ethanol; “MeCN” refers to acetonitrile; “DIPEA” or “DIEA” refers to N,N-diisopropylethylamine; “TEA” refers to trimethylamine; “Py” refers to pyridine; “t- BuOK” refers to potassium tert-butoxide; “KOAc” refers to potassium acetate; “n-BuLi” refers to n- butyllithium; “TFA” refers to trifluoroacetic acid, “FA” refers to formic acid; “Ac2O” refers to acetic anhydride; “DHP” refers to 3,4-dihydro-2H-pyran; “NCS” refers to 1-chloropyrrolidine-2,5-dione; “MeI” refers to methyl iodide; “Fe” refers to iron powder; “TosCl” refers to paratoluensulfonyl chloride; “HATU” refers to 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate; “EDCI” refers to 1-ethyl-3-(3-dimethylamino-propyl)-carbodiimide hydrochloride; “PyBOP” refers to Benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluoroph; “Xantphos” refers to 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; “Pd2dba3” refers to Tris(dibenzylideneacetone)dipalladium; “Pd(PPh3)4” refers to Tetrakis(triphenylphosphine)palladium; “Pd(dppf)Cl2” refers to [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II); “HPLC” refers to high performance liquid chromatography; “LCMS” or “LC-MS” refers to liquid chromatography / mass spectrometry; “min” refers to minute; “Pet. Ether” refers to Pet. Ether; “TLC” refers to thin layer chromatography; “Rf refers to Retention factor; “RT” refers to retention time,; “r.t.” refers to room temperature.

[0299] Solvents, reagents and starting materials were purchased from commercial vendors and used as received unless otherwise described. All reactions were performed at r.t. unless otherwise stated.

[0300] Compound identity and purity confirmations were performed by LCMS UV using a SHIMADZU LCMS-2020. The PDA wavelength was 220&254 nM and the MS was in positive electrospray mode (m / z: 100-1000). The aliquot was injected onto a HPLC column (Kinetex® EVO C182.1x30 mm, 2.6 um) in sequence maintained at 50 °C. The samples were eluted at a flow rate of 1.5 mL / min with a mobile phase system composed of A (0.0375% (v / v) TFA in water) and B (0.01875% (v / v) TFA in Acetonitrile) according to the gradients outlined in Table 1 below. Retention times (RT) are reported in min. Table 1

[0301] Compound identity and purity confirmations were performed by LCMS UV using a SHIMADZU LCMS-2020. The PDA wavelength was 220&254 nM and the MS was in positive electrospray mode (m / z: 100-1000). The aliquot was injected onto a HPLC column (XBridge C182.1x50 mm, 5 um) in sequence maintained at 40 °C. The samples were eluted at a flow rate of 1.5-2.0 mL / min with a mobile phase system composed of A (0.025% (v / v) NH3•H2O in water) and B (Acetonitrile) according to the gradients outlined in Table 2 below. Retention times RT are reported in min. Table 2

[0302] Compound identity and purity confirmations were performed by LCMS UV using a Agilent 1260\G6125B. The DAD wavelength was 220&254 nM and the MS was in positive electrospray mode (m / z: 100-1000). The aliquot was injected onto a HPLC column (XBridge C182.1x50 mm, 5 um) in sequence maintained at 40 °C. The samples were eluted at a flow rate of 1.5-2.0 mL / min with a mobile phase system composed of A (0.025% (v / v) NH3•H2O in water) and B (Acetonitrile) according to the gradients outlined in Table 3 below. Retention times RT are reported in min. Table 3

[0303] NMR was also used to characterize final compounds.1H NMR spectra were obtained at r.t., unless otherwise stated, on a Bruker AVANCE III 400 with a 5 mm BBO probe with Z gradients, a Bruker AVANCE III HD 400 with a 5 mm BBO probe with Z gradients, a Bruker AVANCE NEO 400 with either a 5 mm BBO probe or 5 mm BBO prodigy cryoprobe with Z gradients, a Bruker NEO NANOBAY 400 with either a 5 mm BBO probe or 5 mm BBO iProbe with Z gradients. Chemical shifts are reported in ppm and referenced to either DMSO-d6 (2.50 ppm), CDCl3 (7.26 ppm), or MeOD-d4 (3.31 ppm). NH or OH signals that exchange with deuterated solvent are not reported.

[0304] Optionally, compound Rf values on silica thin Iayer chromatography (TLC) plates were measured.

[0305] Compound purification was performed by flash column chromatography on silica or by preparative HPLC. HPLC purification was performed using either Gilson-281 or Shimadzu LC-20AP in positive electrospray mode (m / z: 100-1000) with a Shimadzu SPD-20A. Samples were eluted at a flow rate of 25 mL / min on a Phenomenex Luna C18150x25 mmx10 um column with a mobile phase system composed of: 1. Basic conditions: A (0.05% ammonia (v / v) in H2O) and B (Acetonitrile), 2. TFA conditions: A (0.075% TFA (v / v) in H2O and B (Acetonitrile), 3. A (0.225% FA (v / v) in H2O and B (Acetonitrile), 4. HCl conditions: A (0.05% HCl (v / v) in H2O and B (Acetonitrile), 5. Neutral conditions: A (H2O) and B (Acetonitrile) or A (10 mmol NH4•HCO3) in H2O and B (Acetonitrile) according to the different linear gradient for samples. General route for the synthesis of Intermediate 1-2:

[0306] To a mixture of 6, 7,8,9-tetrahydrobenzo[7]annulen-5-one (25 g, 156.04 mmol, 23.36 mL, 1 eq) in THF (150 mL) was added HMPA (33.56 g, 187.25 mmol, 32.90 mL, 1.2 eq), 1.0M solution of LiHMDS (1 M, 156.04 mL) was added, the reaction mixture was stirred an 0 °C for 30 min, then ethyl 2- bromoacetate (62.54 g, 374.50 mmol, 41.42 mL) added in one portion, the reaction mixture was stirred at 25 °C for 2 hr. The reaction mixture was poured into the saturated solution of NH4Cl (1000 mL), extracted with Ethyl acetate (300 mL x 2). The combined organic layers were washed with brine (300 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography eluting with 0-10% EtOAc in Pet. Ether to give ethyl 2-(5- oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)acetate (34 g, 138.04 mmol, 44.23% yield) as a yellow oil.

[0307] To the solution of ethyl 2-(5-oxo-6,7,8,9-tetrahydrobenzo[7]annulen-6-yl)acetate (31 g, 125.86 mmol) in EtOH (200 mL) and H2O (100 mL) was added KOH (21.18 g, 377.59 mmol) the reacction was stirred at 80 °C for 2 hr. The reaction mixture was poured into water (500 ml), extracted with ethyl acetate (200 mL x 2). The aqueous phase was adjust to pH = 2 with 1 N HCl and Ethyl acetate (200 mL x 2). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrated. The mixture was filtered to give 2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6- yl)acetic acid (26 g, 119.13 mmol, 94.65% yield) as a yellow solid.

[0308] To a mixture of 2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)acetic acid (26 g, 119.13 mmol) in EtOH (120 mL)was added N2H4.H2O (7.79 g, 152.49 mmol, 7.56 mL, 98% purity), then the mixture was stirred at 80 °C for 2 hr. The reacation mixture was cooled to 25 °C , a lot of solid was formed , the solid was collented by filtertion. The reaction mixture was filtered to give phenyl 4a,5,6,7- tetrahydro-2H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3(4H)-one (16.8 g, 78.41 mmol, 65.82% yield) as a white solid. LC-MS (ES+, Method A), 0.366 min, m / z 215.2 [M+H]+.

[0309] To a mixture of 4a,5,6,7-tetrahydro-2H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3(4H)-one (16.8 g, 78.41 mmol) in MeCN (168 mL) was added CuCl2 (21.08 g, 156.82 mmol), then the mixture was stirred at 80 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The mixture was filtered through sodium silicate , the filtrate was concentrated to give 6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazin-3-ol (11 g, 51.83 mmol, 66.10% yield). LC-MS (ES+, Method A), 0.35 min, m / z 213.3 [M+H]+.

[0310] A mixture of 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-ol (11 g, 51.83 mmol, 1 eq) in POCl3(74.25 g, 484.24 mmol, 45.00 mL) was stirred at 100 °C for 2 hr. The reacation mixture was dropwise into water (700 mL), extracted with Ethyl acetate (300 mL x 2). The combined organic layers were washed with brine (200 mL x 2), dried over Na2SO4, filtered and concentrated. The reaction solution was filtered and the filter to give phenyl 3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (11 g, 47.68 mmol, 92.0% yield) as a brown solid. LC-MS (ES+, Method A), 0.42 min, m / z 231.2 [M+H]+.

[0311] To a mixture of 3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (1 g, 4.33 mmol) in toluene (10 mL) was added Pd(PPh3)4(500.91 mg, 433.48 umol), tributyl(1- ethoxyvinyl)stannane (3.09 g, 8.56 mmol) at 20°C, then the mixture was stirred at 110 °C for 4 hr under N2. The reaction was pour into 1M HCl (50mL) solution to stirred 1h. The reaction mixture was quenched by addition saturared KF aqueous solution 70 mL and stirred for 1hr, the aqueous phase was extracted with EtOAc (60 mL x 3). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography eluting with 0-15% EtOAc in Pet. Ether to give 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin- 3-yl)ethanone (700 mg, 2.94 mmol, 67.77% yield) as yellow oil. LC-MS (ES+, Method A), 0.43 min, m / z 239.1 [M+H]+General route for the of Intermediate 3:

[0312] To a solution of 3-chloro-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (11 g, 47.68 mmol) in EtOH (110 mL) was added Pd(dppf)Cl2(3.49 g, 4.77 mmol) and TEA (9.65 g, 95.37 mmol, 13.27 mL). The mixture was stirred at 80°C for 12 h under CO (50 psi) atmosphere. The mixture was filtered, the filtrate was concentrated The residue was purified by flash silica gel chromatography eluting with 0-35% EtOAc in Pet. Ether to give ethyl 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3- carboxylate (7 g, 26.09 mmol, 54.71% yield) as a yellow oil. LC-MS (ES+, Method A), 0.464 min, m / z 269.1 [M+H]+.

[0313] To a solution of ethyl 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-carboxylate (7 g, 26.09 mmol, 1 eq) in MeOH (100 mL) was added N2H4.H2O (6.66 g, 130.45 mmol, 6.47 mL, 98% purity). The mixture was stirred at 68 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to remove solvent. The residue was diluted with water (100 mL) and extracted with EA (50 mL x 3). The combined organic layers were washed with brine (50 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The reaction solution was filtered and the filter to give 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-carbohydrazide (6 g, 23.60 mmol, 90.44% yield) as a yellow solid. LC-MS (ES+, Method A), 0.357 min, m / z 255.1 [M+H]+. General route for the synthesis of Intermediates 4-7:

[0002]

[0314] To a solution of cold H2SO4 (11.51 g, 117.34 mmol) was added HNO3 (8.75 g, 138.88 mmol) dropwise over 30 min. then the resulting solution was added dropwise to a solution of 5,6,8,9- tetrahydrobenzo[7]annulen-7-one (5 g, 31.21 mmol) in CH3NO2 (30 mL) at 0 °C for 40 min. After the addition, the reaction mixture was stirred at 0 °C for 2 h. The cold water (200 mL) was added to the reaction mixture, and the mixture was stirred for additional 20 min. The reaction mixture was extracted with EtOAc (200mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography eluting with 0-50% EtOAc in pet. ether to give yellow solid. The solid was triturated with MTBE (40 mL) at 50°C for 3 h to give 3-nitro-5,6,8,9-tetrahydrobenzo[7]annulen-7-one (4.8 g, 23.39 mmol, 24.98% yield) as a yellow solid

[0315] To a mixture of 3-nitro-5,6,8,9-tetrahydrobenzo[7]annulen-7-one (3 g, 14.62 mmol), pyrrolidine (1.25 g, 17.54 mmol) and NaBH(OAc)3(4.65 g, 21.93 mmol) in DCE (108 mL) was added AcOH (877.91 mg, 14.62 mmol), the mixture was degassed and purged with N2, and then the mixture was stirred at 25 °C for 11 h under N2. The reaction mixture was quenched with saturated NaHCO3, and the product was extracted with EtOAc (200 ml x 3), the organic layers were combined and dried over Na2SO4, filtered and concentrated under reduced pressure to give 1-(3-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7- yl)pyrrolidine (3.6 g, 13.83 mmol, 94.59% yield) as a yellow oil. Intermediate 4: 7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-amine

[0316] To a mixture of 1-(3-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)pyrrolidine (3.6 g, 13.83 mmol) in MeOH (108 mL) was added Pd / C (1.2 g, 13.83 mmol, 10% purity), the mixture was stirred at 25 °C for 16 h under H2 (40Psi). The reaction mixture was filtered and the mother solution was concentrated under reduced pressure to give 7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-amine (3.15 g, 13.67 mmol, 98.89% yield) as a yellow oil.

[0317] To a solution of 7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-amine (5.5 g, 23.88 mmol, 1 eq), NaHCO3 (4.01 g, 47.75 mmol, 1.86 mL) in THF (30 mL) and H2O (30 mL) was added phenyl carbonochloridate (3.74 g, 23.88 mmol, 2.99 mL). The mixture was stirred at 0 °C for 0.5 hr. The reaction mixture was poured into water (300 mL), extracted with Ethyl acetate (200 mL x 3). The combined organic layers were washed with brine (100 mL x 2), dried over Na2SO4, filtered and concentrated. The reaction solution was filtered and the filter to give phenyl N-(7-pyrrolidin-1-yl-6,7,8,9- tetrahydro-5H-benzo[7]annulen-3-yl)carbamate (8 g, 22.83 mmol, 95.61% yield) as a yellow solid. LC- MS (ES+, Method A), 0.49 min, m / z 351.3 [M+H]+.

[0318] To a solution of 7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-amine (500 mg, 2.17 mmol) in DCM (10 mL) was added 1-(2-oxopyridine-1-carbothioyl)pyridin-2-one (504.15 mg, 2.17 mmol). The mixture was stirred at 20 °C for 1h. The reaction mixture was poured into water (30 mL), extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated to give 1-(3-isothiocyanato-6,7,8,9-tetrahydro-5H- benzo[7]annulen-7-yl)pyrrolidine (590 mg, 2.17 mmol, 99.78% yield) as brown solid. LC-MS (ES+, Method A), 0.37 min, m / z 273.1 [M+H]+.

[0319] To a solution of 1-(3-isothiocyanato-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)pyrrolidine (590 mg, 2.17 mmol) in MeCN (10 mL) was added NH3.H2O (113.86 mg, 909.69 umol, 28% purity). The mixture was stirred at 20 °C for 16 hr. The reaction mixture was concentrated under reduced pressure to remove solvent to give 1-(7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl)thiourea (590 mg, 2.04 mmol, 94.12% yield) as yellow solid. General route for the of Intermediate 8:

[0320] A mixture of 3-chloro-6-phenyl-pyridazine (2 g, 10.49 mmol), Pd(dppf)Cl2 (685.32 mg, 839.20 umol) and Et3N (5.31 g, 52.45 mmol, 7.30 mL, 5 eq) in DMF (5 mL) and MeOH (20 mL) was degassed and purged with N2for 3 times, and then the mixture was stirred at 80 °C for 16 hr under CO (40 psi) atmosphere. The mixture was filtered, the filtrate was concentrated. The residue was triturated with MeOH (10 mL) and filtered to give methyl 6-phenylpyridazine-3-carboxylate (1.66 g, 7.75 mmol, 73.87% yield) as a brown solid. LC-MS (ES+, Method A), 0.39 min, m / z 215.2 [M+H]+. General route for the synthesis of Intermediate 9:

[0321] To a solution of 2,3,4,5-tetrahydro-1H-3-benzazepine (2 g, 13.59 mmol) in TFA (12.39 g, 108.68 mmol, 8.05 mL) and concentrated H2SO4 (5.33 g, 54.34 mmol, 2.90 mL), cooled to 0 °C, was added HNO3 (2.630 g, 27.13 mmol, 1.88 mL, 65% purity) dropwisely. The mixture was stirred at 25 °C for 2 hr. The reaction mixture was poured into ice-water (30 mL), basified pH to 10 with 5 N NaOH, and extracted with EtOAc (30 mL x 3). The organic layer was washed brine (30 mL), dried over Na2SO4, filtered, and concentrated to give 7-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine (2.05 g, 10.67 mmol, 78.50% yield) as a yellow solid. LC-MS (ES+, Method A), 0.19 min, m / z 193.1 [M+H]+.

[0322] To a solution of 7-nitro-2,3,4,5-tetrahydro-1H-3-benzazepine (2.05 g, 10.67 mmol) in DCM (20 mL) was added Boc2O (3.49 g, 16.00 mmol, 3.68 mL). The mixture was stirred at 25 °C for 2 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with 0-9% EtOAc in Pet. Ether to give tert-butyl 7-nitro-1,2,4,5-tetrahydro-3- benzazepine-3-carboxylate (1.25 g, 4.28 mmol, 40.13% yield) as a white solid. LC-MS (ES+, Method A), 0.58 min, m / z 237.0 [M+H]+.

[0323] To a solution of tert-butyl 7-nitro-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylate (1.25 g, 4.28 mmol) in MeOH (10 mL) was added Pd / C (125 mg, 427.60 umol, 10% purity) under N2atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 25 °C for 24 hr. The reaction mixture was filtered and concentrated under reduced pressure to give tert-butyl 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylate (1.1 g, 4.19 mmol, 98.06% yield) as a pink oil. LC-MS (ES+, Method A), 0.32 min, m / z 285.2 [M+Na]+.

[0324] To a solution of tert-butyl 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylate (1.1 g, 4.19 mmol) in DCM (10 mL) was added DIEA (1.08 g, 8.39 mmol, 1.46 mL) and phenyl carbonochloridate (722.12 mg, 4.61 mmol, 577.69 uL). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography eluting with 0-17% EtOAc in pet. ether to give tert-butyl 7-(phenoxycarbonylamino)- 1,2,4,5-tetrahydro-3-benzazepine-3-carboxylate (500 mg, 1.31 mmol, 31.18% yield) as a white solid. LC- MS (ES+, Method A), 0.55 min, m / z 405.2 [M+Na]+. General route for the synthesis of Compound 1:

[0325] To a solution of 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-carbohydrazide (2.5 g, 9.83 mmol), phenyl N-(7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl)carbamate (3.79 g, 10.81 mmol, 1.1 eq) in dioxane (25 mL) was added DIEA (2.54 g, 19.66 mmol, 3.42 mL). The mixture was stirred at 80 °C for 16 hr. The reaction mixture was poured into water (30 mL), extracted with Ethyl acetate (20 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered and concentrated. The reaction solution was filtered and the filter to give 2-(6,7-dihydro- 5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-carbonyl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H- benzo[7]annulen-2-yl)hydrazinecarboxamide (5 g, 9.79 mmol, 99.60% yield) as a yellow solid. LC-MS (ES+, Method A), 0.45 min, m / z 511.5 [M+H]+.

[0326] To a solution of 2-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-carbonyl)-N-(7- (pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)hydrazinecarboxamide (5 g, 9.79 mmol) ,TEA (2.97 g, 29.38 mmol, 4.09 mL) in DMF (50 mL) was added TosCl (4.67 g, 24.48 mmol).The mixture was stirred at 20 °C for 1 hr . The mixture was filtered. The mixture was purified by preparative HPLC (12-42% MeCN in H2O) and preparative HPLC (39-69% MeCN in H2O) to give N-(1-(3- nitrophenyl)-1H-pyrazol-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-amine (2 g, 4.06 mmol, 41.46% yield) as a white solid. LC-MS (ES+, Method A), 0.49 min, m / z 493.5 [M+H]+Compound 1: (R)-5-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(7-(pyrrolidin-1-yl)- 6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1,3,4-oxadiazol-2-amine and (S)-5-(6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H- benzo[7]annulen-2-yl)-1,3,4-oxadiazol-2-amine

[0327] The mixture was separated by preparative SFC (column: DAICEL CHIRALPAK AD(250mmx30mm,10um); mobile phase:[ACN / EtOH(0.1%NH3H2O)];B%: 80%-80%,4;60min) to give (R)-5-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9- tetrahydro-5H-benzo[7]annulen-2-yl)-1,3,4-oxadiazol-2-amine (290 mg, 588.70 umol, 14.50% yield, peak 1) and (S)-5-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9- tetrahydro-5H-benzo[7]annulen-2-yl)-1,3,4-oxadiazol-2-amine (600 mg, 1.22 mmol, 30.00% yield, peak 2) as a yellow solid. (R)-5-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-

[0328] LC-MS (ES+, Method A), 0.49 min, m / z 493.5 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.32 (s, 1H), 7.81 (dd, J = 2.0, 7.2 Hz, 1H), 7.57 - 7.47 (m, 2H), 7.45 - 7.34 (m, 3H), 7.13 (d, J = 8.4 Hz, 1H), 2.98 - 2.98 (m, 1H), 2.97 - 2.97 (m, 1H), 3.08 - 2.88 (m, 2H), 2.65 - 2.59 (m, 4H), 2.55 (d, J = 5.2 Hz, 7H), 2.23 - 2.22 (m, 1H), 2.31 - 2.21 (m, 2H), 1.98 - 1.80 (m, 2H), 1.70 (s, 5H), 1.63 - 1.48 (m, 2H). SFC (Column: Chiralpak AD-350×4.6mm I.D., 3um, Mobile phase: Phase A for CO2, and Phase B for EtOH+CAN (0.05%DEA);Isocratic elution: 60% B in A, Flow rate: 3mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar, retention time: 0.608). (S)-5-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-

[0329] LC-MS (ES+, Method A), 0.49 min, m / z 493.5 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H), 8.32 (s, 1H), 7.84 - 7.77 (m, 1H), 7.51 (t, J = 4.8 Hz, 2H), 7.43 - 7.36 (m, 3H), 7.12 (d, J = 8.0 Hz, 1H), 3.03 - 2.90 (m, 2H), 2.65 - 2.59 (m, 3H), 2.55 (s, 8H), 2.30 - 2.24 (m, 2H), 1.87 (dd, J = 1.2, 6.8 Hz, 2H), 1.70 (s, 4H), 1.62 - 1.45 (m, 2H). SFC (Column: Chiralpak AD-350×4.6 mm I.D., 3 um, Mobile phase: Phase A for CO2, and Phase B for EtOH+CAN (0.05%DEA); Isocratic elution: 60% B in A Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar, retention time: 1.404). General route for the synthesis of Compound 2:

[0003]

[0330] To a solution of 1-(2-isothiocyanato-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)pyrrolidine (4.4 g, 18.47 mmol) in 2-MeTHF (5 mL) was added NaH (3.69 g, 92.33 mmol, 60% purity) at 0 °C. The mixture was stirred at 25 °C for 1 hr. Then to the mixture was added 1-(3-isothiocyanato-6,7,8,9-tetrahydro-5H- benzo[7]annulen-7-yl)pyrrolidine (7.55 g, 27.70 mmol), the mixture was stirred at 25 °C for 1 hr, then CH3I (2.62 g, 18.47 mmol, 1.15 mL) was added to the the mixture, the mixture was stirred at 25 °C for 1 hr. The mixture was quenched by saturated NH4Cl (40 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude product. The residue was purified by flash silica gel chromatography eluting with 0-5% MeOH in DCM to give (Z)-1-(6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-3-(methylthio)-3-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H- benzo[7]annulen-2-yl)amino)prop-2-en-1-one (3.5 g, 6.67 mmol, 36.12% yield) as a brown solid. LC-MS (ES+, Method A), 0.45 min, m / z 525.2 [M+H]+. Step 2: 5-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-

[0331] To a solution of (Z)-1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-3-(methylthio)- 3-((7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)amino)prop-2-en-1-one (4.2 g, 8.00 mmol) in DMF (10 mL) was added NH2OH.HCl (2.78 g, 40.02 mmol). The mixture was stirred at 100 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography eluting with 0-5% MeOH in DCM to give 5-(6,7-dihydro- 5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H- benzo[7]annulen-2-yl)isoxazol-3-amine (1.3 g, 2.64 mmol, 33.04% yield) as a brown solid. LC-MS (ES+, Method A), 0.44 min, m / z 492.3 [M+H]+. Compound 2: (S)-5-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(7-(pyrrolidin-1-yl)- 6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)isoxazol-3-amine and (R)-5-(6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H- benzo[7]annulen-2-yl)isoxazol-3-amine

[0332] The residue was purified by prepative SFC (column: DAICEL CHIRALCEL OD(250 mm x 30 mm,10 um);mobile phase: [ACN / MeOH(0.1%NH3H2O)];B%: 50%-50%,7.8;180min) to give 5-(3,4- diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-5-yl)-N-[(7S)-7-pyrrolidin-1-yl-6,7,8,9- tetrahydro-5H-benzo[7]annulen-3-yl]isoxazol-3-amine (140 mg, 276.23 umol, 12.35% yield, 97% purity, peak 1) as a yellow solid and 5-(3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-5-yl)-N- [(7R)-7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl]isoxazol-3-amine (232 mg, 443.59 umol, 19.83% yield, 94% purity, peak 2) as a yellow solid. (S)-5-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-

[0333] LC-MS (ES+, Method A), 0.42 min, m / z 492.2 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.09 (s, 1H), 7.85 - 7.75 (m, 1H), 7.57 - 7.44 (m, 2H), 7.41 - 7.34 (m, 1H), 7.27 - 7.16 (m, 2H), 7.04 (d, J = 8.0 Hz, 1H), 6.91 (s, 1H), 2.88 - 2.69 (m, 8H), 2.66 - 2.57 (m, 5H), 2.40 - 2.21 (m, 4H), 1.89 - 1.82 (m, 4H), 1.41 - 1.26 (m, 2H). SFC (Column: Chiralcel OD-350x4.6mm I.D., 3um, Mobile phase: Phase A for CO2, and Phase B for MeOH+CAN (0.05%DEA); Gradient elution: 40% MeOH+ACN (0.05% DEA) in CO2, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100Bar, retention time: 1.966). (R)-5-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-

[0334] LC-MS (ES+, Method A), 0.42 min, m / z 492.2 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.11 (s, 1H), 7.82 - 7.78 (m, 1H), 7.55 - 7.45 (m, 2H), 7.43 - 7.36 (m, 1H), 7.34 - 7.30 (m, 1H), 7.27 - 7.16 (m, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.92 (s, 1H), 3.69 - 3.40 (m, 5H), 2.92 - 2.87 (m, 4H), 2.68 - 2.64 (m, 2H), 2.63 - 2.58 (m, 2H), 2.51 - 2.44 (m, 2H), 2.37 - 2.33 (m, 2H), 2.07 (s, 4H), 1.58 - 1.50 (m, 2H). SFC (Column: Chiralcel OD-350x4.6mm I.D., 3um, Mobile phase: Phase A for CO2, and Phase B for MeOH+CAN (0.05%DEA); Gradient elution: 40% MeOH+ACN (0.05% DEA) in CO2, Flow rate: 3 mL / min; Detector: PDA; Column Temp: 35 °C; Back Pressure: 100 Bar, retention time: 3.377). General route for the of 3:

[0335] To a solution of 1-(3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-5-yl)ethanone (50 mg, 209.83 umol) in hydrogen bromide (154.35 mg, 629.50 umol, 33% purity) was added Br2 (36.89 mg, 230.82 umol). The mixture was stirred at 25 °C for 24h. The reaction mixture was poured into MTBE (2 mL), a lot ot gray solid was formed, the gray solid was collected by filtertion to give 2-bromo-1-(6,7- dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)ethanone (50 mg, 157.64 umol, 75.13% yield) as gray solid. Compound 3: 5-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(7-(pyrrolidin-1-yl)-

[0336] To a solution of 2-bromo-1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)ethanone (50 mg, 157.64 umol), (7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl)thiourea (45.63 mg, 157.64 umol) in EtOH (1 mL) was added DIEA (40.75 mg, 315.28 umol, 54.92 uL). The mixture was stirred at 80 °C for 16 h. The mixture was purified by preparative HPLC (22-52% MeCN in H2O) to give 5-(3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-5-yl)-N-(7-pyrrolidin-1-yl- 6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl)thiazol-2-amine (15.3 mg, 28.90 umol, 18.33% yield, 95.9% purity) as yellow solid. LC-MS (ES+, Method A), 0.41 min, m / z 508.3 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.54 (s, 1H), 8.16 (s, 1H), 7.80 - 7.76 (m, 1H), 7.71 (s, 1H), 7.54 (dd, J = 2.4, 8.0 Hz, 1H), 7.51 - 7.44 (m, 2H), 7.41 - 7.36 (m, 2H), 7.15 (d, J = 8.0 Hz, 1H), 3.14 ( m, 5H), 2.94 - 2.75 (m, 4H), 2.68 - 2.57 (m, 4H), 2.44 - 2.29 (m, 4H), 2.00 - 1.92 (m, 4H), 1.57 - 1.41 (m, 2H). General route for the of 4:

[0337] A solution of ethyl 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-carboxylate (500 mg, 1.86 mmol, 1 eq) in THF (20 mL) was cooled to -78 °C under N2 and DIBAL-H (1 M, 2.24 mL, 1.2 eq) was added dropwise in the reaction mixture and the mixture was stirred at -78 °C for 2 h. The mixture was quenched by (MeOH: H2O=1:1, 10 mL) and filtered. The filtrated was extracted with Ethyl acetate (50 mL x 3). The combined organic layer was washed with aq. sat. NaCl (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography eluting with 0-45% EtOAc in Pet. Ether to 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2- c]pyridazine-3-carbaldehyde (200 mg, 891.83 umol, 47.86% yield) as a colorless oil.

[0338] To a solution of 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-carbaldehyde (200 mg, 891.83 umol) in MeOH (3 mL), was added 1-(isocyanomethylsulfonyl)-4-methyl-benzene (191.53 mg, 981.02 umol) and K2CO3 (246.51 mg, 1.78 mmol). The mixture was stirred at 20 °C for 2 hr. The mixture was disolved in water (20 mL) and extracted with Ethyl acetate (30 mL x 3). The combined organic layer was washed with aq. sat. NaCl (20 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give 5-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)oxazole (200 mg, 759.61 umol, 85.17% yield) was obtained as a yellow solid.

[0339] To a solution of 5-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)oxazole (50 mg, 189.90 umol) in THF (1.5 mL) was cooled -78°C under N2. Then LDA (2.5 M, 113.94 uL) was added dropwise into the mixture at -78 °C and then the mixture was stirred at -78 °C for 0.5 h. Then a solution of 1,1,1,2,2,2-hexachloroethane (67.44 mg, 284.85 umol, 32.27 uL, 1.5 eq) in THF (1.5 mL) was added dropwise in the mixture and then the mixture was stirred at 20 °C for 16 hr. The reaction mixture was quenched by addition solvent NH4Cl 20 mL, extracted with Ethyl acetate (15 mL x 3). The combined organic layers were washed with brine (10 mL x 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (SiO2, Petroleum ether : Ethyl acetate = 1:1) to give 2-chloro-5-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3- yl)oxazole (10 mg, 33.59 umol, 17.69% yield) was obtained as off-white oil. Compound 4: 5-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(7-(pyrrolidin-1-yl)-

[0340] To a solution of 2-chloro-5-(3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-5- yl)oxazole (10 mg, 33.59 umol) in n-BuOH (2 mL), was added 7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H- benzo[7]annulen-3-amine (9.28 mg, 40.30 umol) and DIPEA (8.68 mg, 67.17 umol, 11.70 uL, 2 eq). The mixture was stirred at 100 °C for 16 hr. The residue was purified by preparative HPLC (23-53% MeCN in H2O) to give 5-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(7-(pyrrolidin-1-yl)- 6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)oxazol-2-amine (0.8 mg, 1.48 umol, 4.41% yield, 91% purity) as a yellow solid. LC-MS (ES+, Method A), 0.8 min, m / z 492.2. [M+H]+.1H NMR (400 MHz, CDCl3) δ 12.69 - 12.59 (m, 1H), 7.93 (s, 1H), 7.80 - 7.75 (m, 1H), 7.55 - 7.49 (m, 1H), 7.48 - 7.42 (m, 2H), 7.40 - 7.34 (m, 1H), 7.33 -7.28 (m, 2H), 7.21 - 7.15 (m, 1H), 3.78 - 3.71 (m, 2H), 3.48 - 3.40 (m, 1H), 2.99 - 2.88 (m, 4H), 2.85 -2.76 (m, 2H), 2.64 - 2.59 (m, 3H), 2.50 - 2.41 (m, 2H), 2.33 (t, J = 7.2 Hz, 2H), 2.21 - 2.14 (m, 2H), 2.01 - 1.96 (m, 2H). General route for the synthesis of Compounds 5-8:

[0341] To a solution of aniline (2 g, 21.48 mmol, 1.96 mL, 1 eq) in DCM (4 mL) was added DIEA (5.55 g, 42.95 mmol, 7.48 mL) and phenyl carbonochloridate (3.70 g, 23.62 mmol, 2.96 mL). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography eluting with 0-20% EtOAc in Pet. Ether to give phenyl N-phenylcarbamate (1.8 g, 8.44 mmol, 39.31% yield) as a yellow solid. LC-MS (ES+, Method A), 0.47 min, m / z 214.0 [M+H]+. Step 2: 1-(3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaene-5-carbonylamino)-3-phenyl- urea

[0342] To a solution of 3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaene-5-carbohydrazide (200 mg, 786.51 umol) and phenyl N-phenylcarbamate (167.71 mg, 786.51 umol) in dioxane (2 mL) was added DIEA (304.95 mg, 2.36 mmol, 410.98 uL). The mixture was stirred at 80 °C for 16 hr. The reaction mixture filtered and concentrated under reduced pressure to give a residue. The residue was washed with ethyl acetate (5 mL) and dried under vacuum to give 1-(3,4-diazatricyclo[9.4.0.02,7]pentadeca- 1(15),2,4,6,11,13-hexaene-5-carbonylamino)-3-phenyl-urea (170 mg, 455.27 umol, 57.88% yield) as a brown solid. LC-MS (ES+, Method A), 0.51 min, m / z 374.1 [M+H]+. General Method A for the of 5: Compound 5: 5-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-phenyl-1,3,4-oxadiazol- 2-amine

[0343] To a solution of 2-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-carbonyl)-N- phenylhydrazinecarboxamide (80 mg, 214.24 umol, 1 eq) in DMF (1 mL) was added TosCl (102.11 mg, 535.61 umol) and TEA (65.04 mg, 642.73 umol, 89.46 uL). The mixture was stirred at 40 °C for 2 hr. The reaction mixture was diluted with H2O (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layers were washed with aqueous NaCl (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was triturated with MeOH (2 mL) at 25 °C for 20 min and filtered to give 5-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N- phenyl-1,3,4-oxadiazol-2-amine (4.1 mg, 11.08 umol, 5.17% yield, 96% purity) as a brown solid. LC-MS (ES+, Method A), 0.55 min, m / z 356.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.35 (s, 1H), 7.85 - 7.78 (m, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.55 - 7.47 (m, 2H), 7.45 - 7.39 (m, 3H), 7.11 - 7.04 (m, 1H), 2.66 - 2.60 (m, 2H), 2.57 - 2.53 (m, 2H), 2.31 - 2.22 (m, 2H).

[0344] Compounds prepared in a similar manner to that set out above are given below in Table 4. Table 4 General method for the synthesis of Compounds 9-10:

[0345] To a solution of methyl pyridazine-3-carboxylate (2 g, 14.48 mmol, 1 eq) in MeOH (10 mL) was added N2H4.H2O (7.53 g, 148.91 mmol, 7.31 mL, 99% purity, 10.28 eq). The mixture was stirred at 70 °C for 4 hr. The reaction mixture was concentrated under reduced pressure to give pyridazine-3- carbohydrazide (1.2 g, 8.69 mmol, 60.00% yield) as a white solid. Step 2: 1-(pyridazine-3-carbonylamino)-3-(7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3- yl)urea

[0346] To a solution of pyridazine-3-carbohydrazide (157.66 mg, 1.14 mmol, 1 eq) and phenyl N-(7- pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl)carbamate (400 mg, 1.14 mmol) in dioxane (3 mL) was added DIEA (295.03 mg, 2.28 mmol, 397.62 uL). The mixture was stirred at 80 °C for 2 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (1-27% MeCN in H2O) to give 1-(pyridazine-3-carbonylamino)-3-(7-pyrrolidin-1- yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl)urea (40 mg, 101.40 umol, 8.88% yield) as a yellow solid. LC-MS (ES+, Method A), 0.25 min, m / z 395.2 [M+H]+. Compound 9: 5-pyridazin-3-yl-N-(7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl)-1,3,4- oxadiazol-2-amine

[0347] To a solution of 1-(pyridazine-3-carbonylamino)-3-(7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H- benzo[7]annulen-3-yl)urea (35 mg, 88.73 umol) in DCM (0.5 mL) was added TosCl (33.83 mg, 177.45 umol) and TEA (22.45 mg, 221.82 umol, 30.87 uL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (1-28% MeCN in H2O) and preparative HPLC (5-36% MeCN in H2O) to give 5- pyridazin-3-yl-N-(7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazol-2- amine (20.7 mg, 45.60 umol, 51.40% yield, 98.998% purity, 2HCl) as a white solid. LC-MS (ES+, Method A), 0.30 min, m / z 377.2 [M+H]+.1H NMR (400 MHz, MeOD) δ 9.31 (dd, J = 5.2, 1.2 Hz, 1H), 8.40 (dd, J = 8.4, 1.2 Hz, 1H), 7.91 (dd, J = 8.4, 5.2 Hz, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.34 (dd, J = 8.4, 2.0 Hz, 1H), 7.19 (d, J = 8.4 Hz, 1H), 3.63 - 3.58 (m, 3H), 3.26 - 3.16 (m, 2H), 3.01 - 2.80 (m, 4H), 2.52 - 2.38 (m, 2H), 2.21 - 2.07 (m, 2H), 2.06 - 1.92 (m, 2H), 1.63 - 1.45 (m, 2H).

[0348] Compounds prepared in a similar manner to that set out above are given below in Table 5. Table 5 General method for the synthesis of Compounds 18 and 19 Step 1: 5-phenylpyridazine-3-carbohydrazide

[0349] To a solution of methyl 5-phenylpyridazine-3-carboxylate (1.4 g, 6.54 mmol) in MeOH (15 mL) was added N2H4-H2O (3.27 g, 65.35 mmol, 3.18 mL). The reaction mixture was filtered and the filter cake was washed with MeOH (10 mL) and dried over under vacumn to afford 5-phenylpyridazine-3- carbohydrazide (900 mg, 4.20 mmol, 64.28% yield) as a white solid. Step 2: 1-[(5-phenylpyridazine-3-carbonyl)amino]-3-(7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H- benzo[7]annulen-3-yl)urea

[0350] The mixture of 5-phenylpyridazine-3-carbohydrazide (300 mg, 1.40 mmol) and phenyl N-(7- pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl)carbamate (490.78 mg, 1.40 mmol) in dioxane (7 mL) was added DIEA (542.98 mg, 4.20 mmol, 731.78 uL). The reaction mixture was stirred at 80 °C for 12 hr. The reaction mixture was cooled to room temperature, filtered and the filter cake was collected to give 1-[(5-phenylpyridazine-3-carbonyl)amino]-3-(7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H- benzo[7]annulen-3-yl)urea (160 mg, crude) as a white solid. Compound 18: 5-(5-phenylpyridazin-3-yl)-N-(7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H- benzo[7]annulen-3-yl)-1,3,4-oxadiazol-2-amine

[0351] To a solution of 1-[(5-phenylpyridazine-3-carbonyl)amino]-3-(7-pyrrolidin-1-yl-6,7,8,9-tetrahydro- 5H-benzo[7]annulen-3-yl)urea (140 mg, 297.51 umol) in DMF (2 mL) was added TosCl (141.80 mg, 743.79 umol) and TEA (90.32 mg, 892.54 umol, 124.23 uL). The mixture was stirred at 40 °C for 2 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (16-46% MeCN in H2O) to give 5-(5-phenylpyridazin-3-yl)-N-(7- pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazol-2-amine (10.2 mg, 17.64 umol, 5.93% yield, 98% purity, TFA salt) as a yellow solid. LC-MS (ES+, Method A), 0.446 min, m / z 453.2 [M+H]+.1H NMR (400 MHz, METHANOL-d4) δ = 9.68 (d, J = 2.4 Hz, 1H), 8.62 (d, J = 2.4 Hz, 1H), 7.98 (dd, J = 1.6, 8.0 Hz, 2H), 7.70 - 7.55 (m, 3H), 7.42 - 7.32 (m, 2H), 7.15 (d, J = 8.0 Hz, 1H), 3.38 - 3.32 (m, 4H), 3.38 - 3.32 (m, 4H), 2.99 - 2.70 (m, 1H), 2.70 - 2.70 (m, 1H), 2.98 - 2.68 (m, 6H), 2.68 - 2.58 (m, 1H), 2.30 (br d, J = 8.0 Hz, 2H), 1.90 (s, 1H), 1.88 (s, 4H), 1.52 - 1.34 (m, 2H).

[0352] Compounds prepared in a similar manner to that set out above are given below in Table 5A. Table 5A General route for the synthesis of Compounds 28 and 29:

[0353] To a solution of tetralin-2-one (2 g, 13.68 mmol, 1.82 mL) in H2SO4 (10 mL) was slowly added KNO3(1.7 g, 16.81 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hr. The mixture was stirred at 25 °C for 3 hr. The reaction mixture was slowly poured into ice / water (100 mL) at 0°C and stirred 30 min, then extracted with EtOAc (100 mL * 3). The combined organic layers were washed with brine (100 mL * 2), dried over Na2SO4, filtered and concentrated under reduced pressure and purified by flash silica gel chromatography eluting with 0-50% EtOAc in Pet. Ether to give 7-nitrotetralin-2-one (600 mg, 3.14 mmol, 22.94% yield) as brown oil. Step 2: 1-(7-nitrotetralin-2-yl)pyrrolidine

[0354] To a solution of 7-nitrotetralin-2-one (600 mg, 3.14 mmol), pyrrolidine (267.84 mg, 3.77 mmol, 314.37 uL) in DCE (10 mL) was added NaBH(OAc)3 (997.72 mg, 4.71 mmol) and AcOH (188.46 mg, 3.14 mmol, 179.49 uL). The mixture was stirred at 25 °C for 16 hr. The mixture was quenched by saturated NH4Cl aqueous solution (10 mL), extracted by DCM (10 mL*3), washed by brine (10 mL*2), dried over anhydrous Na2SO4, filtered and concentrated reduced pressure and purified by flash silica gel chromatography eluting with 0-20% MeOH in EtOAc to give 1-(7-nitrotetralin-2-yl)pyrrolidine (700 mg, 2.84 mmol, 90.56% yield) as a brown oil. LC-MS (ES+, Method A), 0.23 min, m / z 247.1 [M+H]+. Step 3: 3-pyrrolidin-1-yltetralin-6-amine

[0355] To a solution of 1-(7-nitrotetralin-2-yl)pyrrolidine (700 mg, 2.84 mmol) in MeOH (10 mL) was added Pd / C (10%, 100 mg) under N2 atmosphere. The suspension was degassed and purged with H2 for 3 times. The mixture was stirred under H2 (15 Psi) at 25 °C for 16 hr. The mixture was filtered and concentrated under reduced pressure to give 3-pyrrolidin-1-yltetralin-6-amine (500 mg, 2.31 mmol, 81.33% yield) as white solid. LC-MS (ES+, Method A), 0.12 min, m / z 217.3 [M+H]+.

[0356] To a solution of 3-pyrrolidin-1-yltetralin-6-amine (150 mg, 693.41 umol), phenyl carbonochloridate (130.28 mg, 832.10 umol, 104.22 uL) in THF (2 mL), H2O (2 mL) was added NaHCO3(145.63 mg, 1.73 mmol, 67.42 uL). The mixture was stirred at 25 °C for 1 hr. The mixture was extracted with EtOAc (5 mL*3), washed with brine (5 mL*2), dried over Na2SO4, filtered and concentrated under reduced pressure to give phenyl N-(3-pyrrolidin-1-yltetralin-6-yl)carbamate (210 mg, crude) as yellow oil. LC-MS (ES+, Method A), 0.32 min, m / z 337.3 [M+H]+. Step 5: 1-(3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaene-5-carbonylamino)-3-(3- pyrrolidin-1-yltetralin-6-yl)urea

[0357] To a solution of phenyl N-(3-pyrrolidin-1-yltetralin-6-yl)carbamate (200 mg, 594.48 umol), 3,4- diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaene-5-carbohydrazide (90.70 mg, 356.69 umol) in dioxane (5 mL) was added DIEA (192.08 mg, 1.49 mmol, 258.87 uL). The mixture was stirred at 80 °C for 16 hr. The mixture was concentrated under reduced pressure then was purified by preparative HPLC (14-44% MeCN in H2O) to give 1-(3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13- hexaene-5-carbonylamino)-3-(3-pyrrolidin-1-yltetralin-6-yl)urea (60 mg, 120.82 umol, 20.32% yield) as a white solid. LC-MS (ES+, Method A), 0.32 min, m / z 497.4 [M+H]+. Compound 28: 5-(3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-5-yl)-N-(3-pyrrolidin- 1-yltetralin-6-yl)-1,3,4-oxadiazol-2-amine

[0358] To a solution of 1-(3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaene-5- carbonylamino)-3-(3-pyrrolidin-1-yltetralin-6-yl)urea (50 mg, 100.68 umol) in DCM (2 mL) was added TosCl (28.79 mg, 151.03 umol) and TEA (25.47 mg, 251.71 umol, 35.03 uL). The mixture was stirred at 25 °C for 1 hr. The mixture was concentrated under reduced pressure and purified by preparative HPLC (19-49% MeCN in H2O) to give 5-(3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13- hexaen-5-yl)-N-(3-pyrrolidin-1-yltetralin-6-yl)-1,3,4-oxadiazol-2-amine (3.3 mg, 6.36 umol, 6.32% yield, 99.281% purity, HCl) as a yellow solid. LC-MS (ES+, Method A), 0.40 min, m / z 479.0 [M+H]+.1H NMR (400 MHz, METHANOL-d4) δ = 8.30 (s, 1H), 7.82 (dd, J = 1.6, 7.2 Hz, 1H), 7.57 (d, J = 2.0 Hz, 1H), 7.55 - 7.47 (m, 2H), 7.42 - 7.38 (m, 1H), 7.31 (dd, J = 2.4, 8.4 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 3.67 - 3.54 (m, 2H), 3.51 - 3.32 (m, 4H), 3.11 - 2.92 (m, 3H), 2.72 - 2.58 (m, 4H), 2.47 - 2.33 (m, 3H), 2.24 - 2.06 (m, 4H), 2.00 - 1.86 (m, 1H).

[0359] Compounds prepared in a similar manner to that set out above are given below in Table 5B. Table 5B General route for the synthesis of Compound 23:

[0360] To a solution of 4-[[5-(3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-5-yl)-1,3,4- oxadiazol-2-yl]amino]phenol (1 g, 2.69 mmol), ethyl 2-bromoacetate (449.66 mg, 2.69 mmol, 297.79 uL) in DMF (10 mL) was added DIEA (695.99 mg, 5.39 mmol, 938.00 uL). The mixture was stirred at 40 °C for 16 hr. The reaction mixture was diluted with H2O (50 mL) and extracted with EtOAc (50 mL * 3). The combined organic layers were washed with brine (50 mL * 2), dried over Na2SO4, filtered and concentrated under reduced and purified by preparative-TLC (eluting with 10% MeOH in DCM) to give ethyl 2-[4-[[5-(3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-5-yl)-1,3,4-oxadiazol-2- yl]amino]phenoxy]acetate (230 mg, crude) as a white solid. LC-MS (ES+, Method A), 0.422 min, m / z 458.3 [M+H]+. Step 2: 2-[4-[[5-(3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-5-yl)-1,3,4-oxadiazol-2- yl]amino]phenoxy]ethanol

[0361] To a solution of ethyl 2-[4-[[5-(3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-5- yl)-1,3,4-oxadiazol-2-yl]amino]phenoxy]acetate (230 mg, 502.75 umol) in THF (5 mL) was added LiAlH4 (29.52 mg, 777.87 umol) at -78 °C under N2. The mixture was stirred at -78 °C for 0.5 hr. The mixture was quenched followed by added H2O (0.04 mL), NaOH (15 % aqueous solution, 0.04 mL) and H2O (0.12 mL) at 0°C, and then filtered and concentrated under reduced pressure to give 2-[4-[[5- (3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-5-yl)-1,3,4-oxadiazol-2- yl]amino]phenoxy]ethanol (210 mg, crude) as a yellow solid. LC-MS (ES+, Method A), 0.394 min, m / z 416.1 [M+H]+. Step 3: 2-[4-[[5-(3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-5-yl)-1,3,4-oxadiazol-2-

[0362] The solution of 2-[4-[[5-(3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-5-yl)- 1,3,4-oxadiazol-2-yl]amino]phenoxy]ethanol (210 mg, 505.48 umol), TosCl (289.11 mg, 1.52 mmol) in Py (4.90 g, 61.95 mmol, 5 mL) was stirred at 25 °C for 1 hr. The mixture was concentrated under reduced pressure and purified by column chromatography eluting with 10% MeOH in DCM to give 2-[4-[[5-(3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-5-yl)-1,3,4-oxadiazol-2- yl]amino]phenoxy]ethyl 4-methylbenzenesulfonate (50 mg, crude) as a white solid. LC-MS (ES+, Method A), 0.463 min, m / z 570.4 [M+H]+. Compound 23: 5-(3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-5-yl)-N-[4-(2- pyrrolidin-1-ylethoxy)phenyl]-1,3,4-oxadiazol-2-amine

[0363] To a solution of 2-[4-[[5-(3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-5-yl)- 1,3,4-oxadiazol-2-yl]amino]phenoxy]ethyl 4-methylbenzenesulfonate (25.00 mg, 43.89 umol), pyrrolidine (4.68 mg, 65.83 umol, 5.49 uL) in MeCN (2 mL) was added K2CO3 (15.16 mg, 109.72 umol). The mixture was stirred at 50 °C for 16 hr. The mixture was concentrated under reduced pressure and purified by preparative HPLC (14-44% MeCN in H2O) to give 5-(3,4-diazatricyclo[9.4.0.02,7]pentadeca- 1(15),2,4,6,11,13-hexaen-5-yl)-N-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-1,3,4-oxadiazol-2-amine (3.1 mg, 5.89 umol, 6.71% yield, 97.8% purity, FA) as a white solid. LC-MS (ES+, Method A), 0.364 min, m / z 469.4 [M+H]+.1H NMR (400 MHz, METHANOL-d4) δ = 8.58 - 8.49 (m, 1H), 8.29 (s, 1H), 7.84 - 7.79 (m, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.53 - 7.47 (m, 2H), 7.42 - 7.38 (m, 1H), 7.05 (d, J = 8.8 Hz, 2H), 4.26 (t, J = 5.6 Hz, 2H), 3.36 (s, 2H), 3.16 (s, 4H), 2.70 - 2.66 (m, 2H), 2.62 (t, J = 6.8 Hz, 2H), 2.40 - 2.32 (m, 2H), 2.02 (s, 4H). General route for the synthesis of Compounds 20 and 21:

[0364] To a solution of 3-[[5-(3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-5-yl)-1,3,4- oxadiazol-2-yl]amino]phenol (50.00 mg, 134.63 umol), 2-(dimethylamino)ethanol (14.40 mg, 161.55 umol, 16.22 uL) in THF (1.5 mL) was added PPh3 (42.37 mg, 161.55 umol) and DIAD (32.67 mg, 161.55 umol, 31.41 uL). The mixture was stirred at 25 °C for 16 hr. The mixture was concentrated under reduced pressure and purified by preparative HPLC (14-44% MeCN in H2O) to give 5-(3,4- diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-5-yl)-N-[3-[2- (dimethylamino)ethoxy]phenyl]-1,3,4-oxadiazol-2-amine (1.3 mg, 2.77 umol, 1.03% yield, 94.342% purity) as a white solid. LC-MS (ES+, Method A), 0.373 min, m / z 443.4 [M+H]+.1H NMR (400 MHz, METHANOL-d4) δ = 8.51 (d, J = 4.0 Hz, 1H), 8.31 (s, 1H), 7.84 - 7.80 (m, 1H), 7.54 - 7.47 (m, 3H), 7.42 - 7.39 (m, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.11 (dd, J = 1.6, 8.0 Hz, 1H), 6.74 (dd, J = 2.0, 8.0 Hz, 1H), 4.31 (t, J = 5.2 Hz, 2H), 3.29 - 3.26 (m, 2H), 2.74 (s, 6H), 2.68 (t, J = 7.2 Hz, 2H), 2.62 (t, J = 6.8 Hz, 2H), 2.36 (t, J = 7.2 Hz, 2H).

[0365] Compounds prepared in a similar manner to that set out above are given below in Table 5C. Table 5C General route for the synthesis of Compounds 30, 31, and 57: Step 1: tert-butyl N-[5-(hydrazinecarbonyl)-3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13- hexaen-13-yl]carbamate

[0366] To a solution of methyl 13-(tert-butoxycarbonylamino)-3,4-diazatricyclo[9.4.0.02,7]pentadeca- 1(15),2,4,6,11,13-hexaene-5-carboxylate (50.00 mg, 135.35 umol) in MeOH (1 mL) was added N2H4.H2O (0.110 g, 2.15 mmol, 106.80 uL, 98% purity). The mixture was stirred at 70 °C for 1 h. The mixture was diluted with H2O (1 mL) and concentrated to removed MeOH, extracted with EtOAc (2 mL * 3). dried over Na2SO4, filtered and concentrated under reduced pressure to give tert-butyl N-[5- (hydrazinecarbonyl)-3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-13-yl]carbamate (50 mg, crude) as yellow solid. LC-MS (ES+, Method A), 0.401 min, m / z 370.0 [M+H]+. Step 2: tert-butyl N-[5-[[(7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3- yl)carbamoylamino]carbamoyl]-3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-13- yl]carbamate

[0367] To a solution of tert-butyl N-[5-(hydrazinecarbonyl)-3,4-diazatricyclo[9.4.0.02,7]pentadeca- 1(15),2,4,6,11,13-hexaen-13-yl]carbamate (40 mg, 108.28 umol) and phenyl N-(7-pyrrolidin-1-yl-6,7,8,9- tetrahydro-5H-benzo[7]annulen-3-yl)carbamate (82.34 mg, 234.97 umol) in dioxane (2 mL) was added DIEA (34.98 mg, 270.70 umol, 47.15 uL). The mixture was stirred at 80 °C for 16 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (15% MeOH in DCM) to give tert-butyl N-[5-[[(7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H- benzo[7]annulen-3-yl)carbamoylamino]carbamoyl]-3,4-diazatricyclo[9.4.0.02,7]pentadeca- 1(15),2,4,6,11,13-hexaen-13-yl]carbamate (20 mg, crude) was obtained as a brown solid. LC-MS (ES+, Method A), 0.405 min, m / z 626.4 [M+H]+. Step 3: tert-butyl N-[5-[5-[(7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl)amino]-1,3,4-

[0368] To a solution of tert-butyl N-[5-[[(7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl) carbamoylamino] carbamoyl]-3,4-diazatricyclo [9.4.0.02,7] pentadeca-1(15), 2,4,6,11,13-hexaen-13- yl]carbamate (17.00 mg, 27.17 umol) in DCM (1 mL) was added TEA (13.75 mg, 135.84 umol, 18.91 uL) and TosCl (12.95 mg, 67.92 umol). The mixture was stirred at 25 °C for 0.5 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative-TLC (10% MeOH in DCM) to give tert-butyl N-[5-[5-[(7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3- yl)amino]-1,3,4-oxadiazol-2-yl]-3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-13- yl]carbamate (15 mg, crude) as a brown solid. LC-MS (ES+, Method A), 0.437 min, m / z 608.2 [M+H]+. Step 4: 5-(13-amino-3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-5-yl)-N-(7-

[0369] The reactant of tert-butyl N-[5-[5-[(7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3- yl)amino]-1,3,4-oxadiazol-2-yl]-3,4-diazatricyclo[9.4.0.02,7] pentadeca-1(15),2,4,6,11,13-hexaen-13- yl]carbamate (15 mg, 24.68 umol) in HCl / dioxane (4 M, 1.50 mL) was stirred at 25 °C for 0.5 h . The mixture was concentrated under reduced pressure to give 5-(13-amino-3,4- diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-5-yl)-N-(7-pyrrolidin-1-yl-6,7,8,9- tetrahydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazol-2-amine (13 mg, crude, HCl) as a yellow solid. LC- MS (ES+, Method A), 0.330 min, m / z 508.3 [M+H]+. Method A Compound 30: N-[5-[5-[(7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl)amino]-1,3,4-

[0370] To a solution of 5-(13-amino-3,4-diazatricyclo[9.4.0.02,7] pentadeca-1(15),2,4,6,11,13-hexaen-5- yl)-N-(7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazol-2-amine (13.00 mg, 23.89 umol, HCl salt) in THF (0.5 mL), H2O (0.5 mL) was added NaHCO3(5.02 mg, 59.73 umol, 2.32 uL) and then added dropwise slowly prop-2-enoyl chloride (4.33 mg, 47.79 umol, 3.90 uL). The mixture was stirred at 25 °C for 0.5 hr. The mixture was concentrated under reduced pressure to give a residue. The residue was purified was by preparative HPLC (16-46% MeCN in H2O) to give N-[5-[5-[(7- pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen-3-yl)amino]-1,3,4-oxadiazol-2-yl]-3,4- diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-13-yl]prop-2-enamide (4.1 mg, 6.17 umol, 25.83% yield) as white solid. LC-MS (ES+, Method A), 0.376 min, m / z 562.5 [M+H]+.1H NMR (400 MHz, METHANOL-d4) δ = 8.54 (s, 1H), 8.28 (s, 1H), 7.82 - 7.72 (m, 3H), 7.46 (d, J = 2.0 Hz, 1H), 7.34 (dd, J = 2.3, 8.2 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 6.53 - 6.38 (m, 2H), 5.82 (dd, J = 2.4, 9.6 Hz, 1H), 3.74 - 3.54 (m, 1H), 3.43 - 3.32 (m, 2H), 3.30 - 3.26 (m, 2H), 2.99 - 2.79 (m, 4H), 2.69 (b t, J = 7.0 Hz, 2H), 2.65 - 2.58 (m, 2H), 2.47 - 2.33 (m, 4H), 2.07 - 1.97 (m, 4H), 1.60 - 1.44 (m, 2H). Method B Compound 31: (E)-4-(dimethylamino)-N-[5-[5-[(7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H- benzo[7]annulen-3-yl)amino]-1,3,4-oxadiazol-2-yl]-3,4-diazatricyclo[9.4.0.02,7]pentadeca- 1(15),2,4,6,11,13-hexaen-13-yl]but-2-enamide

[0371] To a solution of (E)-4-(dimethylamino) but-2-enoic acid (18.26 mg, 110.28 umol, HCl salt) in DCM (1 mL) was added HATU (13.63 mg, 35.84 umol) and then added 5-(13-amino-3,4- diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-5-yl)-N-(7-pyrrolidin-1-yl-6,7,8,9-tetrahydro- 5H-benzo[7]annulen-3-yl)-1,3,4-oxadiazol-2-amine (15.00 mg, 27.57 umol, HCl salt), DIEA (17.82 mg, 137.85 umol, 24.01 uL). The mixture was stirred at 25 °C for 16 hr. The mixture was concentrated under reduced pressure to give a residue. The residue was purified was by preparative HPLC (8-38% MeCN in H2O) to give (E)-4-(dimethylamino)-N-[5-[5-[(7-pyrrolidin-1-yl-6,7,8,9-tetrahydro-5H-benzo[7]annulen- 3-yl)amino]-1,3,4-oxadiazol-2-yl]-3,4-diazatricyclo[9.4.0.02,7]pentadeca-1(15),2,4,6,11,13-hexaen-13- yl]but-2-enamide (0.9 mg, 1.03 umol, 3.74% yield, TFA) as a yellow solid. LC-MS (ES+, Method A), 0.295 min, m / z 619.5 [M+H]+.1H NMR (400 MHz, METHANOL-d4) δ = 8.31 (s, 1H), 7.84 - 7.81 (m, 1H), 7.79 - 7.75 (m, 2H), 7.49 (d, J = 2.4 Hz, 1H), 7.36 (dd, J = 2.4, 8.2 Hz, 1H), 7.22 - 7.19 (m, 1H), 6.95 - 6.87 (m, 1H), 6.59 (d, J = 15.4 Hz, 1H), 4.02 (d, J = 6.9 Hz, 2H), 3.63 - 3.53 (m, 3H), 3.23 - 3.18 (m, 2H), 2.97 - 2.86 (m, 10H), 2.73 - 2.68 (m, 2H), 2.65 - 2.60 (m, 2H), 2.47 - 2.35 (m, 4H), 2.18 - 2.10 (m, 2H), 2.05 - 1.96 (m, 2H), 1.61 - 1.50 (m, 2H).

[0372] Compounds prepared in a similar manner to that set out above are given below in Table 5D. Table 5D General method for the synthesis of Compounds 11-16:

[0373] To a solution of 6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3-carbohydrazide (100 mg, 393.26 umol) and tert-butyl 7-(phenoxycarbonylamino)-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylate (150.40 mg, 393.26 umol) in DMF (2 mL) was added DIEA (101.65 mg, 786.51 umol, 137.00 uL). The mixture was stirred at 80 °C for 16 hr. The reaction mixture was concentrated under reduced pressure to give tert-butyl 7-(2-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3- carbonyl)hydrazinecarboxamido)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (200 mg, 368.58 umol, 93.72% yield) as a yellow oil. LC-MS (ES+, Method A), 0.57 min, m / z 543.4 [M+H]+. Step 2: tert-butyl 7-((5-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-1,3,4-oxadiazol-2-

[0374] To a solution of tert-butyl 7-(2-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine-3- carbonyl)hydrazinecarboxamido)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (200 mg, 368.58 umol) in DMF (2 mL) was added TosCl (140.54 mg, 737.15 umol) and DIEA (119.09 mg, 921.44 umol, 160.50 uL). The mixture was stirred at 25 °C for 1 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography eluting with 0-50% EtOAc in Pet. Ether to give tert-butyl 7-((5-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-1,3,4- oxadiazol-2-yl)amino)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (180 mg, 343.11 umol, 93.09% yield) as a yellow oil. LC-MS (ES+, Method A), 0.63 min, m / z 525.4 [M+H]+. Step 3: 5-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(2,3,4,5-tetrahydro-1H- benzo[d]azepin-7-yl)-1,3,4-oxadiazol-2-amine

[0375] A mixture of tert-butyl 7-((5-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-1,3,4- oxadiazol-2-yl)amino)-4,5-dihydro-1H-benzo[d]azepine-3(2H)-carboxylate (180 mg, 343.11 umol, 1 eq) in HCl / dioxane (4 M, 85.78 uL, 1 eq) was stirred at 25 °C for 16 hr. The reaction mixture was concentrated under reduced pressure to give 5-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3- yl)-N-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)-1,3,4-oxadiazol-2-amine (150 mg, 325.41 umol, 94.84% yield, HCl) as a yellow solid. LC-MS (ES+, Method A), 0.37 min, m / z 425.2 [M+H]+. General Method for the synthesis of Compound 11:

[0376] To a solution of 5-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(2,3,4,5- tetrahydro-1H-benzo[d]azepin-7-yl)-1,3,4-oxadiazol-2-amine (20 mg, 43.39 umol, HCl salt), AcOH (2.61 mg, 43.39 umol, 2.48 uL) and HCHO (5.28 mg, 65.08 umol, 4.85 uL, 37% purity) in MeOH (0.5 mL) was added NaBH3CN (4.09 mg, 65.08 umol). The mixture was stirred at 25 °C for 16 hr. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (19-49% MeCN in H2O) to give 5-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(3-methyl-2,3,4,5- tetrahydro-1H-benzo[d]azepin-7-yl)-1,3,4-oxadiazol-2-amine (3.5 mg, 7.22 umol, 16.65% yield, 100% purity, FA) as a white solid. LC-MS (ES+, Method A), 0.38 min, m / z 439.3 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.52 (s, 1H), 8.31 (s, 1H), 7.84 - 7.79 (m, 1H), 7.55 - 7.46 (m, 3H), 7.44 - 7.37 (m, 2H), 7.22 (d, J = 8.0 Hz, 1H), 3.25 - 3.03 (m, 8H), 2.79 (s, 3H), 2.71 - 2.59 (m, 4H), 2.41 - 2.30 (m, 2H).

[0377] Compounds prepared in a similar manner to that set out above are given below in Table 6. Table 6 General route for the of 37, 39, 40, 41, and 43:

[0378] To a mixture of 5-(trifluoromethyl)-1H-1,2,4-triazol-3-amine (0.3 g, 1.97 mmol) and 3-chloro-6,7- dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (409.57 mg, 1.78 mmol) in NMP (10 mL) was added KF (137.53 mg, 2.37 mmol, 55.45 μL) and Cs2CO3(964.10 mg, 2.96 mmol) at 20 °C, and the reaction vessel was sealed and heated in microwave at 100 °C for 0.5 hr. The reaction mixture was poured into H2O (100 mL) and extracted with EtOAc (70 mL × 2). The combined organic layers were washed with saturated NaCl (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (HCl condition: column: Welch Xtimate C18150*25mm*5μm; mobile phase: [water(HCl)-ACN];B%: 48%-78%,8min) to afford 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-3-(trifluoromethyl)-1H-1,2,4- triazol-5-amine (62 mg, 179.03 μmol, 9.08% yield) as a light yellow solid. Other residue 3-(3- (trifluoromethyl)-1H-1,2,4-triazol-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (650 mg, crude) was obtained as a black brown gum. Step 2: 3-(5-bromo-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2- c]pyridazine

[0379] To a solution of 3-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)-6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazine (0.2 g, 577.52 μmol) and CuBr2 (167.69 mg, 750.77 μmol, 35.15 μL) in MeCN (4 mL) was added tert-butyl nitrite (77.42 mg, 750.77 μmol, 89.30 μL) dropwise at 20 °C, the mixture was stirred at 70°C for 2 h. The reaction mixture was poured into water (10 mL), extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (HCl condition; column: Welch Xtimate C18 150*25mm*5um;mobile phase: [water(HCl)-ACN];B%: 55%-85%,8min) to afford 3-(5-bromo-3- (trifluoromethyl)-1H-1,2,4-triazol-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (40 mg, 97.52 μmol, 16.89% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 7.82 (dd, J = 1.6, 7.2 Hz, 1H), 7.52 (dt, J = 1.2, 7.2 Hz, 2H), 7.45 - 7.41 (m, 1H), 2.65 (t, J = 7.2 Hz, 2H), 2.58 - 2.53 (m, 2H), 2.28 (d, J = 7.2 Hz, 2H). Compound 37: 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(7-(pyrrolidin-1-yl)- 6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-amine

[0380] A solution of 3-(5-bromo-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)-6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazine (10 mg, 24.38 μmol), 7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H- benzo[7]annulen-2-amine (16.85 mg, 73.14 μmol), Pd2(dba)3 (2.23 mg, 2.44 μmol), Xantphos (2.82 mg, 4.88 μmol,) and Cs2CO3(15.89 mg, 48.76 μmol) in dioxane (0.1 mL) with stirred at 110 °C for 12 h. The mixture was quenched with water (2 mL) and extracted with ethyl acetate (5 mL x 3). The organic layers were combined, washed with brine (5 mL x 3) and dried over anhydrous Na2SO4. The residue was purified by preparative HPLC (column: Phenomenex luna C18150*25mm* 10um; mobile phase: [water(FA)-ACN]; B%: 38%-68%,7min) to afford 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2- c]pyridazin-3-yl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-3- (trifluoromethyl)-1H-1,2,4-triazol-5-amine (2 mg, 3.47 μmol, 97.0% yield) as a white solid. LC-MS (ES+, Method A), 0.57 min, m / z 560.4 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 10.92 (s, 1H), 8.24 (s, 1H), 8.21 (s, 1H), 7.80 (dd, J = 2.0, 7.2 Hz, 1H), 7.55 - 7.49 (m, 3H), 7.44 - 7.40 (m, 2H), 7.17 (d, J = 8.4 Hz, 1H), 3.05 - 2.87 (m, 3H), 2.73 - 2.58 (m, 10H), 2.25 (t, J = 6.8 Hz, 2H), 2.02 - 1.90 (m, 2H), 1.73 (s, 4H), 1.61 - 1.49 (m, 2H).

[0381] Compounds prepared in a similar manner to that set out above are given below in Table 7. Table 7 General route for the synthesis of Compound 44: Step 1: tert-butyl 5-((1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-3-(trifluoromethyl)- 1H-1,2,4-triazol-5-yl)amino)isoindoline-2-carboxylate

[0382] To a mixture of tert-butyl 5-aminoisoindoline-2-carboxylate (42.84 mg, 182.84 μmol) and 3-(5- bromo-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (50 mg, 121.89 μmol) and Xantphos (14.11 mg, 24.38 μmol) and Cs2CO3 (79.43 mg, 243.79 μmol) in dioxane (1 mL) was added Pd2(dba)3 (11.16 mg, 12.19 μmol) in one portion at 20 °C under N2. The mixture was stirred at 100 °C for 16 h. The reaction mixture was poured into water (5 ml), extracted with ethyl acetate (8 mL × 2). The combined organic layers were washed with brine (8 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18150*25mm* 10 um; mobile phase: [water(TFA)- ACN]; gradient: 80%-100% B over min) to give tert-butyl 5-((1-(6,7-dihydro-5H benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)amino)isoindoline- 2-carboxylate (58 mg, 102.91 μmol, 42.21% yield) as a white solid. LC-MS (ES+, Method A), 0.75 min, m / z 564.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 11.01 (br d, J = 4.6 Hz, 1H), 8.29 - 8.24 (m, 1H), 7.86 - 7.77 (m, 1H), 7.75 - 7.70 (m, 1H), 7.69 - 7.61 (m, 1H), 7.56 - 7.49 (m, 2H), 7.45 - 7.36 (m, 2H), 4.70 - 4.53 (m, 4H), 3.40 - 3.34 (m, 2H), 2.64 (br d, J = 2.1 Hz, 2H), 2.57 - 2.53 (m, 2H), 2.32 - 2.19 (m, 3H), 1.47 (s, 9H). Compound 44: N-(1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-3-(trifluoromethyl)- 1H-1,2,4-triazol-5-yl)-2-methylisoindolin-5-amine

[0383] To a solution of tert-butyl 5-((1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-3- (trifluoromethyl)-1H-1,2,4-triazol-5-yl)amino)isoindoline-2-carboxylate (35 mg, 62.10 μmol) in THF (2 mL) was added LiAlH4 (2.5 M, 149.05 μL, 6 eq) dropwise at 0 °C. The solution was stirred at 60 °C for 6 h. The solution was quenched with water (0.1 mL) and 15% sodium hydroxide solution (0.1 mL), extracted with ethyl acetate (5 mL × 3), the solvent was remove under reduce pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150*25mm*10um;mobile phase: [water(TFA)-ACN]; gradient:36%-66% B over 9 min) to give N-(1- (6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-yl)-2- methylisoindolin-5-amine (3.7 mg, 6.11 μmol, 9.84% yield, 97.7% purity, TFA) as a yellow solid. LCMS (ES+, Method A), 0.52 min, m / z=478.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ = 11.15 - 11.11 (m, 1H), 10.57 - 10.49 (m, 1H), 8.28 (s, 1H), 7.86 (s, 1H), 7.81 -7.72 (m, 2H), 7.56 - 7.40 (m, 4H), 4.94 - 4.68 (m, 2H), 4.64 - 4.38 (m, 2H), 3.05 (s, 3H), 2.72 - 2.65 (m, 2H), 2.58 -2.54 (m, 2H), 2.30 - 2.22 (m, 2H). General route for the of 46:

[0384] To a solution of 5-methyl-1H-1,2,4-triazol-3-amine (300 mg, 3.06 mmol) and 3-chloro-6,7-dihydro- 5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (705.44 mg, 3.06 mmol) NMP (10 mL) in was added Cs2CO3 (1.99 g, 6.12 mmol) and KF (177.65 mg, 3.06 mmol, 71.63 uL). The mixture was stirred at 150 °C for 2 hr under M.W. condition. The crude mixture was diluted with water (100 mL) and brine (50 mL) and filtered through a pad of celite, then the filtrate was extracted by EtOAc (50 mL x 2). The organic phase was washed by brine (50 mL) and dried by Na2SO4. The organic phase was concentrated under reduce pressure. The residue was purified by chromatography on silica gal eluting with PE / EtOAc = 1 / 1 to 12 / 88 to give 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-3-methyl-1H-1,2,4-triazol-5-amine (550 mg, 1.88 mmol, 61.53% yield) as orange solid. LC-MS (ES+, Method A), 0.46 min, m / z 293.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.84 - 7.80 (m, 1H), 7.46 - 7.43 (m, 2H), 7.31 - 7.28 (m, 1H), 6.92 (s, 2H), 2.84 (s, 3H), 2.64 - 2.57 (m, 4H), 2.31 - 2.25 (m, 2H). Step 2: 3-(5-bromo-3-methyl-1H-1,2,4-triazol-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2- c]pyridazine

[0385] A mixture of CuBr (539.77 mg, 3.76 mmol) and isopentyl nitrite (440.79 mg, 3.76 mmol, 506.66 uL) in MeCN (5 mL) was stirred at 65 °C for 0.5 hr under N2 atmosphere, then 1-(6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-3-methyl-1H-1,2,4-triazol-5-amine (550.00 mg, 1.88 mmol) in MeCN (2 mL) was added to the mixture and the mixture was stirred at 65 °C for 12 hr under N2 atmosphere. The crude mixture was diluted with water (100 mL) and extracted by EtOAc (50 mL x 2), then the organic phase was washed by brine (50 mL) and dried with Na2SO4. The organic phase was filtered through a pad of celite and concentrated under reduce pressure. The residue was purified by chromatography on silica gal eluting with PE / EtOAc = 100 / 0 to 15 / 85 to give 3-(5-bromo-3-methyl-1H- 1,2,4-triazol-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (30 mg, 84.22 umol, 4.48% yield) as white solid. LC-MS (ES+, Method A), 0.58 min, m / z 356.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.90 (dd, J = 3.0, 5.8 Hz, 1H), 7.53 - 7.43 (m, 2H), 7.33 (dd, J = 3.6, 5.0 Hz, 1H), 3.05 (s, 3H), 2.72 - 2.53 (m, 4H), 2.33 (t, J = 7.2 Hz, 2H). Compound 46: 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-3-methyl-N-(7-

[0386] To a solution of 3-(5-bromo-3-methyl-1H-1,2,4-triazol-1-yl)-6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazine (20 mg, 56.15 μmol) and 7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro- 5H-benzo[7]annulen-2-amine (12.93 mg, 56.15 umol) in dioxane (2 mL) was added Pd2(dba)3(5.14 mg, 5.61 μmol), Xantphos (6.50 mg, 11.23 μmol) and Cs2CO3(54.88 mg, 168.44 μmol), then the mixture was stirred at 100 °C for 16 hr under N2atmosphere. The crude mixture was filtered through a pad of silica gal using DCM / MeOH = 10 / 1, then the filtrate was concentrated under reduce pressure. The residue was purified by prep-HPLC(column: Phenomenex luna C18150 × 25mm × 10um; mobile phase: [water(FA)- ACN];B%: 25%-55%,7min) to give 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-3- methyl-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-1,2,4-triazol-5-amine (7 mg, 13.15 μmol, 23.42% yield, 95% purity) as white solid. LC-MS (ES+, Method A), 0.49 min, m / z 506.3 [M+H]+.1H NMR (400 MHz, MeOD) δ 8.11 (s, 1H), 7.80 - 7.72 (m, 1H), 7.53 - 7.43 (m, 3H), 7.38 (d, J = 6.8 Hz, 1H), 7.28 (s, 1H), 7.07 (d, J = 8.0 Hz, 1H), 3.06 (s, 5H), 2.90 (s, 3H), 2.87 - 2.73 (m, 4H), 2.71 - 2.58 (m, 4H), 2.41 - 2.28 (m, 4H), 1.94 (s, 4H), 1.44 (quin, J = 12.4 Hz, 2H). General route for the synthesis of Compounds 47 and 48:

[0387] To a mixture of 3-(trifluoromethyl)-1H-1,2,4-triazol-5-amine (1 g, 6.58 mmol) and 3-chloro-6- phenylpyridazine (1.13 g, 5.92 mmol) in NMP (10 mL) was added Cs2CO3 (4.28 g, 13.15 mmol) and KF (764.04 mg, 13.15mmol) at 20 °C, and the reaction vessel was sealed and heated in microwave at 120 °C for 3 h. The reaction mixture was poured into water (60 ml), extracted with ethyl acetate (70 mL × 2). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC(column: YMC Triart C18150*25mm*5um;mobile phase: [water(FA)-ACN];gradient:45%-75% B over 10 min). The compound ethyl 2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)acetate (750 mg, 2.45 mmol, 37.24% yield) was obtained as an off-white solid. LC-MS (ES+, Method A), 0.54 min, m / z 307.0 [M+H]+. Step 2: 3-(5-bromo-3-(trifluoromethyl)-1H-1, 2, 4-triazol-1-yl)-6-phenylpyridazine

[0388] To a solution of the 2-(5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-6-yl)acetate and CuBr2(911.66 mg, 4.08 mmol) in MeCN (5 mL) was added tert-butyl nitrite (420.90 mg, 4.08 mmol, 485.47 μL) drop wise at 20 °C, the mixture was stirred at 70 °C for 2 h. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (200 mL × 2). The combined organic layers were washed with brine (200 mL ), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18150*25mm* 10um;mobile phase: [water(FA)-ACN]; gradient:58%-88% B over 7 min). The compound 3-(5-bromo-3- (trifluoromethyl)-1H-1,2,4-triazol-1-yl)-6-phenylpyridazine (370 mg, 999.66 μmol, 61.23% yield) was obtained as a white solid. LC-MS (ES+, Method A), 0.58 min, m / z 369.9 [M+H]+. Compound 47: 1-(6-phenylpyridazin-3-yl)-N-(7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H benzo[7]annulen-2-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-amine

[0389] To a mixture of 3-(5-bromo-3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)-6-phenylpyridazine (320 mg, 864.57 μmol) and 7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-amine (199.15 mg, 864.57 μmol) and Xantphos (100.05 mg, 172.91 μmol) and Cs2CO3 (563.39 mg, 1.73 mmol) in dioxane (3.2 mL) was added Pd2(dba)3 (79.17 mg, 86.46 μmol) in one portion at 20 °C under N2. The mixture was stirred at 100 °C for 16 h. The reaction mixture was poured into water (50 mL), extracted with ethyl acetate (60 mL × 2). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC(column: YMC-Actus Triart C18150*30mm*7um; mobile phase: [water(FA)-ACN]; gradient:33%-63% B over 10 min) The compound 1-(6-phenylpyridazin-3-yl)-N-(7-(pyrrolidin-1-yl)- 6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-amine (99.8 mg, 174.80 μmol, 20.22% yield, 91% purity) was obtained as a yellow solid. LC-MS (ES+, Method A), 0.56 min, m / z 520.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ (ppm) = 10.78 (s, 1H), 8.58 (d, J = 9.4 Hz, 1H), 8.27 (d, J = 9.4 Hz, 1H),8.25 - 8.21 (m, 2H), 7.65 - 7.57 (m, 3H), 7.54 (dd, J = 2.3, 8.1 Hz, 1H), 7.41 (d, J = 2.3 Hz, 1H), 7.18 (d, J = 8.1 Hz,1H), 3.04 - 2.92 (m, 2H), 2.64 (br s, 5H), 2.60 (br s, 2H), 2.05 - 1.82 (m, 2H), 1.72 (br s, 4H), 1.63 - 1.42 (m, 2H).

[0390] Compounds prepared in a similar manner to that set out above are given below in Table 8. Table 8 General route for the of 56:

[0391] To a mixture of 1H-benzo[d]imidazole (256.05 mg, 2.17 mmol), 1,4,7,10,13,16- hexaoxacyclooctadecane (57.29 mg, 216.74 μmol) and 3-chloro-6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazine (0.5 g, 2.17 mmol) in DMA (10 mL) was added iodocopper (82.56 mg, 433.48 μmol) and K2CO3(898.63 mg, 6.50 mmol) under N2. The mixture was stirred at 180 °C for 5 hours. The mixture was poured into water (80 mL) and ethyl acetate (80 mL). The mixture was filtered and the filter was extracted with ethyl acetate (150 mL × 3). The combined organic phase was washed with brine (180 mL × 3), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 5 / 1, 0 / 1) to give 3-(1H-benzo[d]imidazol-1-yl)-6,7-dihydro-5H- benzo[6,7]cyclohepta[1,2-c]pyridazine (660 mg, 2.07 mmol, 95.34% yield, 97.8% purity) as yellow solid. LC-MS (ES+, Method A), 0.51 min, m / z 313.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.46 (d, J = 8.0 Hz, 1H), 8.35 (s, 1H), 7.87 - 7.75 (m, 2H), 7.52 - 7.39 (m, 5H), 2.66 - 2.55 (m, 4H), 2.35 - 2.22 (m, 2H).

[0392] To a mixture of 3-(1H-benzo[d]imidazol-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2- c]pyridazine (300 mg, 960.41 μmol) in dioxane (10 mL) was added NBS (256.41 mg, 1.44 mmol). The mixture was stirred at 100 °C for 5 hours. The mixture was poured into water (120 mL). The aqueous phase was extracted with ethyl acetate (180 mL × 3). The combined organic phase was washed with brine (120 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, Petroleum ether / Ethyl acetate = 10 / 1, 1 / 1) to give 3-(2-bromo-1H-benzo[d]imidazol-1-yl)-6,7-dihydro- 5H-benzo[6,7]cyclohepta[1,2-c]pyridazine (140 mg, 329.19 μmol, 34.28% yield, 92% purity) as yellow solid. LC-MS (ES+, Method A), 0.56 min, m / z 392.9 [M+H]+. Compound 56: 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(7-(pyrrolidin-1-yl)-

[0393] To a mixture of 3-(2-bromo-1H-benzo[d]imidazol-1-yl)-6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2- c]pyridazine (100 mg, 255.58 μmol) and 7-(pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2- amine (117.75 mg, 511.16 μmol) in n-BuOH (10 mL) was added TsOH (88.02 mg, 511.16 μmol). The mixture was stirred at 100 °C for 2 hours. The mixture was concentrated in reduced pressure. The residue was diluted with ethyl acetate (50 mL) and saturated solution of NaHCO3. The aqueous phase was extracted with ethyl acetate (80 mL × 3). The combined organic phase was washed with brine (30 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuum. The residue was purified by prep- HPLC (column: Welch Xtimate C18150 × 25mm × 5um;mobile phase: [water(FA)-ACN];gradient:15%- 45% B over 10 min) to give 1-(6,7-dihydro-5H-benzo[6,7]cyclohepta[1,2-c]pyridazin-3-yl)-N-(7- (pyrrolidin-1-yl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-yl)-1H-benzo[d]imidazol-2-amine (66.4 mg, 113.17 μmol, 44.28% yield, 100% purity) as yellow solid. LC-MS (ES+, Method A), 0.45 min, m / z 541.3 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.11 (s, 1H), 7.89 - 7.82 (m, 1H), 7.58 - 7.50 (m, 4H), 7.49 - 7.41 (m, 3H), 7.21 (t, J = 7.8 Hz, 1H), 7.15 - 7.03 (m, 2H), 2.97 - 2.86 (m, 2H), 2.65 - 2.56 (m, 11H), 2.31 - 2.21 (m, 2H), 1.90 (dt, J = 2.4, 4.6 Hz, 2H), 1.70 (s, 4H), 1.66 - 1.20 (m, 2H). General route for the synthesis of Example 58: Step 1: 3-chloro-5-phenylpyridazine

[0394] A mixture of 5-bromo-3-chloro-pyridazine (500 mg, 2.58 mmol, 1 eq), phenylboronic acid (378.21 mg, 3.10 mmol, 1.2 eq), K2CO3 (714.53 mg, 5.17 mmol, 2 eq), Pd(dppf)Cl2.CH2Cl2 (211.10 mg, 258.49 μmol, 0.1 eq) in dioxane (5 mL), H2O (0.5 mL) was degassed and purged with N2 for 3 times, and then the mixture was stirred at 85 °C for 16 hr under N2 atmosphere. The reaction mixture was diluted with H2O (150 mL) and extracted with EtOAc (150 mL × 3). The combined organic layers were washed with NaCI (150 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 0 / 1 to 5 / 1) to afford 3-chloro-5-phenylpyridazine (300 mg, 1.57 mmol, 60.88% yield) as a yellow solid. LC-MS (ES+, Method A), 0.462 min, m / z 191.1 [M+H]+. Step 2: 1-(5-phenylpyridazin-3-yl)-3-(trifluoromethyl)-1H-1,2,4-triazol-5-amine

[0395] To a solution of 3-chloro-5-phenyl-pyridazine (300 mg, 1.57 mmol, 1 eq), 3-(trifluoromethyl)-1H- 1,2,4-triazol-5-amine (287.20 mg, 1.89 mmol, ...

Claims

CLAIMS What is claimed is:

1. A compound of Formula (IIʹ):or a pharmaceutically acceptable salt thereof, wherein: Ring A is a C6-10 aryl or 5-10 membered heteroaryl ring; RBis optionally substituted alkyl, halogen, or optionally substituted haloalkyl; Y1is –N(RN2)–, –O–, –S–, or –C(=O)–; YAis a bond, –C(RC)2– or –C(=O)–, wherein each instance of RCis independently hydrogen, halogen, or optionally substituted alkyl; each instance of RA, R2a, R2b, R3a, and R3bis independently hydrogen, halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; each instance of R2cand R3cis independently halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; or wherein R2aand an atom in the group RAare joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl; or wherein any two instances of R3a, R3b, and R3care joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl; each instance of RNand RN2is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, optionally substituted sulfonyl, or a nitrogen protecting group; or wherein two RNor RN1bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of ROis independently hydrogen, optionally substituted alkyl, optionally substitutedalkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; each instance of RSis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; w is 0, 1, 2, 3, or 4, as valency permits; and m is 0, 1, 2, or 3.

2. A compound of Formula (II):or a pharmaceutically acceptable salt thereof, wherein: Ring A is a C6-10aryl or 5-10 membered heteroaryl ring; RBis optionally substituted alkyl, halogen, or optionally substituted haloalkyl; Y1is –N(RN2)–, –O–, –S–, or –C(=O)–; each instance of RA, R2a, R2b, R3a, and R3bis independently hydrogen, halogen, –CN, –NO2, –N3, – SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; each instance of R2cand R3cis independently halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, – SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; or wherein R2aand an atom in the group RAare joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl; or wherein any two instances of R3a, R3b, and R3care joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl; each instance of RNand RN2is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionallysubstituted acyl, optionally substituted sulfinyl, optionally substituted sulfonyl, or a nitrogen protecting group; or wherein two RNor RN1bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of ROis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; each instance of RSis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; w is 0, 1, 2, 3, or 4, as valency permits; and m is 0, 1, 2, or 3.

3. The compound of claim 1 or 2, wherein the compound is of Formula (II-a):or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 or 2, wherein the compound is of Formula (II-b):or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 or 2, wherein the compound is of the formula:, or a pharmaceutically acceptable salt thereof, wherein: G1is N or CR1a; G2, G3, G4, and G5are each independently N or CR1b; and each instance of R1aand R1bis independently hydrogen, halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; or wherein R1aand R2aare joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl.

6. The compound of claim 5, wherein the compound is of the formula:, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3, or 4.

7. The compound of claim 6, wherein the compound is of the formula:, or a pharmaceutically acceptable salt thereof, wherein: Y2is optionally substituted C1-4alkylene or optionally substituted C1-4heteroalkylene.

8. The compound of claim 7, wherein the compound is of the formula:, or a pharmaceutically acceptable salt thereof, wherein: s is 0, 1, 2, or 3; p is 1, 2, 3, or 4; each instance of R6is independently hydrogen, optionally substituted alkyl, halogen, –CN, –ORO, –N(RN3)2, or –SRS; optionally wherein two R6on the same carbon atom are taken together to form =O; and each instance of RN3is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, optionally substituted sulfonyl, or a nitrogen protecting group; optionally wherein two RN3bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl.

9. The compound of claim 8, wherein the compound is of the formula:, or a pharmaceutically acceptable salt thereof.

10. The compound of claim 8, wherein the compound is of the formula:,or a pharmaceutically acceptable salt thereof.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein RBis optionally substituted haloalkyl.

12. The compound of any one of claims 1-11, or a pharmaceutically acceptable salt thereof, wherein RBis unsubstituted C1-3haloalkyl.

13. The compound of any one of claims 1-12, or a pharmaceutically acceptable salt thereof, wherein RBis unsubstituted C1haloalkyl.

14. The compound of any one of claims 1-13, or a pharmaceutically acceptable salt thereof, wherein RBis -CF3.

15. A compound of Formula (III):or a pharmaceutically acceptable salt thereof, wherein: X4, X5, X6, and X7are independently selected from N and CRX; Ring A is a C6-10 aryl or 5-10 membered heteroaryl ring; RBis optionally substituted alkyl, halogen, or optionally substituted haloalkyl; Y1is –N(RN2)–, –O–, –S–, or –C(=O)–; each instance of RA, R2a, R2b, R3a, R3b, and RXis independently hydrogen, halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; each instance of R2cand R3cis independently halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; or wherein R2aand an atom in the group RAare joined together with the intervening atoms to formoptionally substituted carbocyclyl or optionally substituted heterocyclyl; or wherein any two instances of R3a, R3b, and R3care joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl; each instance of RNand RN2is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, optionally substituted sulfonyl, or a nitrogen protecting group; or wherein two RNor RN1bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of ROis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; each instance of RSis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; w is 0, 1, 2, 3, or 4, as valency permits; and m is 0, 1, 2, or 3.

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

17. The compound of claim 15, wherein the compound is of Formula (III-b):or a pharmaceutically acceptable salt thereof.

18. The compound of claim 15, wherein the compound is of the formula:, or a pharmaceutically acceptable salt thereof, wherein: G1is N or CR1a; G2, G3, G4, and G5are each independently N or CR1b; and each instance of R1aand R1bis independently hydrogen, halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; or wherein R1aand R2aare joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl.

19. The compound of claim 18, wherein the compound is of the formula:, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3, or 4.

20. The compound of claim 19, wherein the compound is of the formula:, or a pharmaceutically acceptable salt thereof, wherein: Y2is optionally substituted C1-4 alkylene or optionally substituted C1-4 heteroalkylene.

21. The compound of claim 20, wherein the compound is of the formula:, or a pharmaceutically acceptable salt thereof, wherein: s is 0, 1, 2, or 3; p is 1, 2, 3, or 4; each instance of R6is independently hydrogen, optionally substituted alkyl, halogen, –CN, –ORO, –N(RN3)2, or –SRS; optionally wherein two R6on the same carbon atom are taken together to form =O; and each instance of RN3is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, optionally substituted sulfonyl, or a nitrogen protecting group; optionally wherein two RN3bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl.

22. The compound of claim 21, wherein the compound is of the formula:, or a pharmaceutically acceptable salt thereof.

23. The compound of claim 21, wherein the compound is of the formula:, or a pharmaceutically acceptable salt thereof.

24. The compound of any one of claims 14-23, or a pharmaceutically acceptable salt thereof, wherein X4, X5, X6, and X7are each independently CRX.

25. The compound of any one of claims 13-24, or a pharmaceutically acceptable salt thereof, wherein X4, X5, X6, and X7are each CH.

26. The compound of any one of claims 14-23, or a pharmaceutically acceptable salt thereof, wherein X4, X6, and X7are each independently CRX; and X5is N.

27. The compound of any one of claims 14-23 and 26, or a pharmaceutically acceptable salt thereof, wherein X4, X6, and X7are each CH; and X5is N.

28. The compound of any one of the preceding claims, wherein the group of the formula:one of the following formulae:29.or a pharmaceutically acceptable salt thereof, wherein: X1, X2, and X3are each independently N, NRN1, O, S, or CR4; Y1is –N(RN2)–, –O–, –S–, or –C(=O)–; RAis hydrogen, halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; each instance of R2a, R2b, R3a, R3b, R3c, and R4is independently hydrogen, halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; or wherein R2aand an atom in ring RAare joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl; or wherein any two instances of R3a, R3b, or R3care joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl; each instance of RN, RN1, and RN2is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl,optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, optionally substituted sulfonyl, or a nitrogen protecting group; or wherein two RNor RN1bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl; each instance of ROis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or an oxygen protecting group; each instance of RSis independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, or a sulfur protecting group; and m is 0, 1, 2, or 3; provided that when RAis hydrogen or halogen, then X1is not O or S; or X3is not N.

31. The compound of claim 30, wherein the compound is of one of the following formulae:or a pharmaceutically acceptable salt thereof.

32. The compound of claim 30 or 31, or a pharmaceutically acceptable salt thereof, provided that when RAis hydrogen or halogen, then X1is N and / or X3is O.

33. The compound of claim 30 or 31, or a pharmaceutically acceptable salt thereof, provided that when RAis hydrogen or halogen, then X1is N; X2is N; and X3is O.

34. The compound of claim 30 or 31, wherein RAis a ring selected from optionally substituted aryl or optionally substituted 6-10 membered heteroaryl.

35. The compound of claim 30 or 31, wherein the compound is of the formula:, or a pharmaceutically acceptable salt thereof, wherein: G1is N or CR1a; G2, G3, G4, and G5are each independently N or CR1b; and each instance of R1aand R1bis independently hydrogen, halogen, –CN, –NO2, –N3, –SCN, –ORO, –N(RN)2, –SRS, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, or optionally substituted sulfonyl; or wherein R1aand R2aare joined together with the intervening atoms to form optionally substituted carbocyclyl or optionally substituted heterocyclyl.

36. The compound of claim 35, wherein the compound is of the formula:, or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3, or 4.

37. The compound of claim 36, wherein the compound is of the formula:, or a pharmaceutically acceptable salt thereof, wherein: Y2is optionally substituted C1-4 alkylene or optionally substituted C1-4 heteroalkylene.

38. The compound of claim 37, wherein the compound is of the formula:, or a pharmaceutically acceptable salt thereof, wherein: s is 0, 1, 2, or 3; p is 1, 2, 3, or 4; r is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12, as valency permits; each instance of R6is independently hydrogen, optionally substituted alkyl, halogen, –CN, –ORO, –N(RN3)2, or –SRS; or wherein two R6on the same carbon atom are taken together to form =O; and each instance of RN3is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted acyl, optionally substituted sulfinyl, optionally substituted sulfonyl, or a nitrogen protecting group; or wherein two RN3bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted heterocyclyl or optionally substituted heteroaryl.

39. The compound of claim 38, wherein the compound is of the formula:, or a pharmaceutically acceptable salt thereof.

40. The compound of claim 38, wherein the compound is of the formula:, or a pharmaceutically acceptable salt thereof.

41. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X1is O, N, or CR4.

42. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X2is N or O.

43. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X3is N, CR4, O, or S.

44. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X1is O; X2is N; and X3is CR4.

45. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X1is N; X2is N; and X3is O.

46. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X1is CR4; X2is N; and X3is S.

47. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X1is CR4; X2is N; and X3is O.

48. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X1is O; X2is N; and X3is N.

49. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein X1is N; X2is O; and X3is N.

50. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R4is hydrogen.

51. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each instance of R4is hydrogen.

52. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R4is –NH2.

53. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof,wherein Y1is –N(RN2)–.

54. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein RN2is hydrogen.

55. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein RAis optionally substituted phenyl.

56. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein RAis hydrogen.

57. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein G1is CR1a.

58. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein G2is CR1b.

59. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein G3is CR1b.

60. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein G4is CR1b.

61. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein G5is CR1b.

62. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R1ais optionally substituted C1-6 alkyl.

63. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R1bis hydrogen.

64. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each instance of R1bis hydrogen.

65. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R1bis.

66. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2ais optionally substituted C1-6alkyl.

67. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2ais optionally substituted phenyl.

68. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2ais unsubstituted phenyl.

69. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2bis hydrogen.

70. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2bis optionally substituted phenyl.

71. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2bis unsubstituted phenyl.

72. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R1aand R2aare joined together with the intervening atoms to form optionally substituted carbocyclyl.

73. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R1aand R2aare joined together with the intervening atoms to form optionally substituted C7 carbocyclyl.

74. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Y2is optionally substituted C1-4 alkylene.

75. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Y2is optionally substituted C3alkylene.

76. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein, wherein s is 0, 1, 2, or 3.

77. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof,wherein s is 2.

78. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein n is 0.

79. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein RAis one of the following:

80. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3ais optionally substituted C1-6alkyl.

81. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3bis optionally substituted C1-6alkyl.

82. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3aand R3bare joined together with the intervening atoms to form optionally substituted carbocyclyl.

83. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3aand R3bare joined together with the intervening atoms to form optionally substituted C7carbocyclyl.

84. The compound of 78 or 79, or a pharmaceutically acceptable salt thereof, wherein the carbocyclyl formed by joining R3aand R3bis substituted with at least one instance of –N(RN3)2.

85. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3aand R3bare joined together with the intervening atoms to form optionally substituted heterocyclyl.

86. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3aand R3bare joined together with the intervening atoms to form optionally substituted 6- or 7- membered heterocyclyl comprising 1 or 2 ring heteroatoms selected from N, O, and S.

87. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3aand R3bare joined together with the intervening atoms to form optionally substituted 6- or 7- membered heterocyclyl comprising one ring nitrogen atom.

88. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3aand R3bare joined together with the intervening atoms to form:wherein v1 and v2 are independently 0 or 1.

89. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3aand R3bare joined together with the intervening atoms to form:

90. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3aand R3bare joined together with the intervening atoms to form: ,91. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein p is 3.

92. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3ais optionally substituted –O-C1-6 alkylene-R6.

93. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3ais –O-(CH2)1-6-R6.

94. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3ais –O-(CH2)1-6-N(RN3)2.

95. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3ais:

96. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3ais hydrogen.

97. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof,wherein R3bis optionally substituted –O-C1-6alkylene-R6.

98. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3bis –O-(CH2)1-6-R6.

99. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3bis –O-(CH2)1-6-N(RN3)2.

100. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof,101. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3bis hydrogen.

102. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R6is –N(RN3)2.

103. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each instance of RN3is independently hydrogen or optionally substituted C1-6 alkyl.

104. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein each instance of RN3is independently hydrogen, methyl, or iso-propyl.

105. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein two RN3bonded to the same nitrogen atom are joined together with the intervening atoms to form optionally substituted 5- or 6-membered heterocyclyl.

106. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein at least one instance of R6is:

107. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein r is 1.

108. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein m is 0.

109. The compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein w is 0.

110. The compound of claim 1, wherein the compound is selected from those in Table II, and pharmaceutically acceptable salts thereof.

111. The compound of claim 15, wherein the compound is selected from those in Table III, and pharmaceutically acceptable salts thereof.

112. The compound of claim 30, wherein the compound is selected from those in Table I, and pharmaceutically acceptable salts thereof.

113. A pharmaceutical composition comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

114. A method of preventing and / or treating an infectious disease in a subject comprising administering to the subject a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

115. The method of claim 114, wherein the infectious disease is a viral infection.

116. The method of claim 115, wherein the viral infection is an infection with a coronavirus.

117. The method of claim 115, wherein the viral infection is an infection with a SARS-CoV-2 virus or variant thereof.

118. The method of claim 115, wherein the viral infection is COVID-19.

119. A method of inhibiting the replication of a virus in a cell comprising contacting the cell with a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

120. The method of claim 119, wherein the virus is a coronavirus.

121. The method of claim119, wherein the virus is a SARS-CoV-2 virus or a variant thereof.

122. The method of any one of claims 119-121, wherein the cell is in vivo in a subject.

123. The method of any one of claims 119-121, wherein the cell is in vitro.

124. The method of any one of claims 114-118, and 122, wherein the subject is a human.

125. The method of any one of claims 114-118, and 122, wherein the subject is a non-human animal.

126. The method of claim 125, wherein the non-human animal is a non-human mammal.

127. The method of any one of the preceding claims comprising administering the compound, pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof, to a subject via inhalation, nebulizer, intratracheal administration, oral administration, or intravenous administration.

128. The method of any one of the preceding claims further comprising administering an additional antiviral or anti-inflammatory agent to the subject.

129. The method of any one of the preceding claims, wherein the compound or pharmaceutically acceptable salt thereof does not inhibit AXL receptor tyrosine kinase activity.

130. The method of any one of the preceding claims, wherein the compound or pharmaceutically acceptable salt thereof shows reduced inhibition of AXL receptor tyrosine kinase activity compared to bemcentinib.

131. A compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in preventing and / or treating an infectious disease in a subject.

132. Use of a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the preparation of a medicament.

133. A kit comprising a compound of any one of the preceding claims, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, and optionally instructions for use.

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