Methods to treat lymphoplasmacytic lymphoma

BACKGROUND OF THE INVENTION

Waldenström's macroglobulinemia (WM) is a distinct clinicopathological entity resulting from the accumulation, predominantly in the bone marrow, of clonally related lymphoplasmacytic cells which secrete a monoclonal IgM protein. This condition is considered to correspond to lymphoplasmacytic lymphoma (LPL) as defined by the World Health Organization classification system. WM is a rare disorder, with fewer than 1,500 cases occurring in the United States annually. There is a 2- to 3-fold risk increase of developing WM in people with a personal history of autoimmune diseases with autoantibodies and particularly elevated risks associated with hepatitis, human immunodeficiency virus, and rickettsiosis (Arch. Intern. Med., 2008, 168(17), 1903-9). There is no single accepted treatment for WM, and there can be a marked variation in clinical outcome. Objective response rates are high (>80%) but complete response rates are low (0-15%) (Clin. Adv. Hematol. Oncol., 2009, 7(10), 677-81, 687-90). Thus, there is a need for effective treatment of WM.

SUMMARY OF THE INVENTION

The present invention is based, at least in part, on the discovery of compounds of the Formula (I):

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or a pharmaceutically acceptable salt thereof, wherein X, Y, Q, U, R^A, R^B, R^X, k, and l are defined herein, for the treatment of Waldenström's macroglobulinemia. The activity of these compounds was established by in vitro screening against several kinases (e.g., BTK, HCK, TAK1, HPK1).

In certain embodiments, compounds of Formula (I) are of the formula:

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and pharmaceutically acceptable salts thereof.

The present invention also provides compounds of any one of Formulae (II) to (V):

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and pharmaceutically acceptable salts thereof, wherein Ring A′, Ring C′, Cy, X′, Y′, Z′, Q′, U′, R^A′, R^B′, R^D′, R^X′, k′, l′, and m′ are as defined herein.

The present invention is also based, at least in part, on the discovery that Waldenström's macroglobulinemia may be treated by administration of a compound of the invention to a subject in need thereof. The activity of these compounds was established by in vitro screening against several kinases (e.g., BTK, HCK, TAK1, HPK1) that are involved in the regulation of aberrant cell growth, as well as cell-based screening against several cell lines (e.g., BCWM.1, MWCL-1) that are disease state models of Waldenström's macroglobulinemia (Ditzel et al. Exp Hematol. 2007 September; 35(9):1366-75; Hodge et al. Blood. 2011 May 12; 117(19)).

The methods of treatment utilizing a compound of the invention also apply to B cell neoplasms of the group consisting of Hodgkin's lymphomas and most non-Hodgkin's lymphomas, such as diffuse large B cell lymphoma, Follicular lymphoma, mucosa-associated lymphatic tissue lymphoma (MALT), small cell lymphocytic lymphoma (overlaps with chronic lymphocytic leukemia), mantle cell lymphoma (MCL), Burkitt lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma (NMZL), splenic marginal zone lymphoma (SMZL), Intravascular large B-cell lymphoma, Primary effusion lymphoma, and Lymphomatoid granulomatosis.

The present invention is also based, at least in part, on pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition may be useful for modulating the activity of a kinase in vitro or in a subject in need thereof, and/or for treating and/or preventing in a subject in need thereof a condition associated with aberrant activity of a kinase (e.g., a proliferative disease). In certain embodiments, the pharmaceutical composition may be useful for treatment of Waldenström's macroglobulinemia in a subject in need thereof.

The present invention also provides kits comprising a container with a compound of the invention, or a pharmaceutical composition thereof. The kits may include a single dose or multiple doses of a compound described herein or a pharmaceutical composition thereof. The kits may be useful for modulating the activity of a kinase in a subject in need thereof. The kits may also be useful for treating and/or preventing in a subject in need thereof a condition associated with aberrant activity of a kinase. In certain embodiments, the kits further include instructions for using the kit (e.g., for administering a compound described herein, or a pharmaceutical composition thereof).

The details of particular embodiments of the invention are set forth herein. Other features, objects, and advantages of the invention will be apparent from the Detailed Description, the Examples, and the Claims.

DEFINITIONS
Chemical Definitions

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

Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972). The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of ¹⁹F with ¹⁸F, or the replacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example “C_1-6alkyl” is intended to encompass, C₁, C₂, C₃, C₄, C₅, C₆, C_1-6, C_1-5, C_1-4, C_1-3, C_1-2, C_2-6, C_2-5, C_2-4, C_2-3, C_3-6, C_3-5, C_3-4, C_4-6, C_4-5, and C_5-6alkyl.

The term “aliphatic,” as used herein, refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” as used herein, refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.

The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“C_1-10alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C_1-9alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C_1-8alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C_1-7alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C_1-6alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C_1-5alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C_1-4alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C_1-3alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C_1-2alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C₁alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C_2-6alkyl”). Examples of C_1-6alkyl 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 C_1-10alkyl (such as unsubstituted C_1-6alkyl, 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 (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C_1-10alkyl (such as substituted C_1-6alkyl, e.g., —CF₃, Bn).

As used herein, “haloalkyl” is a substituted alkyl group as defined herein wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In certain embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C_1-8haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C_1-6haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C_1-4haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C_1-3haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C_1-2haloalkyl”). In certain embodiments, all of the haloalkyl hydrogen atoms are replaced with fluoro to provide a perfluoroalkyl group. In certain embodiments, all of the haloalkyl hydrogen atoms are replaced with chloro to provide a “perchloroalkyl” group. Examples of haloalkyl groups include —CF₃, —CF₂CF₃, —CF₂CF₂CF₃, —CCl₃, —CFCl₂, —CF₂Cl, and the like.

As used herein, “heteroalkyl” refers to an alkyl group as defined herein 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 (“heteroC_1-10alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC_1-9alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC_1-8alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC_1-7alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC_1-6alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC_1-5alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC_1-4alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC_1-3alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC_1-2alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC₁alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC_2-6alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC_1-10alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC_1-10alkyl.

As used herein, “alkenyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, 3, or 4 double bonds). In certain embodiments, an alkenyl group has 2 to 9 carbon atoms (“C_2-9alkenyl”). In certain embodiments, an alkenyl group has 2 to 8 carbon atoms (“C_2-8alkenyl”). In certain embodiments, an alkenyl group has 2 to 7 carbon atoms (“C_2-7alkenyl”). In certain embodiments, an alkenyl group has 2 to 6 carbon atoms (“C_2-6alkenyl”). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms (“C_2-5alkenyl”). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C_2-4alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms (“C_2-3alkenyl”). In certain 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 C_2-4alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl (C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like. Examples of C_2-6alkenyl groups include the aforementioned C_2-4alkenyl 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 C_2-10alkenyl. In certain embodiments, the alkenyl group is a substituted C_2-10alkenyl.

As used herein, “heteroalkenyl” refers to an alkenyl group as defined herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC_2-10alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC_2-9alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC_2-8alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC_2-7alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC_2-6alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC_2-5alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC_2-4alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC_2-3alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC_2-6alkenyl”). 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 heteroC_2-10alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC_2-10alkenyl. In an alkenyl group, a C═C double bond for which the stereochemistry is not specified (e.g., —CH═CHCH₃or

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may be an (E)- or (Z)-double bond.

As used herein, “alkynyl” refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C_2-10alkynyl”). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms (“C_2-9alkynyl”). In certain embodiments, an alkynyl group has 2 to 8 carbon atoms (“C_2-8alkynyl”). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (“C_2-7alkynyl”). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (“C_2-6alkynyl”). In certain embodiments, an alkynyl group has 2 to 5 carbon atoms (“C_2-5alkynyl”). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms (“C_2-4alkynyl”). In certain embodiments, an alkynyl group has 2 to 3 carbon atoms (“C_2-3alkynyl”). In certain 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 C_2-4alkynyl groups include, without limitation, ethynyl (C₂), 1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), and the like. Examples of C_2-6alkenyl groups include the aforementioned C_2-4alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and the like. Additional examples of alkynyl include heptynyl (C₇), octynyl (C₈), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C_2-10alkynyl. In certain embodiments, the alkynyl group is a substituted C_2-10alkynyl.

As used herein, “heteroalkynyl” refers to an alkynyl group as defined herein 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 (“heteroC_2-10alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC_2-9alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC_2-8alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC_2-7alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC_2-6alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC_2-5alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC_2-4alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC_2-3alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC_2-6alkynyl”). 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 heteroC_2-10alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC_2-10alkynyl.

As used herein, “carbocyclyl” or “carbocyclic” refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms (“C_3-14carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C_3-10carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C_3-8carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C_3-7carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C_3-6carbocyclyl”). In certain embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C_4-6carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C_5-6carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C_5-10carbocyclyl”). Exemplary C_3-6carbocyclyl 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 C_3-8carbocyclyl groups include, without limitation, the aforementioned C_3-6carbocyclyl groups as well as cycloheptyl (C₇), cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇), cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇), bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C_3-10carbocyclyl groups include, without limitation, the aforementioned C_3-8carbocyclyl 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 C_3-14carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C_3-14carbocyclyl. In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C_3-14cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C_3-10cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C_3-8cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C_3-6cycloalkyl”). In certain embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C_4-6cycloalkyl”). In certain embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C_5-6cycloalkyl”). In certain embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C_5-10cycloalkyl”). Examples of C_5-6cycloalkyl groups include cyclopentyl (C₅) and cyclohexyl (C₅). Examples of C_3-6cycloalkyl groups include the aforementioned C_5-6cycloalkyl groups as well as cyclopropyl (C₃) and cyclobutyl (C₄). Examples of C_3-8cycloalkyl groups include the aforementioned C_3-6cycloalkyl 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 C_3-14cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C_3-14cycloalkyl.

As used herein, “heterocyclyl” or “heterocyclic” refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“3-14 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”) or tricyclic system (“tricyclic heterocyclyl”)), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.

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

Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetra-hydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.

As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C_6-14aryl”). In certain embodiments, an aryl group has 6 ring carbon atoms (“C₆aryl”; e.g., phenyl). In certain embodiments, an aryl group has 10 ring carbon atoms (“C₁₀aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In certain embodiments, an aryl group has 14 ring carbon atoms (“C₁₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C_6-14aryl. In certain embodiments, the aryl group is a substituted C_6-14aryl.

“Aralkyl” is a subset of “alkyl” and refers to an alkyl group, as defined herein, substituted by an aryl group, as defined herein, wherein the point of attachment is on the alkyl moiety.

As used herein, “heteroaryl” refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-14 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).

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

Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyrrolyl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing 4 heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.

“Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl group, as defined herein, substituted by a heteroaryl group, as defined herein, wherein the point of attachment is on the alkyl moiety.

As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl moieties) as herein defined.

As used herein, the term “saturated” refers to a ring moiety that does not contain a double or triple bond, i.e., the ring contains all single bonds.

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.

As understood from the above, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are, in certain embodiments, 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.

Exemplary carbon atom substituents include, but are not limited to, halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^aa, —ON(R^bb)₂, —N(R^bb)₂, —N(R^bb)₃⁺X⁻, —N(OR^cc)R^bb, —SH, —SR^aa, —SSR^cc, —C(═O)R^aa, —CO₂H, —CHO, —C(OR^cc)₂, —CO₂R^aa, —OC(═O)R^aa, —OCO₂R^aa, —C(═O)N(R^bb)₂, —OC(═O)N(R^bb)₂, —NR^bbC(═O)R^aa, —NR^bbCO₂R^aa, NR^bbC(═O)N(R^bb)₂, —C(═NR^bb)R^aa, —C(═NR^bb)OR^aa, —OC(═NR^bb)R^aa, —OC(═NR^bb)OR^aa, —C(═NR^bb)N(R^bb)₂, —OC(═NR^bb)N(R^bb)₂, —NR^bbC(═NR^bb)N(R^bb)₂, —C(═O)NR^bbSO₂R^aa, NR^bbSO₂R^aa, —SO₂N(R^bb)₂, —SO₂R^aa, —SO₂OR^aa, —OSO₂R^aa, —S(═O)R^aa, —OS(═O)R^aa, —Si(R^aa)₃, —OSi(R^aa)₃—C(═S)N(R^bb)₂, —C(═O)SR^aa, —C(═S)SR^aa, —SC(═S)SR^aa, —SC(═O)SR^aa, —OC(═O)SR^aa, —SC(═O)OR^aa, —SC(═O)R^aa, —P(═O)₂R^aa, —OP(═O)₂R^aa, —P(═O)(R^aa)₂, —OP(═O)(R^aa)₂, —OP(═O)(OR^cc)₂, —P(═O)₂N(R^bb)₂, —OP(═O)₂N(R^bb)₂, —P(═O)(NR^bb)₂, —OP(═O)(NR^bb)₂, —NR^bbP(═O)(OR^cc)₂, —NR^bbP(═O)(NR^bb)₂, —P(R^cc)₂, —P(R^cc)₃, —OP(R^cc)₂, —OP(R^cc)₃, —B(R^aa)₂, —B(OR^cc)₂, —BR^aa(OR^cc), C_1-10alkyl, C_1-10perhaloalkyl, C_2-10alkenyl, C_2-10alkynyl, heteroC_1-10alkyl, heteroC_2-10alkenyl, heteroC_2-10alkynyl, C_3-10carbocyclyl, 3-14 membered heterocyclyl, C_6-14aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^ddgroups;

or two geminal hydrogens on a carbon atom are replaced with the group ═O, ═S, ═NN(R^bb)₂, ═NNR^bbC(═O)R^aa, ═NNR^bbC(═O)OR^aa, ═NNR^bbS(═O)₂R^aa, ═NR^bb, or ═NOR^cc;

each instance of R^aais, independently, selected from C_1-10alkyl, C_1-10perhaloalkyl, C_2-10alkenyl, C_2-10alkynyl, heteroC_1-10alkyl, heteroC_2-10alkenyl, heteroC_2-10alkynyl, C_3-10carbocyclyl, 3-14 membered heterocyclyl, C_6-14aryl, and 5-14 membered heteroaryl, or two R^aagroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^ddgroups;

each instance of R^bbis, independently, selected from hydrogen, —OH, —OR^aa, —N(R^cc)₂, —CN, —C(═O)R^aa, —C(═O)N(R^cc)₂, —CO₂R^aa, —SO₂R^aa, —C(═NR^cc)OR^aa, —C(═NR^cc)N(R^cc)₂, —SO₂N(R^cc)₂, —SO₂R^cc, —SO₂OR^cc, —SOR^aa, —C(═S)N(R^cc)₂, —C(═O)SR^cc, —C(═S)SR^cc, —P(═O)₂R^aa, —P(═O)(R^aa)₂, —P(═O)₂N(R^cc)₂, —P(═O)(NR^cc)₂, C_1-10alkyl, C_1-10perhaloalkyl, C_2-10alkenyl, C_2-10alkynyl, heteroC_1-10alkyl, heteroC_2-10alkenyl, heteroC_2-10alkynyl, C_3-10carbocyclyl, 3-14 membered heterocyclyl, C_6-14aryl, and 5-14 membered heteroaryl, or two R^bbgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^ddgroups;

each instance of R^ccis, independently, selected from hydrogen, C_1-10alkyl, C_1-10perhaloalkyl, C_2-10alkenyl, C_2-10alkynyl, heteroC_1-10alkyl, heteroC_2-10alkenyl, heteroC_2-10alkynyl, C_3-10carbocyclyl, 3-14 membered heterocyclyl, C_6-14aryl, and 5-14 membered heteroaryl, or two R^ccgroups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^ddgroups;

each instance of R^ddis, independently, selected from halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OR^ee, —ON(R^ff)₂, —N(R^ff)₂, —N(R^ff)₃⁺X⁻, —N(OR^ee)R^ff, —SH, —SR^ee, —SSR^ee, —C(═O)R^ee, —CO₂H, —CO₂R^ee, —OC(═O)R^ee, —OCO₂R^ee, —C(═O)N(R^ff)₂, —OC(═O)N(R^ff)₂, —NR^ffC(═O)R^ee, —NR^ffCO₂R^ee, —NR^ffC(═O)N(R^ff)₂, —C(═NR^ff)OR^ee, —OC(═NR^ff)R^ee, —OC(═NR^ff)OR^ee, —C(═NR^ff)N(R^ff)₂, —OC(═NR^ff)N(R^ff)₂, —NR^ffC(═NR^ff)N(R^ff)₂, —NR^ffSO₂R^ee, —SO₂N(R^ff)₂, —SO₂R^ee, —SO₂OR^ee, —OSO₂R^ee, —S(═O)R^ee, —Si(R^ee)₃, —OSi(R^ee)₃, —C(═S)N(R^ff)₂, —C(═O)SR^ee, —C(═S)SR^ee, —SC(═S)SR^ee, —P(═O)₂R^ee, —P(═O)(R^ee)₂, —OP(═O)(R^ee)₂, —OP(═O)(OR^ee)₂, C_1-6alkyl, C_1-6perhaloalkyl, C_2-6alkenyl, C_2-6alkynyl, heteroC_1-6alkyl, heteroC_2-6alkenyl, heteroC_2-6alkynyl, C_3-10carbocyclyl, 3-10 membered heterocyclyl, C_6-10aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^gggroups, or two geminal R^ddsubstituents can be joined to form ═O or ═S;

each instance of R^eeis, independently, selected from C_1-6alkyl, C_1-6perhaloalkyl, C_2-6alkenyl, C_2-6alkynyl, heteroC_1-6alkyl, heteroC_2-6alkenyl, heteroC_2-6alkynyl, C_3-10carbocyclyl, C_6-10aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^gggroups;

each instance of R^ffis, independently, selected from hydrogen, C_1-6alkyl, C_1-6perhaloalkyl, C_2-6alkenyl, C_2-6alkynyl, heteroC_1-6alkyl, heteroC_2-6alkenyl, heteroC_2-6alkynyl, C_3-10carbocyclyl, 3-10 membered heterocyclyl, C_6-10aryl and 5-10 membered heteroaryl, or two R^ffgroups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^gggroups; and

each instance of R^ggis, independently, halogen, —CN, —NO₂, —N₃, —SO₂H, —SO₃H, —OH, —OC_1-6alkyl, —ON(C_1-6alkyl)₂, —N(C_1-6alkyl)₂, —N(C_1-6alkyl)₃⁺X⁻, —NH(C_1-6alkyl)₂⁺X⁻, —NH₂(C_1-6alkyl)⁺X⁻, —NH₃⁺X⁻, —N(OC_1-6alkyl)(C_1-6alkyl), —N(OH)(C_1-6alkyl), —NH(OH), —SH, —SC_1-6alkyl, —SS(C_1-6alkyl), —C(═O)(C_1-6alkyl), —CO₂H, —CO₂(C_1-6alkyl), —OC(═O)(C_1-6alkyl), —OCO₂(C_1-6alkyl), —C(═O)NH₂, —C(═O)N(C_1-6alkyl)₂, —OC(═O)NH(C_1-6alkyl), —NHC(═O)(C_1-6alkyl), —N(C_1-6alkyl)C(═O)(C_1-6alkyl), —NHCO₂(C_1-6alkyl), —NHC(═O)N(C_1-6alkyl)₂, —NHC(═O)NH(C_1-6alkyl), —NHC(═O)NH₂, —C(═NH)O(C_1-6alkyl), —OC(═NH)(C_1-6alkyl), —OC(═NH)OC_1-6alkyl, —C(═NH)N(C_1-6alkyl)₂, —C(═NH)NH(C_1-6alkyl), —C(═NH)NH₂, —OC(═NH)N(C_1-6alkyl)₂, —OC(NH)NH(C_1-6alkyl), —OC(NH)NH₂, —NHC(NH)N(C_1-6alkyl)₂, —NHC(═NH)NH₂, —NHSO₂(C_1-6alkyl), —SO₂N(C_1-6alkyl)₂, —SO₂NH(C₁₄alkyl), —SO₂NH₂, —SO₂C_1-4alkyl, —SO₂OC_1-6alkyl, —OSO₂C_1-6alkyl, —SOC_1-6alkyl, —Si(C_1-6alkyl)₃, —OSi(C_1-6alkyl)₃-C(═S)N(C_1-6alkyl)₂, C(═S)NH(C_1-6alkyl), C(═S)NH₂, —C(═O)S(C_1-6alkyl), —C(═S)SC_1-6alkyl, —SC(═S)SC_1-6alkyl, —P(═O)₂(C_1-6alkyl), —P(═O)(C_1-6alkyl)₂, —OP(═O)(C_1-6alkyl)₂, —OP(═O)(OC_1-6alkyl)₂, C_1-6alkyl, C_1-6perhaloalkyl, C_2-6alkenyl, C_2-6alkynyl, heteroC_1-6alkyl, heteroC_2-6alkenyl, heteroC_2-6alkynyl, C_3-10carbocyclyl, C_6-10aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R^ggsubstituents can be joined to form ═O or ═S; wherein X⁻ is a counterion.

As used herein, the term “halo” or “halogen” refers to fluorine (fluoro, —F), chlorine (chloro, —Cl), bromine (bromo, —Br), or iodine (iodo, —I).

In certain embodiments, the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an “amino protecting group”). Nitrogen protecting groups include, but are not limited to, —OH, —OR^aa, —N(R^cc)₂, —C(═O)R^aa, —C(═O)N(R^cc)₂, —CO₂R^aa, —SO₂R^aa, —C(═NR^cc)R^aa, —C(═NR^cc)OR^aa, —C(═NR^cc)N(R^cc)₂, —SO₂N(R^cc)₂, —SO₂R^cc, —SO₂OR^cc, —SOR^aa, —C(═S)N(R^cc)₂, —C(═O)SR^cc, —C(═S)SR^cc, C_1-10alkyl (e.g., alkyl, aralkyl, heteroaralkyl), C_2-10alkenyl, C_2-10alkynyl, C_1-10heteroalkyl, C_2-10heteroalkenyl, C_2-10heteroalkynyl, C_3-10carbocyclyl, 3-14 membered heterocyclyl, C_6-14aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R^ddgroups, and wherein R^aa, R^bb, R^ccand R^ddare as described herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

For example, nitrogen protecting groups such as amide groups (e.g., —C(═O)R^aa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitophenylacetamide, o-nitrophenoxyacetamide, acetoacetamide, (N′-dithiobenzyloxyacylamino)acetamide, 3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide, 2-methyl-2-(o-nitrophenoxy)propanamide, 2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine derivative, o-nitrobenzamide and o-(benzoyloxymethyl)benzamide.

Nitrogen protecting groups such as carbamate groups (e.g., —C(═O)OR^aa) include, but are not limited to, methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and 4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.

Nitrogen protecting groups such as sulfonamide groups (e.g., —S(═O)₂R^aa) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.

Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacyl derivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N—(N′,N′-dimethylaminomethylene)amine, N,N′-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).

In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include, but are not limited to, —R^aa, —N(R^bb)₂, —C(═O)SR^aa, —C(═O)R^aa, —CO₂R^aa, —C(═O)N(R^bb)₂, —C(═NR^bb)R^aa, —C(═NR^bb)OR^aa, —C(═NR^bb)N(R^bb)₂, —S(═O)R^aa, —SO₂R^aa, —Si(R^aa)₃, —P(R^cc)₂, —P(R^cc)₃, —P(═O)₂R^aa, —P(═O)(R^aa)₂, —P(═O)(OR^cc)₂, —P(═O)₂N(R^bb)₂, and —P(═O)(NR^bb)₂, wherein R^aa, R^bb, and R^ccare as described herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC), 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, o-naphthoate, nitrate, alkyl N,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

In certain embodiments, the substituent present on an sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). Sulfur protecting groups include, but are not limited to, —R^aa, —N(R^bb)₂, —C(═O)SR^aa, —C(═O)R^aa, —CO₂R^aa, —C(═O)N(R^bb)₂, —C(═NR^bb)R^aa, —C(═NR^bb)OR^aa, —C(═NR^bb)N(R^bb)₂, —S(═O)R^aa, —SO₂R^aa, —Si(R^aa)₃, —P(R^cc)₂, —P(R^cc)₃, —P(═O)₂R^aa, —P(═O)(R^aa)₂, —P(═O)(OR^cc)₂, —P(═O)₂N(R^bb)₂, and —P(═O)(NR^bb)₂, wherein R^aa, R^bb, and R^ccare as described herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3^rdedition, John Wiley & Sons, 1999, incorporated herein by reference.

As used herein, a “leaving group”, or “LG”, is a term understood in the art to refer to a molecular fragment that departs with a pair of electrons upon heterolytic bond cleavage, wherein the molecular fragment is an anion or neutral molecule. See, for example, Smith, March Advanced Organic Chemistry 6th ed. (501-502). Examples of suitable leaving groups include, but are not limited to, halides (such as chloride, bromide, or iodide), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, haloformates, —NO₂, trialkylammonium, and aryliodonium salts. In certain embodiments, the leaving group is a sulfonic acid ester. In certain embodiments, the sulfonic acid ester comprises the formula —OSO₂R^LG1wherein R^LG1is selected from the group consisting alkyl optionally, alkenyl optionally substituted, heteroalkyl optionally substituted, aryl optionally substituted, heteroaryl optionally substituted, arylalkyl optionally substituted, and heterarylalkyl optionally substituted. In certain embodiments, R^LG1is substituted or unsubstituted C₁-C₆alkyl. In certain embodiments, R^LG1is methyl. In certain embodiments, R^LG1is —CF₃. In certain embodiments, R^LG1is substituted or unsubstituted aryl. In certain embodiments, R^LG1is substituted or unsubstituted phenyl. In certain embodiments R^LG1is:

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In some cases, the leaving group is toluenesulfonate (tosylate, Ts), methanesulfonate (mesylate, Ms), p-bromobenzenesulfonyl (brosylate, Bs), or trifluoromethanesulfonate (triflate, Tf). In some cases, the leaving group is a brosylate (p-bromobenzenesulfonyl). In some cases, the leaving group is a nosylate (2-nitrobenzenesulfonyl). In certain embodiments, the leaving group is a sulfonate-containing group. In certain embodiments, the leaving group is a tosylate group. The leaving group may also be a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate.

These and other exemplary substituents are described in more detail in the Detailed Description, Examples, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.

Other Definitions

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

As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N⁺(C_1-4alkyl)₄⁻ salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. Compounds of the invention 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 isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.

The term “hydrate” refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R·×H₂O, wherein R is the compound and wherein x is a number greater than 0. A given compound may form more than one type of hydrates, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R·0.5H₂O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R·2H₂O) and hexahydrates (R·6H₂O)).

The term “tautomers” refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of it electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.

It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.

Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

The term “polymorphs” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, 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 of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers 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 of this invention are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly the C₁-C₈alkyl, C₂-C₈alkenyl, C₂-C₈alkynyl, aryl, C₇-C₁₂substituted aryl, and C₇-C₁₂arylalkyl esters of the compounds of the invention (e.g., the compounds of Formula (I) and compounds of any one of Formulae (II) to (V)).

DETAILED DESCRIPTION OF THE INVENTION

In an effort to identify novel treatments for Waldenström's macroglobulinemia, in vitro screens were carried out against several kinases (e.g., BTK, HCK, TAK1). These kinases are involved in the regulation of aberrant cell growth associated with this condition. Cell-based screening was also carried out in several disease state model lines of Waldenström's macroglobulinemia (e.g., BCWM.1, MWCL-1). Based on these screening efforts and subsequent lead optimization, compounds of the invention were identified.

In one aspect, the present invention provides compounds of Formula (I):

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and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof;

wherein:

each instance of R^Ais independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, —OR^A1, —N(R^A1)₂, —CN, —C(═O)R^A1, —C(═O)OR^A1, —C(═O)N(R^A1)₂, —NO₂, —NR^A1C(═O)R^A1, —NR^A1C(═O)OR^A1, —NR^A1S(═O)₂R^A1, —S(═O)₂R^A1, or —S(═O)₂N(R^A1)₂;

each instance of R^Bis independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR^A1, —N(R^A1)₂, —CN, —C(═O)R^A1, —C(═O)OR^A1, —C(═O)N(R^A1)₂, —NO₂, —NR^A1C(═O)R^A1, —NR^A1C(═O)OR^A1, —NR^A1S(═O)₂R^A1, —S(═O)₂R^A1, or —S(═O)₂N(R^A1)₂;

each instance of R^A1is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R^A1groups are joined to form an optionally substituted heterocyclic ring;

R^Xis R^Dor is selected from the group consisting of optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and —N(R^A1)(R^Xa);

each instance of R^Xais selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)R^A1, —C(═O)OR^A1, —C(═O)N(R^A1)₂, —S(═O)R^A1, —S(═O)N(R^A1)₂, —S(═O)₂R^A1, —S(═O)₂OR^A1, —S(═O)₂N(R^A1)₂, and a nitrogen protecting group;

k is 0, 1, 2, 3, or 4;

l is 1, 2, 3, 4, or 5;

X and Y are taken together to be —NR^A(C═O)— or —(C═O)NR^A—;

Q and U are taken together to be —NR^A(C═O)— or —(C═O)NR^A—; and

R^Dis an electrophilic moiety as described herein.

In certain embodiments, the present invention provides compounds from the group consisting of:

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and pharmaceutically acceptable salts thereof.

In another aspect, the present invention provides methods for treating Waldenström's macroglobulinemia (WM) in a subject using compounds of the invention. The methods comprise administering to a subject in need thereof an effective amount of a compound of the invention. Also provided are methods to treat other B cell neoplasms using compounds of the invention in combination with inhibitors of Bruton's tyrosine kinase (BTK), interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), bone marrow on X chromosome kinase (BMX), phosphoinositide 3-kinase (PI3K), transforming growth factor b-activated kinase-1 (TAK1), and/or a Src family kinase. In certain embodiments, one or more compounds of the invention are used in combination with an inhibitor of the phosphoinositide 3-kinase delta isoform (PI3Kδ). In certain embodiments, combinations of 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the agents described herein are used for treating WM. In certain embodiments, the agents described herein are used in combination with kinase inhibitors such as inhibitors of Bruton's tyrosine kinase (BTK), interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), bone marrow on X chromosome kinase (BMX), phosphoinositide 3-kinase (PI3K), and/or transforming growth factor b-activated kinase-1 (TAK1), and/or a Src family kinase.

Waldenstrom's macroglobulinemia (WM) is a distinct clinicopathological entity resulting from the accumulation, predominantly in the bone marrow, of clonally related lymphoplasmacytic cells which secrete a monoclonal IgM protein. This condition is considered to correspond to lymphoplasmacytic lymphoma (LPL) as defined by the World Health Organization classification system. Genetic factors play an important role in the pathogenesis of WM, with 25% of patients demonstrating a family history. IgM monoclonal gammopathy of unknown significance (MGUS) often precedes the development of WM.

As used herein, a B cell neoplasm includes both Hodgkin's lymphoma and non-Hodgkin's lymphomas. Classical Hodgkin's lymphoma (HL) includes various subtypes such as Nodular sclerosing HL, Mixed-cellularity subtype, Lymphocyte-rich or Lymphocytic predominance and Lymphocyte depleted. Examples of B cell non-Hodgkin's lymphomas include, but are not limited to, Waldenström's macroglobulinemia, diffuse large B cell lymphoma, follicular lymphoma, mucosa-associated lymphatic tissue lymphoma (MALT), small cell lymphocytic lymphoma (overlaps with chronic lymphocytic leukemia), mantle cell lymphoma (MCL), Burkitt lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma (NMZL), splenic marginal zone lymphoma (SMZL), intravascular large B-cell lymphoma, primary effusion lymphoma, and lymphomatoid granulomatosis.

In certain embodiments, the subject is administered a compound of Formula (I):

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and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof;

wherein:

k is 0, 1, 2, 3, or 4;

l is 1, 2, 3, 4, or 5;

X and Y are taken together to be —NR^A(C═O)— or —(C═O)NR^A—;

Q and U are taken together to be —NR^A(C═O)— or —(C═O)NR^A—; and

R^Dis an electrophilic moiety as described herein.

In certain embodiments, the subject is adminstered a compound (I-1):

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or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is adminstered a compound (I-2):

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or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is adminstered a compound (I-3):

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or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is adminstered a compound (I-4):

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or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is adminstered a compound (I-5):

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or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is adminstered a compound (I-6):

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or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is adminstered a compound (I-7):

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or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is adminstered a compound (I-8):

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or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is adminstered a compound (I-9):

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or a pharmaceutically acceptable salt thereof.

Compounds of Formula (I) include a phenyl Ring A optionally substituted with one or more R^Agroups. In certain embodiments, k is 0. In certain embodiments, Ring A is of the formula:

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In certain embodiments, Ring A is of the formula:

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In certain embodiments, k is 2. In certain embodiments, Ring A is of the formula:

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In certain embodiments, Ring A is of the formula:

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In certain embodiments, k is 3. In certain embodiments, Ring A is of the formula:

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In certain embodiments, Ring A is of the formula:

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In certain embodiments, k is 4. In certain embodiments, Ring A is of the formula:

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In compounds of Formula (I), Ring A may be substituted with one or more R^Agroups. In certain embodiments, at least one R^Ais H. In certain embodiments, at least two R^Agroups are H. In certain embodiments, at least three R^Agroups are H. In certain embodiments, at least four R^Agroups are H. In certain embodiments, at least one R^Ais not H. In certain embodiments, at least two R^Agroups are not H. In certain embodiments, at least three R^Agroups are not H. In certain embodiments, at least one R^Ais halogen. In certain embodiments, at least one R^Ais F. In certain embodiments, at least one R^Ais Cl. In certain embodiments, at least one R^Ais Br. In certain embodiments, at least one R^Ais I (iodine). In certain embodiments, one R^Ais F. In certain embodiments, one R^Ais Cl. In certain embodiments, at least one R^Ais substituted alkyl. In certain embodiments, at least one R^Ais unsubstituted alkyl. In certain embodiments, at least one R^Ais substituted C_1-6alkyl. In certain embodiments, at least one R^Ais unsubstituted C_1-6alkyl. In certain embodiments, at least one R^Ais methyl. In certain embodiments, at least one R^Ais ethyl. In certain embodiments, at least one R^Ais propyl. In certain embodiments, at least one R^Ais butyl. In certain embodiments, at least one R^Ais substituted carbocyclyl. In certain embodiments, at least one R^Ais unsubstituted carbocyclyl. In certain embodiments, at least one R^Ais —OR^A1. In certain embodiments, at least one R^Ais —O(C_1-6alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R^Ais —OMe. In certain embodiments, at least one R^Ais —OH. In certain embodiments, at least one R^Ais —N(R^A1)₂. In certain embodiments, at least one R^Ais —NH₂. In certain embodiments, at least one R^Ais —CN. In certain embodiments, at least one R^Ais —C(═O)R^A1. In certain embodiments, at least one R^Ais acetyl. In certain embodiments, at least one R^Ais —C(═O)OR^A1. In certain embodiments, at least one R^Ais —C(═O)N(R^A1)₂. In certain embodiments, at least one R^Ais —C(═O)NHR^A1. In certain embodiments, at least one R^Ais —C(═O)NH(C_1-6alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R^Ais —C(═O)NHMe. In certain embodiments, at least one R^Ais —C(═O)NH₂. In certain embodiments, at least one R^Ais —NO₂. In certain embodiments, at least one R^Ais —NR^A1C(═O)R^A1. In certain embodiments, at least one R^Ais —NR^A1C(═O)OR^A1. In certain embodiments, at least one R^Ais —NR^A1S(═O)₂R^A1. In certain embodiments, at least one R^Ais —NHS(═O)₂R^A1. In certain embodiments, at least one R^Ais —NHS(═O)₂(C_1-6alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R^Ais —NHS(═O)₂Me. In certain embodiments, at least one R^Ais —S(═O)₂R^A1. In certain embodiments, at least one R^Ais —S(═O)₂N(R^A1)₂. In certain embodiments, at least one R^Ais —S(═O)₂N(R^A1)₂. In certain embodiments, at least one R^Ais —S(═O)₂N(C_1-6alkyl)₂. In certain embodiments, at least one R^Ais —S(═O)₂NH(C_1-6alkyl). In certain embodiments, at least one R^Ais —S(═O)₂NH(t-Bu). In certain embodiments, at least one R^Ais —S(═O)₂NH₂.

In certain embodiments, R^Ais —OR^A1; and k is 1. In certain embodiments, R^Ais —O(C_1-6alkyl); and k is 1. In certain embodiments, R^Ais —OMe; and k is 1. In certain embodiments, R^Ais —OH; and k is 1.

In certain embodiments, R^Ais substituted C_1-6alkyl; and k is 1. In certain embodiments, R^Ais unsubstituted C_1-6alkyl; and k is 1. In certain embodiments, R^Ais methyl; and k is 1. In certain embodiments, R^Ais —CF₃; and k is 1. In certain embodiments, R^Ais ethyl; and k is 1. In certain embodiments, R^Ais propyl; and k is 1. In certain embodiments, R^Ais butyl; and k is 1. In certain embodiments, R^Ais propyl; and k is 1. In certain embodiments, R^Ais butyl; and k is 1.

In certain embodiments, R^Ais halogen; and k is 1. In certain embodiments, R^Ais F; and k is 1. In certain embodiments, R^Ais Cl; and k is 1. In certain embodiments, R^Ais Br; and k is 1. In certain embodiments, R^Ais I (iodine); and k is 1.

In certain embodiments, one instance of R^Ais halogen; another instance of R^Ais substituted C_1-6alkyl; and k is 2. In certain embodiments, one instance of R^Ais F; another instance of R^Ais substituted C_1-6alkyl; and k is 2. In certain embodiments, one instance of R^Ais Cl; another instance of R^Ais substituted C_1-6alkyl; and k is 2. In certain embodiments, one instance of R^Ais halogen; another instance of R^Ais unsubstituted C_1-6alkyl; and k is 2. In certain embodiments, one instance of R^Ais F; another instance of R^Ais unsubstituted C_1-6alkyl; and k is 2. In certain embodiments, one instance of R^Ais Cl; another instance of R^Ais unsubstituted C_1-6alkyl; and k is 2. In certain embodiments, one instance of R^Ais halogen; another instance of R^Ais methyl; and k is 2. In certain embodiments, one instance of R^Ais F; another instance of R^Ais methyl; and k is 2. In certain embodiments, one instance of R^Ais Cl; another instance of R^Ais methyl; and k is 2. In certain embodiments, one instance of R^Ais halogen; another instance of R^Ais —CF₃; and k is 2. In certain embodiments, one instance of R^Ais F; another instance of R^Ais —CF₃; and k is 2. In certain embodiments, one instance of R^Ais Cl; another instance of R^Ais —CF₃; and k is 2.

In certain embodiments, at least one R^A1is H. In certain embodiments, at least one R^A1is substituted acyl. In certain embodiments, at least one R^A1is unsubstituted acyl. In certain embodiments, at least one R^A1is acetyl. In certain embodiments, at least one R^A1is substituted alkyl. In certain embodiments, at least one R^A1is unsubstituted alkyl. In certain embodiments, at least one R^A1is C_1-6alkyl. In certain embodiments, at least one R^A1is methyl. In certain embodiments, at least one R^A1is ethyl. In certain embodiments, at least one R^A1is propyl. In certain embodiments, at least one R^A1is butyl. In certain embodiments, at least one R^A1is substituted alkenyl. In certain embodiments, at least one R^A1is unsubstituted alkenyl. In certain embodiments, at least one R^A1is substituted alkynyl. In certain embodiments, at least one R^A1is unsubstituted alkynyl. In certain embodiments, at least one R^A1is substituted carbocyclyl. In certain embodiments, at least one R^A1is unsubstituted carbocyclyl. In certain embodiments, at least one R^A1is substituted heterocyclyl. In certain embodiments, at least one R^A1is unsubstituted heterocyclyl. In certain embodiments, at least one R^A1is substituted aryl. In certain embodiments, at least one R^A1is unsubstituted aryl. In certain embodiments, at least one R^A1is substituted phenyl. In certain embodiments, at least one R^A1is unsubstituted phenyl. In certain embodiments, at least one R^A1is substituted heteroaryl. In certain embodiments, at least one R^A1is unsubstituted heteroaryl. In certain embodiments, at least one R^A1is substituted pyridyl. In certain embodiments, at least one R^A1is unsubstituted pyridyl. In certain embodiments, at least one R^A1is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R^A1is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R^A1is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R^A1is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R^A1is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R^A1is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom.

In compounds of Formula (I), two R^A1groups may be joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring. In certain embodiments, two R^A1groups are joined to form a substituted carbocyclic ring. In certain embodiments, two R^A1groups are joined to form an unsubstituted carbocyclic ring. In certain embodiments, two R^A1groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R^A1groups are joined to form an unsubstituted heterocyclic ring. In certain embodiments, two R^A1groups are joined to form a substituted aryl ring. In certain embodiments, two R^A1groups are joined to form an unsubstituted aryl ring. In certain embodiments, two R^A1groups are joined to form a substituted phenyl ring. In certain embodiments, two R^A1groups are joined to form an unsubstituted phenyl ring. In certain embodiments, two R^A1groups are joined to form a substituted heteroaryl ring. In certain embodiments, two R^A1groups are joined to form an unsubstituted heteroaryl ring.

Compounds of Formula (I) include a phenyl Ring C optionally substituted with one or more R^Bgroups. In certain embodiments, l is 1. In certain embodiments, Ring C is of the formula:

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In certain embodiments, Ring C is of the formula:

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In certain embodiments, l is 2. In certain embodiments, Ring C is of the formula:

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In certain embodiments, Ring C is of the formula:

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In certain embodiments, 1 is 3. In certain embodiments, Ring C is of the formula:

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In certain embodiments, Ring C is of the formula:

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In certain embodiments, 1 is 4. In certain embodiments, Ring C is of the formula:

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In certain embodiments, Ring C is of the formula:

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In certain embodiments, 1 is 5. In certain embodiments, Ring C is of the formula:

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In compounds of Formula (I), Ring C may be substituted with one or more R^Bgroups. In certain embodiments, at least one R^Bis H. In certain embodiments, at least two R^Bgroups are H. In certain embodiments, at least three R^Bgroups are H. In certain embodiments, at least four R^Bgroups are H. In certain embodiments, at least one R^Bis not H. In certain embodiments, at least two R^Bgroups are not H. In certain embodiments, at least three R^Bgroups are not H. In certain embodiments, at least one R^Bis halogen. In certain embodiments, at least one R^Bis F. In certain embodiments, at least one R^Bis Cl. In certain embodiments, at least one R^Bis Br. In certain embodiments, at least one R^Bis I (iodine). In certain embodiments, one R^Bis F. In certain embodiments, one R^Bis Cl. In certain embodiments, at least one R^Bis substituted alkyl. In certain embodiments, at least one R^Bis unsubstituted alkyl. In certain embodiments, at least one R^Bis substituted C_1-6alkyl. In certain embodiments, at least one R^Bis unsubstituted C_1-6alkyl. In certain embodiments, at least one R^Bis methyl. In certain embodiments, at least one R^Bis ethyl. In certain embodiments, at least one R^Bis propyl. In certain embodiments, at least one R^Bis

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In certain embodiments, at least one R^Bis

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In certain embodiments, at least one R^Bis butyl. In certain embodiments, at least one R^Bis substituted carbocyclyl. In certain embodiments, at least one R^Bis unsubstituted carbocyclyl. In certain embodiments, at least one R^Bis substituted heterocyclyl. In certain embodiments, at least one R^Bis unsubstituted heterocyclyl. In certain embodiments, at least one R^Bis substituted piperidine. In certain embodiments, at least one R^Bis unsubstituted piperidine. In certain embodiments, at least one R^Bsubstituted piperizine. In certain embodiments, at least one R^Bunsubstituted piperizine. In certain embodiments, at least one R^Bsubstituted pyrrolidine. In certain embodiments, at least one R^Bunsubstituted pyrrolidine. In certain embodiments, at least one R^Bis substituted morpholine. In certain embodiments, at least one R^Bis unsubstituted morpholine. In certain embodiments, at least one R^Bis substituted diazapane. In certain embodiments, at least one R^Bis unsubstituted diazapane. In certain embodiments, at least one R^Bis

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In certain embodiments, at least one R^Bis

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In certain embodiments, at least one R^Bis substituted —(CH₂)(heterocyclyl). In certain embodiments, at least one R^Bis unsubstituted —(CH₂)(heterocyclyl). In certain embodiments, at least one R^Bis

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In certain embodiments, at least one R^Bis

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In certain embodiments, at least one R^Bis substituted —(CH₂)₂(heterocyclyl). In certain embodiments, at least one R^Bis unsubstituted —(CH₂)₂(heterocyclyl). In certain embodiments, at least one R^Bis

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In certain embodiments, at least one R^Bis substituted —(CH₂)₃(heterocyclyl). In certain embodiments, at least one R^Bis unsubstituted —(CH₂)₃(heterocyclyl). In certain embodiments, at least one R^Bis

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In certain embodiments, at least one R^Bis substituted aryl. In certain embodiments, at least one R^Bis unsubstituted aryl. In certain embodiments, at least one R^Bis substituted phenyl. In certain embodiments, at least one R^Bis unsubstituted phenyl. In certain embodiments, at least one R^Bis substituted heteroaryl. In certain embodiments, at least one R^Bis unsubstituted heteroaryl. In certain embodiments, at least one R^Bis substituted pyridyl. In certain embodiments, at least one R^Bis unsubstituted pyridyl. In certain embodiments, at least one R^Bis substituted imidazole. In certain embodiments, at least one R^Bis unsubstituted imidazole. In certain embodiments, at least one R^Bis

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In certain embodiments, at least one R^Bis

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In certain embodiments, at least one R^Bis —OR^A1. In certain embodiments, at least one R^Bis —O(C_1-6alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R^Bis —OMe. In certain embodiments, at least one R^Bis —OPh. In certain embodiments, at least one R^Bis

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In certain embodiments, at least one R^Bis

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In certain embodiments, at least one R^Bis —OH. In certain embodiments, at least one R^Bis —N(R^A1)₂. In certain embodiments, at least one R^Bis —NEt₂. In certain embodiments, at least one R^Bis —NMe₂. In certain embodiments, at least one R^Bis —NHtBu. In certain embodiments, at least one R^Bis

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In certain embodiments, at least one R^Bis

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In certain embodiments, at least one R^Bis —NH₂. In certain embodiments, at least one R^Bis —CN. In certain embodiments, at least one R^Bis —C(═O)R^A1. In certain embodiments, at least one R^Bis acetyl. In certain embodiments, at least one R^Bis —C(═O)OR^A1. In certain embodiments, at least one R^Bis —C(═O)N(R^A1)₂. In certain embodiments, at least one R^Bis —C(═O)NHR^A1. In certain embodiments, at least one R^Bis —C(═O)NH(C_1-6alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R^Bis —C(═O)NHMe. In certain embodiments, at least one R^Bis —C(═O)NH₂. In certain embodiments, at least one R^Bis

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In certain embodiments, at least one R^Bis

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In certain embodiments, at least one R^Bis —NO₂. In certain embodiments, at least one R^Bis —NR^A1C(═O)R^A1. In certain embodiments, at least one R^Bis —NR^A1C(═O)OR^A1. In certain embodiments, at least one R^Bis —NR^A1S(═O)₂R^A1. In certain embodiments, at least one R^Bis —NHS(═O)₂R^A1. In certain embodiments, at least one R^Bis —NHS(═O)₂(C_1-6alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R^Bis —NHS(═O)₂Me. In certain embodiments, at least one R^Bis —S(═O)₂R^A1. In certain embodiments, at least one R^Bis —S(═O)₂N(R^A1)₂. In certain embodiments, at least one R^Bis —S(═O)₂N(R^A1)₂. In certain embodiments, at least one R^Bis —S(═O)₂N(C_1-6alkyl)₂. In certain embodiments, at least one R^Bis —S(═O)₂NH(C_1-6alkyl). In certain embodiments, at least one R^Bis —S(═O)₂NH(t-Bu). In certain embodiments, at least one R^Bis —S(═O)₂NH₂.

In certain embodiments, R^Bis substituted or unsubstituted C_1-6alkyl; and l is 1. In certain embodiments, R^Bis substituted or unsubstituted C_1-6alkyl; l is 1; and R^Bis meta to the point of attachment of U. In certain embodiments, R^Bis substituted or unsubstituted C_1-6alkyl; l is 1; and R^Bis para to the point of attachment of U. In certain embodiments, R^Bis C_1-6alkyl substituted with one —CN group; and l is 1. In certain embodiments, R^Bis C_1-6alkyl substituted with one —CN group; l is 1; and R^Bis meta to the point of attachment of U. In certain embodiments, R^Bis C_1-6alkyl substituted with one —CN group; l is 1; and R^Bis para to the point of attachment of U. In certain embodiments, R^Bis

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and l is 1. In certain embodiments, R^Bis

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l is 1; and R^Bis meta to the point of attachment of U. In certain embodiments, R^Bis

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l is 1; and R is para to the point of attachment of U. In certain embodiments, R^Bis substituted or unsubstituted —CH₂-(piperazinyl); and l is 1. In certain embodiments, R^Bis substituted or unsubstituted —CH₂-(piperazinyl); l is 1; and R^Bis meta to the point of attachment of U. In certain embodiments, R^Bis substituted or unsubstituted —CH₂-(piperazinyl); l is 1; and R^Bis para to the point of attachment of U. In certain embodiments, R^Bis

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and l is 1. In certain embodiments, R^Bis

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l is 1; and R^Bis meta to the point of attachment of U. In certain embodiments, R^Bis

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l is 1; and R^Bis para to the point of attachment of U. In certain embodiments, R^Bis haloalkyl; and l is 1. In certain embodiments, R^Bis haloalkyl; l is 1; and R^Bis meta to the point of attachment of U. In certain embodiments, R^Bis haloalkyl; l is 1; and R^Bis para to the point of attachment of U. In certain embodiments, R^Bis —CF₃; and l is 1. In certain embodiments, R^Bis —CF₃; 1 is 1; and R^Bis meta to the point of attachment of U. In certain embodiments, R^Bis —CF₃; l is 1; and R^Bis para to the point of attachment of U. In certain embodiments, R^Bis substituted or unsubstituted imidazoyl; and l is 1. In certain embodiments, R^Bis substituted or unsubstituted imidazoyl; l is 1; and R^Bis meta to the point of attachment of U. In certain embodiments, R^Bis substituted or unsubstituted imidazoyl; l is 1; and R^Bis para to the point of attachment of U. In certain embodiments, R^Bis

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and l is 1. In certain embodiments, R^Bis

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l is 1; and R^Bis meta to the point of attachment of U. In certain embodiments, R^Bis

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l is 1; and R^Bis para to the point of attachment of U. In certain embodiments, R^Bis substituted or unsubstituted piperazinyl; and l is 1. In certain embodiments, R^Bis substituted or unsubstituted piperazinyl; l is 1; and R^Bis meta to the point of attachment of U. In certain embodiments, R^Bis substituted or unsubstituted piperazinyl; l is 1; and R^Bis para to the point of attachment of U. In certain embodiments, R^Bis

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and l is 1. In certain embodiments, R^Bis

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l is 1; and R^Bis meta to the point of attachment of U. In certain embodiments, R^Bis

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l is 1; and R^Bis para to the point of attachment of U. In certain embodiments, R^Bis substituted or unsubstituted morpholine; and l is 1. In certain embodiments, R^Bis substituted or unsubstituted morpholine; l is 1; and R^Bis meta to the point of attachment of U. In certain embodiments, R^Bis substituted or unsubstituted morpholine; l is 1; and R^Bis para to the point of attachment of U.

In certain embodiments, at least one R^Bgroup is substituted or unsubstituted C_1-6alkyl; and l is 2. In certain embodiments, at least one R^Bgroup is substituted or unsubstituted C_1-6alkyl; l is 2; and at least one R^Bis meta to the point of attachment of U. In certain embodiments, at least one R^Bgroup is substituted or unsubstituted C_1-6alkyl; l is 2; and one R^Bis para to the point of attachment of U. In certain embodiments, at least one R^Bgroup is C_1-6alkyl substituted with one —CN group; and l is 2. In certain embodiments, at least one R^Bgroup is C_1-6alkyl substituted with one —CN group; l is 2; and at least one R^Bis meta to the point of attachment of U. In certain embodiments, at least one R^Bgroup is C_1-6alkyl substituted with one —CN group; l is 2; and one R^Bis para to the point of attachment of U. In certain embodiments, at least one R^Bgroup is

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and l is 2. In certain embodiments, at least one R^Bgroup is

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l is 2; and at least one R^Bis meta to the point of attachment of U. In certain embodiments, at least one R^Bgroup is

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l is 2; and one R^Bis para to the point of attachment of U. In certain embodiments, at least one R^Bgroup is substituted or unsubstituted —CH₂-(piperazinyl); and l is 2. In certain embodiments, at least one R^Bgroup is substituted or unsubstituted —CH₂-(piperazinyl); l is 2; and at least one R^Bis meta to the point of attachment of U. In certain embodiments, at least one R^Bgroup is substituted or unsubstituted —CH₂-(piperazinyl); l is 2; and one R^Bis para to the point of attachment of U. In certain embodiments, at least one R^Bgroup is

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and l is 2. In certain embodiments, at least one R^Bgroup is

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l is 2; and at least one R^Bis meta to the point of attachment of U. In certain embodiments, at least one R^Bgroup is

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l is 2; and one R^Bis para to the point of attachment of U. In certain embodiments, at least one R^Bgroup is haloalkyl; and l is 2. In certain embodiments, at least one R^Bgroup is haloalkyl; l is 2; and at least one R^Bis meta to the point of attachment of U. In certain embodiments, at least one R^Bgroup is haloalkyl; l is 2; and one R^Bis para to the point of attachment of U. In certain embodiments, at least one R^Bgroup is —CF₃; and l is 2. In certain embodiments, at least one R^Bgroup is —CF₃; l is 2; and at least one R^Bis meta to the point of attachment of U. In certain embodiments, at least one R^Bgroup is —CF₃; l is 2; and one R^Bis para to the point of attachment of U. In certain embodiments, at least one R^Bgroup is substituted or unsubstituted imidazoyl; and l is 2. In certain embodiments, at least one R^Bgroup is substituted or unsubstituted imidazoyl; l is 2; and at least one R^Bis meta to the point of attachment of U. In certain embodiments, at least one R^Bgroup is substituted or unsubstituted imidazoyl; l is 2; and one R^Bis para to the point of attachment of U. In certain embodiments, at least one R^Bgroup is

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and l is 2. In certain embodiments, at least one R^Bgroup is

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l is 2; and at least one R^Bis meta to the point of attachment of U. In certain embodiments, at least one R^Bgroup is

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l is 2; and one R^Bis para to the point of attachment of U. In certain embodiments, at least one R^Bgroup is substituted or unsubstituted piperazinyl; and l is 2. In certain embodiments, at least one R^Bgroup is substituted or unsubstituted piperazinyl; l is 2; and at least one R^Bis meta to the point of attachment of U. In certain embodiments, at least one R^Bgroup is substituted or unsubstituted piperazinyl; l is 2; and one R^Bis para to the point of attachment of U. In certain embodiments, at least one R^Bgroup is

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and l is 2. In certain embodiments, at least one R^Bgroup is

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l is 2; and at least one R^Bis meta to the point of attachment of U. In certain embodiments, at least one R^Bgroup is

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l is 2; and one R^Bis para to the point of attachment of U. In certain embodiments, at least one R^Bgroup is substituted or unsubstituted morpholine; and l is 2. In certain embodiments, at least one R^Bgroup is substituted or unsubstituted morpholine; l is 2; and at least one R^Bis meta to the point of attachment of U. In certain embodiments, at least one R^Bgroup is substituted or unsubstituted morpholine; l is 2; and one R^Bis para to the point of attachment of U. In certain embodiments, two R^Bgroups are substituted or unsubstituted morpholine; l is 2; and both R^Bgroups are meta to the point of attachment of U.

In compounds of Formula (I), X and Y are taken together to represent a divalent linker moiety. In certain embodiments, X and Y are taken together to represent

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In certain embodiments, X and Y are taken together to represent

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In compounds of Formula (I), Q and U are taken together to represent a divalent linker moiety. In certain embodiments, Q and U are taken together to represent

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In certain embodiments, Q and U are taken together to represent

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In compounds of Formula (I), the pyridine ring may be substituted with one or more R^Xgroups. In certain embodiments, at least one R^Xis substituted carbocyclyl. In certain embodiments, at least one R^Xis unsubstituted carbocyclyl. In certain embodiments, at least one R^Xis

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In certain embodiments, at least one R^Xis

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In certain embodiments, at least one R^Xis substituted heterocyclyl. In certain embodiments, at least one R^Xis unsubstituted heterocyclyl. In certain embodiments, at least one R^Xis

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In certain embodiments, at least one R^Xis

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In certain embodiments, at least one R^Xis substituted aryl. In certain embodiments, at least one R^Xis unsubstituted aryl. In certain embodiments, at least one R^Xis substituted phenyl. In certain embodiments, at least one R^Xis unsubstituted phenyl. In certain embodiments, at least one R^Xis

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In certain embodiments, at least one R^Xis

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In certain embodiments, at least one R^Xis CN

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In certain embodiments, at least one R^Xis substituted heteroaryl. In certain embodiments, at least one R^Xis unsubstituted heteroaryl. In certain embodiments, at least one R^Xis

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In certain embodiments, at least one R^Xis

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In certain embodiments, at least one R^Xis —N(R^A1)(R^Xa). In certain embodiments at least one R^Xis —NH₂. In certain embodiments, at least one R^Xis

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In certain embodiments, at least one R^Xis

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In certain embodiments, at least one R^Xis R

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In certain embodiments, at least one R^Xis

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In compounds of Formula (I), R^Xmay be substituted with one or more R^Xagroups. Each instance of R^Xais selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)R^A1, —C(═O)OR^A1, —C(═O)N(R^A1)₂, —S(═O)R^A1, —S(═O)N(R^A1)₂, —S(═O)₂R^A1, —S(═O)₂OR^A1, —S(═O)₂N(R^A1)₂, and a nitrogen protecting group; wherein each occurrence of R^A1is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R^A1groups are joined to form an optionally substituted heterocyclic ring.

In certain embodiments, at least one R^Xais H. In certain embodiments, all R^Xagroups are H. In certain embodiments, at least one R^Xais substituted alkyl. In certain embodiments, at least one R^Xais substituted C_1-6alkyl. In certain embodiments, at least one R^Xais substituted methyl. In certain embodiments, at least one R^Xais unsubstituted alkyl. In certain embodiments, at least one R^Xais unsubstituted C_1-6alkyl. In certain embodiments, at least one R^Xais methyl. In certain embodiments, at least one R^Xais ethyl. In certain embodiments, at least one R^Xais propyl. In certain embodiments, at least one R^Xais butyl. In certain embodiments, at least one R^Xais substituted alkenyl. In certain embodiments, at least one R^Xais unsubstituted alkenyl. In certain embodiments, at least one R^Xais substituted alkynyl. In certain embodiments, at least one R^Xais unsubstituted alkynyl. In certain embodiments, at least one R^Xais substituted carbocyclyl. In certain embodiments, at least one R^Xais unsubstituted carbocyclyl. In certain embodiments, at least one R^Xais substituted heterocyclyl. In certain embodiments, at least one R^Xais unsubstituted heterocyclyl. In certain embodiments, at least one R^Xais substituted aryl. In certain embodiments, at least one R^Xais unsubstituted aryl. In certain embodiments, at least one R^Xais substituted phenyl. In certain embodiments, at least one R^Xais unsubstituted phenyl. In certain embodiments, at least one R^Xais substituted heteroaryl. In certain embodiments, at least one R^Xais unsubstituted heteroaryl. In certain embodiments, at least one R^Xais —C(═O)R^A1. In certain embodiments, at least one R^Xais —C(═O)H. In certain embodiments, at least one R^Xais acetyl. In certain embodiments, at least one R^Xais —C(═O)(C_1-6alkyl). In certain embodiments, at least one R^Xais —C(═O)OR^A1. In certain embodiments, at least one R^Xais —C(═O)OH. In certain embodiments, at least one R^Xais —C(═O)O(C_1-6alkyl). In certain embodiments, at least one R^Xais —C(═O)N(R^A1)₂. In certain embodiments, at least one R^Xais —C(═O)NHR^A1. In certain embodiments, at least one R^Xais —C(═O)N(C_1-6alkyl)₂. In certain embodiments, at least one R^Xais —C(═O)NH(C_1-6alkyl). In certain embodiments, at least one R^Xais —C(═O)NH₂. In certain embodiments, at least one R^Xais —S(═O)R^A1. In certain embodiments, at least one R^Xais —S(═O)(C_1-6alkyl). In certain embodiments, at least one R^Xais —S(═O)N(R^A1)₂. In certain embodiments, at least one R^Xais —S(═O)NH(R^A1). In certain embodiments, at least one R^Xais —S(═O)NH₂. In certain embodiments, at least one R^Xais —S(═O)N(C_1-6alkyl)₂. In certain embodiments, at least one R^Xais —S(═O)NH(C_1-6alkyl). In certain embodiments, at least one R^Xais —S(═O)₂R^A1. In certain embodiments, at least one R^Xais —S(═O)₂(C_1-6alkyl). In certain embodiments, at least one R^Xais —S(═O)₂OR^A1. In certain embodiments, at least one R^Xais —S(═O)₂OH. In certain embodiments, at least one R^Xais —S(═O)₂N(R^A1)₂. In certain embodiments, at least one R^Xais —S(═O)₂NH(R^A1). In certain embodiments, at least one R^Xais —S(═O)₂NH₂. In certain embodiments, at least one R^Xais —S(═O)₂N(C_1-6alkyl)₂. In certain embodiments, at least one R^Xais —S(═O)₂NH(C_1-6alkyl).

In compounds of Formula (I), R^Xmay be substituted with one or more R^Xcgroups. Each instance of R^Xcis selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —OR^A1, —N(R^A1)₂, —SR^A1, —CN, —C(═O)R^A1, —C(═O)OR^A1, —C(═O)N(R^A1)₂, —NO₂, —N₃, —NR^A1C(═O)R^A1, —NR^A1C(═O)OR^A1, —NR^A1C(═O)N(R^A1)₂, —NR^A1S(═O)₂R^A1, —NR^A1S(═O)R^A1, —OC(═O)R^A1, —OC(═O)OR^A1, —OC(═O)N(R^A1)₂, —S(═O)R^A1, —S(═O)N(R^A1)₂, —S(═O)₂R^A1, —S(═O)₂N(R^A1)₂; wherein each occurrence of R^A1is independently selected from the group consisting of hydrogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, a nitrogen protecting group when attached to a nitrogen atom, an oxygen protecting group when attached to an oxygen atom, and a sulfur protecting group when attached to a sulfur atom, or two R^A1groups are joined to form an optionally substituted heterocyclic ring.

In certain embodiments, at least one R^Xcis H. In certain embodiments, all R^Xcgroups are H. In certain embodiments, at least one R^Xcis substituted alkyl. In certain embodiments, at least one R^Xcis substituted C_1-6alkyl. In certain embodiments, at least one R^Xcis substituted methyl. In certain embodiments, at least one R^Xcis unsubstituted alkyl. In certain embodiments, at least one R^Xcis unsubstituted C_1-6alkyl. In certain embodiments, at least one R^Xcis methyl. In certain embodiments, at least one R^Xcis ethyl. In certain embodiments, at least one R^Xcis propyl. In certain embodiments, at least one R^Xcis butyl. In certain embodiments, at least one R^Xcis substituted alkenyl. In certain embodiments, at least one R^Xcis unsubstituted alkenyl. In certain embodiments, at least one R^Xcis substituted alkynyl. In certain embodiments, at least one R^Xcis unsubstituted alkynyl. In certain embodiments, at least one R^Xcis substituted carbocyclyl. In certain embodiments, at least one R^Xcis unsubstituted carbocyclyl. In certain embodiments, at least one R^Xcis substituted heterocyclyl. In certain embodiments, at least one R^Xcis unsubstituted heterocyclyl. In certain embodiments, at least one R^Xcis substituted aryl. In certain embodiments, at least one R^Xcis unsubstituted aryl. In certain embodiments, at least one R^Xcis substituted phenyl. In certain embodiments, at least one R^Xcis unsubstituted phenyl. In certain embodiments, at least one R^Xcis substituted heteroaryl. In certain embodiments, at least one R^Xcis unsubstituted heteroaryl. In certain embodiments, at least one R^Xcis —OR^A1. In certain embodiments, at least one R^Xcis —OH. In certain embodiments, at least one R^Xcis —O(C_1-6alkyl). In certain embodiments, at least one R^Xcis —N(R^A1)₂. In certain embodiments, at least one R^Xcis —NH(R^A1). In certain embodiments, at least one R^Xcis —N(C_1-6alkyl)₂. In certain embodiments, at least one R^Xcis —NH(C_1-6alkyl). In certain embodiments, at least one R^Xcis —NH₂. In certain embodiments, at least one R^Xcis —SR^A1. In certain embodiments, at least one R^Xcis —SH. In certain embodiments, at least one R^Xcis —S(C_1-6alkyl). In certain embodiments, at least one R^Xcis —CN. In certain embodiments, at least one R^Xcis —NO₂. In certain embodiments, at least one R^Xcis —N₃. In certain embodiments, at least one R^Xcis —NR^A1C(═O)R^A1. In certain embodiments, at least one R^Xcis —NHC(═O)R^A1. In certain embodiments, at least one R^Xcis —NHC(═O)(C_1-6alkyl). In certain embodiments, at least one R^Xcis —NR^A1C(═O)OR^A1. In certain embodiments, at least one R^Xcis —NHC(═O)OR^A1. In certain embodiments, at least one R^Xcis —NR^A1C(═O)O(C_1-6alkyl). In certain embodiments, at least one R^Xcis —NR^A1C(═O)N(R^A1)₂. In certain embodiments, at least one R^Xcis —NHC(═O)N(C_1-6alkyl)₂. In certain embodiments, at least one R^Xcis —NHC(═O)NH₂. In certain embodiments, at least one R^Xcis —NR^A1S(═O)₂R^A1. In certain embodiments, at least one R^Xcis —NHS(═O)₂R^A1. In certain embodiments, at least one R^Xcis —NHS(═O)₂(C_1-6alkyl). In certain embodiments, at least one R^Xcis —NR^A1S(═O)R^A1. In certain embodiments, at least one R^Xcis —NR^A1S(═O)(C_1-6alkyl). In certain embodiments, at least one R^Xcis —NHS(═O)(C_1-6alkyl). In certain embodiments, at least one R^Xcis —OC(═O)R^A1. In certain embodiments, at least one R^Xcis —OC(═O)(C_1-6alkyl). In certain embodiments, at least one R^Xcis —OC(═O)OR^A1. In certain embodiments, at least one R^Xcis —OC(═O)O(C_1-6alkyl). In certain embodiments, at least one R^Xcis —OC(═O)N(R^A1)₂. In certain embodiments, at least one R^Xcis —OC(═O)NH(R^A1). In certain embodiments, at least one R^Xcis —OC(═O)N(C_1-6alkyl)₂. In certain embodiments, at least one R^Xcis —C(═O)R^A1. In certain embodiments, at least one R^Xcis —C(═O)H. In certain embodiments, at least one R^Xcis acetyl. In certain embodiments, at least one R^Xcis —C(═O)(C_1-6alkyl). In certain embodiments, at least one R^Xcis —C(═O)OR^A1. In certain embodiments, at least one R^Xcis —C(═O)OH. In certain embodiments, at least one R^Xcis —C(═O)O(C_1-6alkyl). In certain embodiments, at least one R^Xcis —C(═O)N(R^A1)₂. In certain embodiments, at least one R^Xcis —C(═O)NHR^A1. In certain embodiments, at least one R^Xcis —C(═O)N(C_1-6alkyl)₂. In certain embodiments, at least one R^Xcis —C(═O)NH(C_1-6alkyl). In certain embodiments, at least one R^Xcis —C(═O)NH₂. In certain embodiments, at least one R^Xcis —S(═O)R^A1. In certain embodiments, at least one R^Xcis —S(═O)(C_1-6alkyl). In certain embodiments, at least one R^Xcis —S(═O)N(R^A1)₂. In certain embodiments, at least one R^Xcis —S(═O)NH(R^A1). In certain embodiments, at least one R^Xcis —S(═O)NH₂. In certain embodiments, at least one R^Xcis —S(═O)N(C_1-6alkyl)₂. In certain embodiments, at least one R^Xcis —S(═O)NH(C_1-6alkyl). In certain embodiments, at least one R^Xcis —S(═O)₂R^A1. In certain embodiments, at least one R^Xcis —S(═O)₂(C_1-6alkyl). In certain embodiments, at least one R^Xcis —S(═O)₂OR^A1. In certain embodiments, at least one R^Xcis —S(═O)₂OH. In certain embodiments, at least one R^Xcis —S(═O)₂N(R^A1)₂. In certain embodiments, at least one R^Xcis —S(═O)₂NH(R^A1). In certain embodiments, at least one R^Xcis —S(═O)₂NH₂. In certain embodiments, at least one R^Xcis —S(═O)₂N(C_1-6alkyl)₂. In certain embodiments, at least one R^Xcis —S(═O)₂NH(C_1-6alkyl).

In compounds of Formula (I), R^Dis an optional electrophilic moiety that is attached to the pyridyl ring. In certain embodiments, R^Dis any one of Formulae (i-1)-(i-18):

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R^D1is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO₂, —OR^D1a, —N(R^D1a)₂, —SR^D1a, —CH₂OR^D1a, —CH₂N(R^D1a)₂, —CH₂SR^D1a, —C(═O)R^D1a, —C(═O)OR^D1a, —C(═O)SR^D1a, —C(═O)N(R^D1a)₂, —C(═S)R^D1a, —C(═S)OR^D1a, —C(═S)SR^D1a, —C(═S)N(R^D1a)₂, —C(═NR^D1a)R^D1a, —C(═NR^D1a)OR^D1a, —C(═NR^D1a)SR^D1a, and —C(═NR^D1a)N(R^D1a)₂, wherein each occurrence of R^D1ais independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R^D1agroups are joined to form an optionally substituted heterocyclic ring;

R^D2is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO₂, —OR^D2a, —N(R^D2a)₂, —SR^D2a, —CH₂OR^D2a, —CH₂N(R^D2a)₂, —CH₂SR^D2a, —C(═O)R^D2a, —C(═O)OR^D2a, —C(═O)SR^D2a, —C(═O)N(R^D2a)₂, —C(═S)R^D2a, —C(═S)OR^D2a, —C(═S)SR^D2a, —C(═S)N(R^D2a)₂, —C(═NR^D2a)R^D2a, —C(═NR^D2a)OR^D2a, —C(═NR^D2a)SR^D2a, and —C(═NR^D2a)N(R^D2a)₂, wherein each occurrence of R^D2ais independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R^D2agroups are joined to form an optionally substituted heterocyclic ring;

R^D3is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO₂, —OR^D3a, —N(R^D3a)₂, —SR^D3a, —CH₂OR^D3a, —CH₂N(R^D3a)₂, —CH₂SR^D3a, —C(═O)R^D3a, —C(═O)OR^D3a, —C(═O)SR^D3a, —C(═O)N(R^D3a)₂, —C(═S)R^D3a, —C(═S)OR^D3a, —C(═S)SR^D3a, —C(═S)N(R^D3a)₂, —C(═NR^D3a)R^D3a, —C(═NR^D3a)OR^D3a, —C(═NR^D3a)SR^D3a, and —C(═NR^D3a)N(R^D3a)₂, wherein each occurrence of R^D3ais independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or two R^D3agroups are joined to form an optionally substituted heterocyclic ring;

optionally R^D1and R^D3, or R^D2and R^D3, or R^D1and R^D2are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;

R^D4is a leaving group;

R^D5is hydrogen, C_1-6alkyl, or a nitrogen protecting group;

Y^Zis —O—, —S—, or —NR^D6—, wherein R^D6is hydrogen, C_1-6alkyl, or a nitrogen protecting group;

a is 1 or 2;

z is 0, 1, 2, 3, 4, 5, or 6; and

optionally R^D5and one R^Care joined to form an optionally substituted heterocyclic ring.

In certain embodiments, R^Dcomprises a Michael acceptor moiety. This Michael acceptor moiety may react with a cysteine or other nucleophilic residue to allow covalent attachment of the compound to the target. In certain embodiments, the covalent attachment is irreversible. In other embodiments, the covalent attachment is reversible. In certain embodiments, R^Dis of Formula (i-1). In certain embodiments, R^Dis of Formula (i-2). In certain embodiments, R^Dis of Formula (i-3). In certain embodiments, R^Dis of Formula (i-4). In certain embodiments, R^Dis of Formula (i-5). In certain embodiments, R^Dis of Formula (i-6). In certain embodiments, R^Dis of Formula (i-7). In certain embodiments, R^Dis of Formula (i-8). In certain embodiments, R^Dis of Formula (i-9). In certain embodiments, R^Dis of Formula (i-10). In certain embodiments, R^Dis of Formula (i-1). In certain embodiments, R^Dis of Formula (i-12). In certain embodiments, R^Dis of Formula (i-13). In certain embodiments, R^Dis of Formula (i-14). In certain embodiments, R^Dis of Formula (i-15). In certain embodiments, R^Dis of Formula (i-16). In certain embodiments, R^Dis of Formula (i-17).

In compounds of Formula (I), R^Dmay include a substituent R^D1. In certain embodiments, R^D1is H. In certain embodiments, R^D1is halogen. In certain embodiments, R^D1is F. In certain embodiments, R^D1is Cl. In certain embodiments, R^D1is Br. In certain embodiments, R^D1is I (iodine). In certain embodiments, R^D1is substituted acyl. In certain embodiments, R^D1is unsubstituted acyl. In certain embodiments, R^D1is acetyl. In certain embodiments, R^D1is substituted alkyl. In certain embodiments, R^D1is unsubstituted alkyl. In certain embodiments, R^D1is C_1-6alkyl. In certain embodiments, R^D1is methyl. In certain embodiments, R^D1is ethyl. In certain embodiments, R^D1is propyl. In certain embodiments, R^D1is butyl. In certain embodiments, R^D1is substituted alkenyl. In certain embodiments, R^D1is unsubstituted alkenyl. In certain embodiments, R^D1is substituted alkynyl. In certain embodiments, R^D1is unsubstituted alkynyl. In certain embodiments, R^D1is substituted carbocyclyl. In certain embodiments, R^D1is unsubstituted carbocyclyl. In certain embodiments, R^D1is substituted heterocyclyl. In certain embodiments, R^D1is unsubstituted heterocyclyl. In certain embodiments, R^D1is substituted aryl. In certain embodiments, R^D1is unsubstituted aryl. In certain embodiments, R^D1is substituted phenyl. In certain embodiments, R^D1is unsubstituted phenyl. In certain embodiments, R^D1is substituted heteroaryl. In certain embodiments, R^D1is unsubstituted heteroaryl. In certain embodiments, R^D1is substituted pyridyl. In certain embodiments, R^D1is unsubstituted pyridyl. In certain embodiments, R^D1is —CN. In certain embodiments, R^D1is —NO₂. In certain embodiments, R^D1is —OR^D1a. In certain embodiments, R^D1is —N(R^D1a)₂. In certain embodiments, R^D1is —SR^D1. In certain embodiments, R^D1is —CH₂OR^D1a. In certain embodiments, R^D1is —CH₂N(R^D1a)₂. In certain embodiments, R^D1is —CH₂SR^D1a.

In certain embodiments, at least one R^D1ais H. In certain embodiments, at least one R^D1ais substituted acyl. In certain embodiments, at least one R^D1ais unsubstituted acyl. In certain embodiments, at least one R^D1ais acetyl. In certain embodiments, at least one R^D1ais substituted alkyl. In certain embodiments, at least one R^D1ais unsubstituted alkyl. In certain embodiments, at least one R^D1ais C_1-6alkyl. In certain embodiments, at least one R^D1ais methyl. In certain embodiments, at least one R^D1ais ethyl. In certain embodiments, at least one R^D1ais propyl. In certain embodiments, at least one R^D1ais butyl. In certain embodiments, at least one R^D1ais substituted alkenyl. In certain embodiments, at least one R^D1ais unsubstituted alkenyl. In certain embodiments, at least one R^D1ais substituted alkynyl. In certain embodiments, at least one R^D1ais unsubstituted alkynyl. In certain embodiments, at least one R^D1ais substituted carbocyclyl. In certain embodiments, at least one R^D1ais unsubstituted carbocyclyl. In certain embodiments, at least one R^D1ais substituted heterocyclyl. In certain embodiments, at least one R^D1ais unsubstituted heterocyclyl. In certain embodiments, at least one R^D1ais substituted aryl. In certain embodiments, at least one R^D1ais unsubstituted aryl. In certain embodiments, at least one R^D1ais substituted phenyl. In certain embodiments, at least one R^D1ais unsubstituted phenyl. In certain embodiments, at least one R^D1ais substituted heteroaryl. In certain embodiments, at least one R^D1ais unsubstituted heteroaryl. In certain embodiments, at least one R^D1ais substituted pyridyl. In certain embodiments, at least one R^D1ais unsubstituted pyridyl. In certain embodiments, at least one R^D1ais a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R^D1ais Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R^D1ais an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R^D1ais silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R^D1ais a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R^D1ais acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two R^D1aa groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R^D1agroups are joined to form an unsubstituted heterocyclic ring.

In compounds of Formula (I), R^Dmay include a substituent R^D2. In certain embodiments, R^D2is H. In certain embodiments, R^D2is halogen. In certain embodiments, R^D2is F. In certain embodiments, R^D2is Cl. In certain embodiments, R^D2is Br. In certain embodiments, R^D2is I (iodine). In certain embodiments, R^D2is substituted acyl. In certain embodiments, R^D2is unsubstituted acyl. In certain embodiments, R^D2is acetyl. In certain embodiments, R^D2is substituted alkyl. In certain embodiments, R^D2is unsubstituted alkyl. In certain embodiments, R^D2is C_1-6alkyl. In certain embodiments, R^D2is methyl. In certain embodiments, R^D2is ethyl. In certain embodiments, R^D2is propyl. In certain embodiments, R^D2is butyl. In certain embodiments, R^D2is substituted alkenyl. In certain embodiments, R^D2is unsubstituted alkenyl. In certain embodiments, R^D2is substituted alkynyl. In certain embodiments, R^D2is unsubstituted alkynyl. In certain embodiments, R^D2is substituted carbocyclyl. In certain embodiments, R^D2is unsubstituted carbocyclyl. In certain embodiments, R^D2is substituted heterocyclyl. In certain embodiments, R^D2is unsubstituted heterocyclyl. In certain embodiments, R^D2is substituted aryl. In certain embodiments, R^D2is unsubstituted aryl. In certain embodiments, R^D2is substituted phenyl. In certain embodiments, R^D2is unsubstituted phenyl. In certain embodiments, R^D2is substituted heteroaryl. In certain embodiments, R^D2is unsubstituted heteroaryl. In certain embodiments, R^D2is substituted pyridyl. In certain embodiments, R^D2is unsubstituted pyridyl. In certain embodiments, R^D2is —CN. In certain embodiments, R^D2is —NO₂. In certain embodiments, R^D2is —OR^D2a. In certain embodiments, R^D2is —N(R^D2a)₂. In certain embodiments, R^D2is —SR^D2a. In certain embodiments, R^D2is —CH₂OR^D2a. In certain embodiments, R^D2is —CH₂N(R^D2a)₂. In certain embodiments, R^D2is —CH₂SR^D2a.

In certain embodiments, at least one R^D2ais H. In certain embodiments, at least one R^D2ais substituted acyl. In certain embodiments, at least one R^D2ais unsubstituted acyl. In certain embodiments, at least one R^D2ais acetyl. In certain embodiments, at least one R^D2ais substituted alkyl. In certain embodiments, at least one R^D2ais unsubstituted alkyl. In certain embodiments, at least one R^D2ais C_1-6alkyl. In certain embodiments, at least one R^D2ais methyl. In certain embodiments, at least one R^D2ais ethyl. In certain embodiments, at least one R^D2ais propyl. In certain embodiments, at least one R^D2ais butyl. In certain embodiments, at least one R^D2ais substituted alkenyl. In certain embodiments, at least one R^D2ais unsubstituted alkenyl. In certain embodiments, at least one R^D2ais substituted alkynyl. In certain embodiments, at least one R^D2ais unsubstituted alkynyl. In certain embodiments, at least one R^D2ais substituted carbocyclyl. In certain embodiments, at least one R^D2ais unsubstituted carbocyclyl. In certain embodiments, at least one R^D2ais substituted heterocyclyl. In certain embodiments, at least one R^D2ais unsubstituted heterocyclyl. In certain embodiments, at least one R^D2ais substituted aryl. In certain embodiments, at least one R^D2ais unsubstituted aryl. In certain embodiments, at least one R^D2ais substituted phenyl. In certain embodiments, at least one R^D2ais unsubstituted phenyl. In certain embodiments, at least one R^D2ais substituted heteroaryl. In certain embodiments, at least one R^D2ais unsubstituted heteroaryl. In certain embodiments, at least one R^D2ais substituted pyridyl. In certain embodiments, at least one R^D2ais unsubstituted pyridyl. In certain embodiments, at least one R^D2ais a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R^D2ais Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R^D2ais an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R^D2ais silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R^D2ais a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R^D2ais acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two R^D2agroups are joined to form a substituted heterocyclic ring. In certain embodiments, two R^D2agroups are joined to form an unsubstituted heterocyclic ring.

In compounds of Formula (I), R^Dmay include a substituent R^D3. In certain embodiments, R^D3is H. In certain embodiments, R^D3is halogen. In certain embodiments, R^D3is F. In certain embodiments, R^D3is Cl. In certain embodiments, R^D3is Br. In certain embodiments, R^D3is I (iodine). In certain embodiments, R^D3is substituted acyl. In certain embodiments, R^D3is unsubstituted acyl. In certain embodiments, R^D3is acetyl. In certain embodiments, R^D3is substituted alkyl. In certain embodiments, R^D3is unsubstituted alkyl. In certain embodiments, R^D3is C_1-6alkyl. In certain embodiments, R^D3is methyl. In certain embodiments, R^D3is ethyl. In certain embodiments, R^D3is propyl. In certain embodiments, R^D3is butyl. In certain embodiments, R^D3is substituted alkenyl. In certain embodiments, R^D3is unsubstituted alkenyl. In certain embodiments, R^D3is substituted alkynyl. In certain embodiments, R^D3is unsubstituted alkynyl. In certain embodiments, R^D3is substituted carbocyclyl. In certain embodiments, R^D3is unsubstituted carbocyclyl. In certain embodiments, R^D3is substituted heterocyclyl. In certain embodiments, R^D3is unsubstituted heterocyclyl. In certain embodiments, R^D3is substituted aryl. In certain embodiments, R^D3is unsubstituted aryl. In certain embodiments, R^D3is substituted phenyl. In certain embodiments, R^D3is unsubstituted phenyl. In certain embodiments, R^D3is substituted heteroaryl. In certain embodiments, R^D3is unsubstituted heteroaryl. In certain embodiments, R^D3is substituted pyridyl. In certain embodiments, R^D3is unsubstituted pyridyl. In certain embodiments, R^D3is —CN. In certain embodiments, R^D3is —NO₂. In certain embodiments, R^D3is —OR^D3a. In certain embodiments, R^D3is —N(R^D3a)₂. In certain embodiments, R^D3is —SR^D3a. In certain embodiments, R^D3is —CH₂OR^D3a. In certain embodiments, R^D3is —CH₂N(R^D3a)₂. In certain embodiments, R^D3is —CH₂SR^D3a.

In certain embodiments, at least one R^D1ais H. In certain embodiments, at least one R^D3ais substituted acyl. In certain embodiments, at least one R^D3ais unsubstituted acyl. In certain embodiments, at least one R^D3ais acetyl. In certain embodiments, at least one R^D3ais substituted alkyl. In certain embodiments, at least one R^D3ais unsubstituted alkyl. In certain embodiments, at least one R^D3ais C_1-6alkyl. In certain embodiments, at least one R^D3ais methyl. In certain embodiments, at least one R^D3ais ethyl. In certain embodiments, at least one R^D3ais propyl. In certain embodiments, at least one R^D3ais butyl. In certain embodiments, at least one R^D3ais substituted alkenyl. In certain embodiments, at least one R^D3ais unsubstituted alkenyl. In certain embodiments, at least one R^D3ais substituted alkynyl. In certain embodiments, at least one R^D3ais unsubstituted alkynyl. In certain embodiments, at least one R^D3ais substituted carbocyclyl. In certain embodiments, at least one R^D3ais unsubstituted carbocyclyl. In certain embodiments, at least one R^D3ais substituted heterocyclyl. In certain embodiments, at least one R^D3ais unsubstituted heterocyclyl. In certain embodiments, at least one R^D3ais substituted aryl. In certain embodiments, at least one R^D3ais unsubstituted aryl. In certain embodiments, at least one R^D3ais substituted phenyl. In certain embodiments, at least one R^D3ais unsubstituted phenyl. In certain embodiments, at least one R^D3ais substituted heteroaryl. In certain embodiments, at least one R^D3ais unsubstituted heteroaryl. In certain embodiments, at least one R^D3ais substituted pyridyl. In certain embodiments, at least one R^D3ais unsubstituted pyridyl. In certain embodiments, at least one R^D3ais a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R^D3ais Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R^D3ais an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R^D3ais silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom. In certain embodiments, R^D3ais a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R^D3ais acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two R^D3agroups are joined to form a substituted heterocyclic ring. In certain embodiments, two R^D3agroups are joined to form an unsubstituted heterocyclic ring.

In compounds of Formula (I), R^Dmay include a substituent R^D4. In certain embodiments, R^D4is a leaving group. In certain embodiments, R^D4is halogen. In certain embodiments, R^D4is F. In certain embodiments, R^D4is Cl. In certain embodiments, R^D4is Br. In certain embodiments, R^D4is I (iodine). In certain embodiments, R^D4is —OS(═O)_wR^D4a. In certain embodiments, w is 1. In certain embodiments, w is 2. In certain embodiments, R^D4is —OMs. In certain embodiments, R^D4is —OTf. In certain embodiments, R^D4is —OTs. In certain embodiments, R^D4is —OBs. In certain embodiments, R^D4is 2-nitrobenzenesulfonyloxy. In certain embodiments, R^D4is —OR^D4a. In certain embodiments, R^D4is —OMe. In certain embodiments, R^D4is —OCF₃. In certain embodiments, R^D4is —OPh. In certain embodiments, R^D4is —OC(═O)R^D4a. In certain embodiments, R^D4is —OC(═O)Me. In certain embodiments, R^D4is —OC(═O)CF₃. In certain embodiments, R^D4is —OC(═O)Ph. In certain embodiments, R^D4is —OC(═O)Cl. In certain embodiments, R^D4is —OC(═O)OR^D4a. In certain embodiments, R^D4is —OC(═O)OMe. In certain embodiments, R^D4is —OC(═O)O(t-Bu).

In certain embodiments, R^D4ais substituted alkyl. In certain embodiments, R^D4ais unsubstituted alkyl. In certain embodiments, R^D4ais C_1-6alkyl. In certain embodiments, R^D4ais methyl. In certain embodiments, R^D4ais ethyl. In certain embodiments, R^D4ais propyl. In certain embodiments, R^D4ais butyl. In certain embodiments, R^D4ais substituted alkenyl. In certain embodiments, R^D4ais unsubstituted alkenyl. In certain embodiments, R^D4ais vinyl. In certain embodiments, R^D4ais substituted alkynyl. In certain embodiments, R^D4ais unsubstituted alkynyl. In certain embodiments, R^D4ais ethynyl. In certain embodiments, R^D4ais substituted carbocyclyl. In certain embodiments, R^D4ais unsubstituted carbocyclyl. In certain embodiments, R^D4ais substituted heterocyclyl. In certain embodiments, R^D4ais unsubstituted heterocyclyl. In certain embodiments, R^D4ais substituted aryl. In certain embodiments, R^D4ais unsubstituted aryl. In certain embodiments, R^D4ais substituted phenyl. In certain embodiments, R^D4ais unsubstituted phenyl. In certain embodiments, R^D4ais substituted heteroaryl. In certain embodiments, R^D4ais unsubstituted heteroaryl. In certain embodiments, R^D4ais substituted pyridyl. In certain embodiments, R^D4ais unsubstituted pyridyl.

In compounds of Formula (I), R^Dmay include a substituent R^D5. In certain embodiments, R^D5is H. In certain embodiments, R^D5is substituted alkyl. In certain embodiments, R^D5is unsubstituted alkyl. In certain embodiments, R^D5is C_1-6alkyl. In certain embodiments, R^D5is methyl. In certain embodiments, R^D5is ethyl. In certain embodiments, R^D5is propyl. In certain embodiments, R^D5is butyl. In certain embodiments, R^D5is a nitrogen protecting group. In certain embodiments, R^D5is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts.

In certain embodiments, R^D1and R^D2are each hydrogen. In certain embodiments, R^D1and R^D3are each hydrogen. In certain embodiments, R^D2and R^D3are each hydrogen. In certain embodiments, R^D1, R^D2, and R^D3are each hydrogen. In certain embodiments, R^D1, R^D2, and R^D3, and R^D5are each hydrogen.

In certain embodiments, a is 1. In certain embodiments, a is 2.

In certain embodiments, z is 0. In certain embodiments, z is 1. In certain embodiments, z is 2. In certain embodiments, z is 3. In certain embodiments, z is 4. In certain embodiments, z is 5. In certain embodiments, z is 6.

In certain embodiments, Y is —O—. In certain embodiments, Y is —C(═O)—. In certain embodiments, Y is —S—. In certain embodiments, Y is —C(═S)—. In certain embodiments, Y is —NR^D6—, wherein R^D6is hydrogen, C_1-6alkyl, or a nitrogen protecting group. In certain embodiments, Y is —NH—. In certain embodiments, Y is —NCH₃—. In certain embodiments, Y is —N(BOC)—. In certain embodiments, Y is —N(Fmoc)-. In certain embodiments, Y is —N(Cbz)-. In certain embodiments, Y is —N(Bn)-. In certain embodiments, Y is —C(═NR^D6)—, wherein R^D6is hydrogen, C_1-6alkyl, or a nitrogen protecting group. In certain embodiments, Y is —C(═NH)—. In certain embodiments, Y is —C(═NCH₃)—. In certain embodiments, Y is —C(═NTs)-. In certain embodiments, Y is —C(═NBn)-. In certain embodiments, Y is —C(═NCH(Ph)₂)—.

In certain embodiments, R^Dis of the formula:

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In certain embodiments, R^Dis of the formula:

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In certain embodiments, R is of the formula:

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In certain embodiments, R^Dis of the formula:

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Various combinations of certain embodiments of Formula (I) are further contemplated herein.

For example, in certain embodiments, a compound of Formula (I) is a compound of Formula (I-a) or (I-b):

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wherein R^X, R^A, R^B, and l are defined herein. In certain embodiments R^Ais substituted or unsubstituted C_1-6alkyl. In certain embodiments, R^Ais methyl. In certain embodiments, l is 1. In certain embodiments, l is 1; and R^Bis meta to the point of attachment of the amide linker. In certain embodiments, l is 2. In certain embodiments, l is 2; and the two R^Bgroups are meta to the point of attachment of the amide linker. In certain embodiments, l is 2; one R^Bgroup is meta to the point of attachment of the amide linker; and the second R^Bgroup is para to the point of attachment of the amide linker. In certain embodiments, one R^Bgroup is substituted or unsubstituted C_1-6alkyl. In certain embodiments, one R^Bgroup is C_1-6alkyl substituted with one —CN group. In certain embodiments, one R^Bgroup is

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In certain embodiments, one R^Bgroup is substituted or unsubstituted —CH₂-(piperazinyl). In certain embodiments, one R^Bgroup is

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where the alkyl is optionally substituted. In certain embodiments, one R^Bgroup is

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where the alkyl is unsubstituted. In certain embodiments, one R^Bgroup is

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In certain embodiments, one R^Bgroup is haloalkyl. In certain embodiments, one R^Bgroup is —CF₃. In certain embodiments, one R^Bgroup is substituted or unsubstituted imidazoyl. In certain embodiments, one R^Bgroup is

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where the alkyl is optionally substituted. In certain embodiments, one R^Bgroup is

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where the alkyl is unsubstituted. In certain embodiments, one R^Bgroup is

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In certain embodiments, one R^Bgroup is substituted or unsubstituted piperazinyl. In certain embodiments, one R^Bgroup is

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where there alkyl is optionally substituted. In certain embodiments, one R^Bgroup is

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where there alkyl is unsubstituted. In certain embodiments, one R^Bgroup is

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In certain embodiments, one R^Bgroup is substituted or unsubstituted morpholine. In certain embodiments, two R^Bgroups are substituted or unsubstituted morpholine. In certain embodiments, R^Xis substituted or unsubstituted heteroaryl. In certain embodiments, R^Xis substituted or unsubstituted thiophene. In certain embodiments, R^Xis substituted or unsubstituted isoxazole. In certain embodiments, R^Xis substituted or unsubstituted pyrazole.

In certain embodiments, a compound of Formula (I-a) is a compound of Formula (I-a1), (I-a2), or (I-a3):

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wherein R^Xa, R^Xc, R^A, R^B, and l are defined herein. In certain embodiments R^Ais substituted or unsubstituted C_1-6alkyl. In certain embodiments, R^Ais methyl. In certain embodiments, l is 1. In certain embodiments, l is 1; and R^Bis meta to the point of attachment of the amide linker. In certain embodiments, l is 2. In certain embodiments, l is 2; and the two R^Bgroups are meta to the point of attachment of the amide linker. In certain embodiments, l is 2; one R^Bgroup is meta to the point of attachment of the amide linker; and the second R^Bgroup is para to the point of attachment of the amide linker. In certain embodiments, one R^Bgroup is substituted or unsubstituted C_1-6alkyl. In certain embodiments, one R^Bgroup is C_1-6alkyl substituted with one —CN group. In certain embodiments, one R^Bgroup is