Methods to Treat Lymphoplasmacytic Lymphoma

GOVERNMENT SUPPORT

This invention was made with govemment support under grant numbers 5R01CA130876-05, 5P50CA090578-10, 5R01CA136851-04, 2R01CA136851-05, and IR01CA172592-01A1, awarded by the National Institutes of Health. The government has certain rights in the invention.

RELATED APPLICATIONS

The present application is a reissue application of U.S. Pat. No. 9,856,223 B2, issued Jan. 2, 2018 from U.S. patent application Ser. No. 15/104,132, filed Jun. 13, 2016, which is a national stage filing under 35 U.S.C. § 371 of international PCT application, PCT/US2014/070162, filed Dec. 12, 2014, which claims priority under 35 U.S.C. § 119(e) to U.S. provisional patent applications, U.S. Ser. No. 62/036,934, filed Aug. 13, 2014, and U.S. Ser. No. 61/915,684, filed Dec. 13, 2013, the entire contents of each of which are incorporated herein by reference.

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 auto-immune 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 out-come. 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 (A):

or a pharmaceutically acceptable salt thereof, wherein Q, U, R A , R B , R K , 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 (A) are of formula:

and pharmaceutically acceptable salts thereof.

Another aspect of the invention relates to the compound of Formula (1-11):

and pharmaceutically acceptable salts thereof.

The present invention also provides compounds of Formula (II) or (V):

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., BCWM1, MWCL1) 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; ll7(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), Intra-vascular 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 (e.g., a compound of Formula (A), (I-11), (II), or (V) (e.g., compounds of Formula (A-1)-(A-18))) 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 (e.g., a compound of Formula (A), (I-11), (II), or (V) (e.g., compounds of Formula (A-1)-(A-18))), 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 FIGURES, 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 th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, N Y, 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 19 F with 18 F, or the replacement of a carbon by a 13 C- or 14 C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.

When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example “C 1-6 alkyl” is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5 , C 3-4 , C 4-6 , C 4-5 , and C 5-6 alkyl.

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 1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2-6 alkyl”). Examples of C 1-6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), propyl (C 3 ) (e.g., n-propyl, isopropyl), butyl (C 4 ) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C 5 ) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C 6 ) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C 7 ), n-octyl (C 8 ), 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 1-10 alkyl (such as unsubstituted C 1-6 alkyl, e.g., —CH 3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C 1-10 alkyl (such as substituted C 1-6 alkyl, e.g., —CF 3 , 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 1-8 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C 1-6 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C 1-4 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C 1-3 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C 1-2 haloalkyl”). 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 —CF 3 , —CF 2 CF 3 , —CF 2 CF 2 CF 3 , —CCl 3 , —CFCl 2 , —CF 2 Cl, 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 1-10 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-9 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-8 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-7 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-6 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 1-5 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 1-4 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1-3 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1-2 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC 1 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC 1-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC 1-10 alkyl.

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 2-9 alkenyl”). In certain embodiments, an alkenyl group has 2 to 8 carbon atoms (“C 2-8 alkenyl”). In certain embodiments, an alkenyl group has 2 to 7 carbon atoms (“C 2-7 alkenyl”). In certain embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2-6 alkenyl”). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms (“C 2-5 alkenyl”). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2-4 alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2-3 alkenyl”). In certain embodiments, an alkenyl group has 2 carbon atoms (“C 2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C 2-4 alkenyl groups include ethenyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), and the like. Examples of C 2-6 alkenyl groups include the aforementioned C 2-4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), 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 2-10 alkenyl. In certain embodiments, the alkenyl group is a substituted C 2-10 alkenyl. In an alkenyl group, a C═C double bond for which the stereochemistry is not specified (e.g., —CH═CHCH 3 or

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

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 10 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-9 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-8 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-7 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-6 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-5 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-4 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC 2-3 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC 2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC 2-10 alkenyl.

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 2-10 alkynyl”). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2-9 alkynyl”). In certain embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2-8 alkynyl”). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2-7 alkynyl”). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (“C 2-6 alkynyl”). In certain embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2-5 alkynyl”). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2-4 -alkynyl”). In certain embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2-3 alkynyl”). In certain embodiments, an alkynyl group has 2 carbon atoms (“C 2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C 2-4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-butynyl (C 4 ), and the like. Examples of C 2-6 alkenyl groups include the aforementioned C 2-4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (C 8 ), 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 2-10 alkynyl. In certain embodiments, the alkynyl group is a substituted C 2-10 alkynyl.

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 2-10 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-9 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-8 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-7 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC 2-6 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-5 alkynyl”). 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 2-4 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC 2-3 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC 2-6 alkynyl”). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an “unsubstituted heteroalkynyl”) or substituted (a “substituted heteroalkynyl”) with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroC 2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC 2-10 alkynyl.

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 3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C 3-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C 3-7 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C 4-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C 5-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5-10 carbocyclyl”). Exemplary C 3-6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like. Exemplary C 3-8 carbocyclyl groups include, without limitation, the aforementioned C 3-6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C 8 ), and the like. Exemplary C 3-10 carbocyclyl groups include, without limitation, the aforementioned C 3-8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro-1H-indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[ 4 .5]decanyl (C 10 ), and the like. 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 ary 1 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 3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C 3-14 carbocyclyl. In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C 3-14 cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C 3-10 cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C 3-8 cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3-4 cycloalkyl”). In certain embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C 4-6 cycloalkyl”). In certain embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C 5-10 cycloalkyl”). In certain embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5-10 cycloalkyl”). Examples of C 5 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ). Examples of C 3-6 cycloalkyl groups include the aforementioned C 5-6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ). Examples of C 3-8 cycloalkyl groups include the aforementioned C 3-4 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C 3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C 3-14 cycloalkyl.

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

“Aralkyl” is a subset of “alkyl” and refers to an alkyl group, 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-bicyelic 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 didderent 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, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR aa , —ON(R bb ) 2 , —N(R bb ) 2 , —N(R bb ), + X − , —N(OR aa )R bb , —SH, —SR aa , —SSR cc , —C(—O)R aa , —CO 2 H, —CHO, —C(OR cc ) 2 , —CO 2 R aa , —OC(═O)R aa , OCO 2 R aa , —C(═O)N(R bb ) 2 , —OC(═O)N(R bb ) 2 , —NR bb C(═O)R aa , —NR bb CO 2 R aa , NR bb C(═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 bb C(═NR bb )N(R bb ) 2 , —C(═O)NR bb SO 2 R aa , —NR bb SO 2 R aa , —SO 2 N(R bb ) 2 , —SO 2 R aa , —SO 2 OR aa , —OSO 2 R 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) 2 R aa , —OP(═O) 2 R aa , —P(═O)(R aa ) 2 , —OP(═O)(R aa ) 2 , —OP(═O)(OR cc ) 2 , —P(═O) 2 N(R bb ) 2 , —OP(═O) 2 N(R bb ) 2 , —P(═O)(NR bb ) 2 , —OP(═O)(NR bb ) 2 , —NR bb P(═O)(OR cc ) 2 , —NR bb P(═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 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10 carbocyclyl. 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups:

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

each instance of R aa is, independently, selected from C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

each instance of R bb is, independently, selected from hydrogen, —OH, —OR aa , —N(R cc ) 2 , —CN, —C(═O)R aa , —C(—O)N(R cc ) 2 , —CO 2 R aa , —SO 2 R aa , —C(═NR cc )OR aa , —C(═NR cc )N(R cc ) 2 , —SO 2 N(R cc ) 2 , —SO 2 R cc , —SO 2 OR cc , —SOR aa , —C(═S)N(R cc ) 2 , —C(═O)SR cc , —C(═S)SR cc , —P(═O) 2 R aa , —P(═O)(R aa ) 2 , —P(═O) 2 N(R cc ) 2 , —P(═O)(NR cc ) 2 , C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, hetero 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R bb groups are joined to form a 3-14 membered heterocycly1 or 5-l4 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

each instance of R cc is, independently, selected from hydrogen C 1-10 alkyl, C 1-10 perhaloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, heteroC 1-10 alkyl, heteroC 2-10 alkenyl, heteroC 2-10 alkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl, or two R cc groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups;

each instance of R dd is, independently, selected from halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OR aa , —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 , —CO 2 H, —CO 2 R ee , —OC(═O)R ee , —OCO 2 R ee , —C(═O)N(R ff ) 2 , —OC(═O)N(R ff ) 2 , —NR ff C(═O)R ee , —NR ff CO 2 R ee , —NR ff C(═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(═RR ff )N(R ff ) 2 , —NR ff C(═NR ff )N(R ff ) 2 , —NR ff SO 2 R ee , —SO 2 N(R ff ) 2 , —SO 2 R ee , —SO 2 OR ee , —OSO 2 R ee , —S(═O)R ee , —Si(R ee ) 3 , —Osi(R ee ) 2 , —C(═S)N(R ff ) 2 , —C(═O)SR ee , —C(═S)SR ee , —SC(═S)SR ee , —P(═O) 2 R ee , —P(═O)(R ee ) 2 , —OP(═O)(R ee ) 2 , —OP(═O)(OR ee ) 2 , C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroC 1-6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl, C 3-10 carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, or two geminal R dd substituents can be joined to form ═O or ═S;

each instance of R ee is, independently, selected from C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroC 1-6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl, C 3-10 carbocyclyl, C 6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups;

each instance of R ff is, independently, selected from hydrogen, C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroC 1-6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl, C 3-10 carbocyclyl, 3-10 membered heterocyclyl, C 6-10 aryl and 5-l0 membered heteroaryl, or two R ff groups are joined to form a 3-10 membered heterocyclyl or 5-10 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; and

each instance of R gg is, independently, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OC 1-6 alkyl, —ON(C 1-6 alkyl) 2 , —N(C 1-6 alkyl) 2 , —N(C 1-6 alkyl) 3 + X − , —NH(C 1-6 alkyl) 2 + X − , —NH 2 (C 1-6 alkyl) + X − , —NH 3 + X − , —N(OC 1-6 alkyl)(C 1-6 alkyl), —N(OH)(C 1-6 alkyl), —NH(OH), —SH, —SC 1-6 alkyl, —SS(C 1-6 alkyl), —C(═O)(C 1-6 alkyl), —CO 2 H, —CO 2 (C 1-6 alkyl), —OC(═O)(C 1-6 alkyl), —OCO 2 (C 1-6 alkyl), —C(═O)NH 2 , —C(═O)N(C 1-6 alkyl) 2 , —OC(═O)NH(C 1-6 alkyl), —NHC(═O)(C 1 alkyl), —N(C 1-6 alkyl)C(═O)(C 1-6 alkyl), —NHCO 2 (C 1-6 alkyl), —NHC(═O)N(C 1-6 alkyl) 2 , —NHC(═O)NH(C 1-6 alkyl), —NHC(═O)NH 2 , —C(═NH)O(C 1-6 alkyl), —OC(═NH)(C 1-6 alkyl), —OC(═NH)OC 1-6 alkyl, —C(═NH)N(C 1-6 alkyl) 2 , —C(═NH)NH(C 1-6 alkyl), —C(═NH)NH 2 , —OC(═NH)N(C 1-6 alkyl) 2 , —OC(NH)NH(C 1-6 alkyl), —OC(NH)NH 2 , —NHC(NH)N(C 1-6 alkyl) 2 , —NHC(═NH)NH 2 , —NHSO 2 (C 1-6 alkyl), —SO 2 N(C 1-6 alkyl) 2 , —SO 2 NH(C 1-6 alkyl), —SO 2 NH 2 , —SO 2 C 1-6 alkyl, —SO 2 OC 1-6 alkyl, —OSO 2 C 1-6 alkyl, —SOC 1-6 alkyl, —Si(C 1-6 alkyl) 3 , —OSi(C 1-6 alkyl) 3 —C(═S)N(C 1-6 alkyl) 2 , C(═S)NH(C 1-6 alkyl), C(═S)NH 2 , —C(═O)S(C 1-6 alkyl), —C(═S)SC 1-6 alkyl, —SC(═S)SC 1-6 alkyl, —P(═O) 2 (C 1-6 alkyl), —P(═O)(C 1-6 alkyl) 2 , —OP(═O)(C 1-6 alkyl) 2 , —OP(═O)OC 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 perhaloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, heteroC 1-6 alkyl, heteroC 2-6 alkenyl, heteroC 2-6 alkynyl, C 3-20 carboxyxlyl, C 6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal R gg substituents can be joined to form ═O or ═S; wherein X − is a counterion.

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, —N(R cc ) 2 , —C(═O)R aa , —C(═O)N(R cc ) 2 , —CO 2 R aa , —SO 2 R aa , —C(═NR cc )R aa , —C(═NR cc )OR aa , —C(═NR cc )N(R cc ) 2 , —SO 2 N(R cc ) 2 , —SO 2 RR ee , —SO 2 OR cc , —SOR aa , —C(═S)N(R cc ) 2 , —C(═O)SR cc , —C(═S)SR cc , C 1-10 alkyl (e.g., alkyl, aralkyl, heteroalkyl), C 2-10 alkenyl, C 2-10 alkynyl, C 1-10 heteroalkyl, C 2-10 heteroalkenyl, C 2-10 heteroalkynyl, C 3-10 carbocyclyl, 3-14 membered heterocyclyl, C 6-14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and wherein R aa , R bb , R cc and R dd are as 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 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

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

Nitrogen protecting groups such as carbamate groups (e.g., —C(═O)OR aa ) include, but are not limited to, methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and 4′-pyridyl) ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido) ethyl carbamate, t-butyl carbamate (BOC), 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, isobornyl 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) 2 R 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-trimethybenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pme), 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 , —CO 2 R aa , —C(═O)N(R bb ) 2 , —C(═NR bb )R aa , —C(═NR bb )OR aa , —C(═NR bb )N(R bb ) 2 , —S(═O)R aa , —SO 2 R aa , —Si(R aa ) 3 , —P(R cc ) 2 , —P(R cc ) 3 , —P(═O) 2 R aa , —P(═O)(R aa ) 2 , —P(═O)(OR cc ) 2 , —P(═O) 2 N(R bb ) 2 , and —P(═O)(NR bb ) 2 , wherein R aa , R bb , and R cc are 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 rd edition, John Wiley & Sons, 1999, incorporated herein by reference.

Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, a-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-fluoronylmethyl 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-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).

In certain embodiments, the substituent present on 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 , —CO 2 R aa , —C(═O)N(R bb ) 2 , —C(═NR bb )R aa , —C(═NR bb )OR aa , —C(═NR bb )N(R bb ) 2 , —S(═O)R aa , —SO 2 R aa , —Si(R aa ) 3 , —P(R cc ) 2 , —P(R cc ) 3 , —P(═O) 2 R aa , —P(═O)(R aa ) 2 , —P(═O)(OR cc ) 2 , —P(═O) 2 N(R bb ) 2 , and —P(═O)(NR bb ) 2 , wherein R aa , R bb , and R cc are 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 rd edition, 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, —NO 2 , 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 —OSO 2 R LG1 wherein R LG1 is 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 LG1 is substituted or unsubstituted C 1 -C 6 alkyl. In certain embodiments, R LG1 is methyl. In certain embodiments, R LG1 is —CF 3 . In certain embodiments, R LG1 is substituted or unsubstituted aryl. In certain embodiments, R LG1 is substituted or unsubstituted phenyl. In certain embodiments R LG1 is:

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, FIGURES, 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. Phannaceutically 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 alkyl) 4 − salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. 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.x H 2 O, 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.0.5H 2 O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R.2H 2 O) and hexahydrates (R.6H 2 O)).

The term “tautomers” refer to compounds that are inter-changeable 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 π 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 diiferent 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 cleavabie 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 C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, aryl, C 7 -C 12 substituted aryl, and C 7 -C 12 arylalkyl esters of the compounds of the invention (e.g., the compounds of Formula (A), (I-11), (II), or (V)).

BRIEIF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows isobolograms demonstrating the synergy between compound (A-17) and a BTK inhibitor. Points below the 1 to 1 line connecting the X and Y axes are ‘synergistic’, points near the line are ‘additive’, and points above it are antagonistic.

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, HPK1). 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 (eg, BCWM.1, MWCL-1). Based on these screening etforts and subsequent lead optimization, compounds of any one of Formulae (A), (I-11), (II), and (V) (e.g., compounds of Formula (A-1)-(A18)) were identified.

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

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

each instance of R A is 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 , —NO 2 , —NR A1 C(═O)R A1 , —NR A1 C(═O)OR A1 , —NR A1 S(═O) 2 R A1 , —S(═O) 2 R A1 , or —S(═O) 2 N(R A1 ) 2 ;

each instance of R B is 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 , —NO 2 , —NR A1 C(═O)R A1 , —NR A1 C(═O)OR A1 , —NR A1 S(═O) 2 R A1 , —S(═O) 2 R A1 , or —S(═O) 2 N(R A1 ) 2 ;

each instance of R A1 is 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 A1 groups are joined to form an optionally substituted heterocyclic ring:

one instance of A that is included in Ring B is CR Y ;

the other instance of A that is included in Ring B is CR Y or N;

each instance of R Y is independently H, halogen, or substituted or unsubstituted C 1-6 alkyl;

each instance of R X is independently selected from the group consisting of R D , optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and —N(R A1 )(R Xa );

each instance of R Xa is 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) 2 R A1 , —S(═O) 2 OR A1 , —S(═O) 2 R A1 , —S(═O) 2 N(R A1 ) 2 , —N(R A1 ) 2 , and a nitrogen protecting group;

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

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

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

R D is an electrophilic moiety as described herein.

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

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), and/or phosphoinositide 3-kinase (PI3K), transforming growth factor b-activated kinase-1 (TAK1), and/or a Src family kinase.

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. 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), intra-vascular large B-cell lymphoma, primary effusion lymphoma, and lymphomatoid granulomatosis.

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

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

each instance of R A is 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 , —NO 2 , —NR A1 C(═O)R A1 , —NR A1 C(═O)OR A1 , —NR A1 S(═O) 2 R A1 , —S(O) 2 R A1 , or —S(═O) 2 N(R A1 ) 2 ;

each instance of R B is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocycl, 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 , —NO 2 , —NR A1 C(═O)R A1 , —NR A1 C(═O)OR A1 , —NR A1 S(═O) 2 R A1 , —S(—O) 2 R A1 , or —S(═O) 2 N(R A1 ) 2 ;

each instance of R A1 is 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 A1 groups are joined to form an optionally substituted heterocyclic ring;

each instance of R X is independently selected from the group consisting of R D , optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and —N(R A1 )(R Xa );

each instance of R Xa is 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) 2 R A1 , —S(═O) 2 OR A1 , —S(═O) 2 N(R A1 ) 2 , —S(═O) 2 N(R A1 ) 2 , —N(R A1 ) 2 , and a nitrogen protecting group;

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

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

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

R D is an electrophilic moiety as described herein.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is adminstered compound (A-10):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is adminstered compound (A-11):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is adminstered compound (A-12):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is adminstered compound (A-13):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is adminstered compound (A-14):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is adminstered compound (A-15):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is adminstered compound (A-16):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is adminstered compound (A-17):

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the subject is adminstered compound (A-18):

or a pharmaceutically acceptable salt thereof.

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

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

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

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

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

In certain embodiments, Ring A is of the formula:

In certain embodiments, Ring A is of the formula:

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

In compounds of Formula (A), Ring A may be substituted with one or more R A groups. In certain embodiments, at least one R A is H. In certain embodiments, at least two R A groups are H. In certain embodiments, at least three R A groups are H. In certain embodiments, at least four R A groups are H. In certain embodiments, at least one R A is not H. In certain embodiments, at least two R A groups are not H. In certain embodiments, at least three R A groups are not H. In certain embodiments, at least one R A is halogen. In certain embodments, at least one R A is F. In certain embodiments, at least one R A is Cl. In certain embodiments, at least one R A is Br. In certain embodiments, at least one R A is I (iodine). In certain embodiments, one R A is F. In certain embodiments, one R A is Cl. In certain embodiments, at least one R A is substituted alkyl. In certain embodiments, at least one R A is unsubstituted alkyl. In certain embodiments, at least one R A is substituted C 1-6 alkyl. In certain embodiments, at least one R A is unsubstituted C 1-6 alkyl. In certain embodiments, at least one R A is methyl. In certain embodiments, at least one R A is ethyl. In certain embodiments, at least one R A is propyl. In certain embodiments, at least one R A is butyl. In certain embodiments, at least one R A is subtituted carbocyclyl. In certain embodiments, at least one R A is unubstituted carbocyclyl. In certain embodiments, at least one R A is —OR A1 . In certain embodiments, at least one R A —O(C 1-6 alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R A is —OMe. In certain embodiments, at least one R A is —OH. In certain embodiments, at least one R A is —N(R A1 ) 2 . In certain embodiments, at least one R A is —NH 2 . In certain embodiments, at least one R A is —CN. In certain embodiments, at least one R A is —C(═O)R A1 . In certain embodiments, at least one R A is acetyl. In certain embodiments, at least one R A is —C(═O)OR A1 . In certain embodiments, at least one R A is —C(═O)N(R A1 ) 2 . In certain embodiments, at least one R A is —C(═O)NHR A1 . In certain embodiments, at least one R A is —C(═O)NH(C 1-6 alkyl) where the alkyl is aubstituted or unsubstituted. In certain embodiments, at least one R A is —C(═O)NHMe. In certain embodiments, at least one R A is —C(═O)NH 2 . In certain embodiments, at least one R A is —NO 2 . In certain embodiments, at least one R A is —NR A1 C(═O)R A1 . In certain embodiments, at least one R A is —NR A1 C(═O)OR A1 . In certain embodiments, at least one R A is —NR A1 S(═O) 2 R A1 . In certain embodiments, at least one R A is —NHS(═O) 2 R A1 . In certain embodiments, at least one R A is —NHS(═O) 2 (C 1-6 alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R A is —NHS(═O) 2 Me. In certain embodiments, at least one R A is —S(═O) 2 R A1 . In certain embodiments, at least one R A is —S(═O) 2 N(R A1 ) 2 . In certain embodiments, at least one R A is —S(═O) 2 N(R A1 ) 2 . In certain embodiments, at least one R A is —S(═O) 2 N(C 1-6 alkyl) 2 . In certain embodiments, at least one R A is —S(═O) 2 NH(C 1-6 alkyl). In certain embodiments, at least one R A is —S(═O) 2 NH(t-Bu). In certain embodiments, at least one R A is —S(═O) 2 NH 2 .

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

In certain embodiments, R A is substituted C 1-6 alkyl; and k is 1. In certain embodiments, R A is unsubstituted C 1-6 alkyl; and k is 1. In certain embodiments, R A is methyl; and k is 1. In certain embodiments, R A is —CF 3 ; and k is 1. In certain embodiments, R A is ethyl; and k is 1. In certain embodiments, R A is propyl; and k is 1. In certain embodiments, R A is butyl; and k is 1. In certain embodiments, R A is propyl; and k is 1 . In certain embodiments, R A is butyl; and k is 1.

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

In certain embodiments, one instance of R A is halogen; another instance of R A is substituted C 1-6 alkyl; and k is 2. In certain embodiments, one instance of R A is F; another instance of R A is substituted C 1-6 alkyl; and k is 2. In certain embodiments, one instance of R A is Cl; another instance of R A is substituted C 1-6 alkyl; and k is 2. In certain embodiments, one instance of R A is halogen; another instance of R A is unsubstituted C 1-6 alkyl; and k is 2. In certain embodiment one instance of R A is F; another instance of R A is unsubstituted C 1-6 alkyl; and k is 2. In certain embodiments, one instance of R A is Cl; another instance of R A is unsubstituted C 1-6 alkyl; and k is 2. In certain embodiments, one instance of R A is halogen; another instance of R A is methyl; and k is 2. In certain embodiments, one instance of R A is F; another instance of R A is methyl; and k is 2. In certain embodiments, one instance of R A is Cl; another instance of R A is methyl; and k is 2. In certain embodiments, one instance of R A is halogen; another instance of R A is —CF 3 ; and k is 2. In certain embodiments, one instance of R A is F; another instance of R A is —CF 3 ; and k is 2. In certain embodiments, one instance of R A is Cl; another instance of R A is —CF 3 ; and k is 2.

In certain embodiments, at least one R A1 is H. In certain embodiments, at least one R A1 is substituted acyl. In certain embodiments, at least one R A1 is unsubstituted acyl. In certain embodiments, at least one R A1 is acetyl. In certain embodiments, at least one R A1 is substituted alkyl. In certain embodiments, at least one R A1 is unsubstituted alkyl. In certain embodiments, at least one R A1 is C 1-6 alkyl. In certain embodiments, at least one R A1 is methyl. In certain embodiments, at least one R A1 is ethyl. In certain embodiments, at least one R A1 is propyl. In certain embodiments, at least one R A1 is butyl. In certain embodiments, at least one R A1 is substituted alkenyl. In certain embodiments, at least one R A1 is unsubstituted alkenyl. In certain embodiments, at least one R A1 is substituted alkynyl. In certain embodiments, at least one R A1 is unsubstituted alkynyl. In certain embodiments, at least one R A1 is substituted carbocyclyl. In certain embodiments, at least one R A1 is unsubstituted carbocyclyl. In certain embodiments, at least one R A1 is substituted heterocyclyl. In certain embodiments, at least one R A1 is unsubstituted heterocyclyl. In certain embodiments, at least one R A1 is substituted aryl. In certain embodiments, at least one R A1 is unsubstituted aryl. In certain embodiments, at least one R A1 is substituted phenyl. In certain embodiments, at least one R A1 is unsubstituted phenyl. In certain embodiments, at least one R A1 is substituted heteroaryl. In certain embodiments, at least one R A1 is unsubstituted heteroaryl. In certain embodiments, at least one R A1 is substituted pyridyl. In certain embodiments, at least one R A1 is unsubstituted pyridyl. In certain embodiments, at least one R A1 is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R A1 is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R A1 is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R A1 is 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 A1 is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R A1 is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom.

In compounds of Formula (A), two R A1 groups 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 A1 groups are joined to form a substituted carbocyclic ring. In certain embodiments, two R A1 groups are joined to form an unsubstituted carbocyclic ring. In certain embodiments, two R A1 groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R A1 groups are joined to form an unsubstituted heterocyclic ring. In certain embodiments, two R A1 groups are joined to form a substituted aryl ring. In certain embodiments, two R A1 groups are joined to form an unsubstituted aryl ring. In certain embodiments, two R A1 groups are joined to form a substituted phenyl ring. In certain embodiments, two R A1 groups are joined to form an unsubstituted phenyl ring. In certain embodiments, two R A1 groups are joined to form a substituted heteroaryl ring. In certain embodiments, two R A1 groups are joined to form an unsubstituted heteroaryl ring.

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

In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of the formula:

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

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

In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of the formula:

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

In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of the formula:

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

In certain embodiments, Ring C is of the formula:

In certain embodiments, Ring C is of the formula:

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

In compounds of Formula (A), Ring C may be substituted with one or more R B groups. In certain embodiments at least one R B is H. In certain embodiments, at least two R B groups are H. In certain embodiments, at least three R B groups are H. In certain embodiments, at least four R B groups are H. In certain embodiments, at least one R B is not H. In certain embodiments, at least two R B groups are not H. In certain embodiments, at least three R B groups are not H. In certain embodiments, at least one R B is halogen. In certain embodiments, at least one R B is F. In certain embodiments, at least one R B is Cl. In certain embodiments, at least one R B is Br. In certain embodiments, at least one R B is I (iodine). In certain embodiments, one R B is F. In certain embodiments, one R B is Cl. In certain embodiments, at least one R B is substituted alkyl. In certain embodiments, at least one R B is unsubstituted alkyl. In certain embodiments, at least one R B is substituted C 1-6 alkyl. In certain embodiments, at least one R B is unsubstituted C 1-6 alkyl. In certain embodiments, at least one R B is methyl. In certain embodiments, at least one R B is ethyl. In certain embodiments, at least one R B is propyl. In certain embodiments, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is butyl. In certain embodiments, at least one R B is substituted carbocyclyl. In certain embodiments, at least one R B is unsubstituted carbocyclyl. In certain embodiments, at least one R B is substituted heterocyclyl. In certain embodiments, at least one R B is unsubstituted heterocyclyl. In certain embodiments, at least one R B is substituted piperidine. In certain embodiments, at least one R B is unsubstituted piperidine. In certain embodiments, at least one R B substituted piperizine. In certain embodiments, at least one R B unsubstituted piperizine. In certain embodiments, at least one R B substituted pyrrolidine. In certain embodiments, at least one R B unsubstituted pyrrolidine. In certain embodiments, at least one R B is substituted morpholine. In certain embodiments, at least one R B is unsubstituted morpholine. In certain embodiments, at least one R B is substituted diazepane. In certain embodiments, at least one R B is unsubstituted diazepane. In certain embodiments, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is substituted —(CH 2 )(heterocyclyl). In certain embodiments, at least one R B is unsubstituted —(CH 2 )(heterocyclyl). In certain embodiments, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is substituted —(CH 2 ) 2 (heterocyclyl). In certain embodiments, at least one R B is unsubstituted —(CH 2 ) 2 (heterocyclyl). In certain embodiments, at least one R B is

In certain embodiments, at least one R B is substituted —(CH 2 ) 2 (heterocyclyl). In certain embodiments, at least one R B is unsubstituted —(CH 2 ) 2 (heterocyclyl). In certain embodiments, at least one R B is

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

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is —OR A1 . In certain embodiments, at least one R B is —O(C 1-6 alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R B is —OMe. In certain embodiments, at least one R B is —OPh. In certain embodiments, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is —OH. In certain embodiments, at least one R B is —N(R A1 ) 2 . In certain embodiments, at least one R B is —NEt 2 . In certain embodiments, at least one R B is —NMe 2 . In certain embodiments, at least one R B is —NHtBu. In certain embodiments, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is —NH 2 . In certain embodiments, at least one R B certain embodiments, at least one R B is —NH 2 . In certain embodiments, at least one R is —CN. In certain embodiments, at least one R B is —C(═O) R A1 . In certain embodiments, at least one R B is acetyl. In certain embodiments, at least one R B is —C(═O)OR A1 . In certain embodiments, at least one R B is —C(═O)N(R A1 ) 2 . In certain embodiments, at least one R B is —C(═O)NHR A1 . In certain embodiments, at least one R B is —C(═O)NH (C 1-6 alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R B is —C(═O)NHMe. In certain embodiments, at least one R B is —C(═O)NH 2 . In certain embodnnents, at least one R B is

In certain embodiments, at least one R B is

In certain embodiments, at least one R B is —NO 2 . In certain embodiments, at least one R B is —NR A1 C(═O)R A1 . In certain embodiments, at least one R B is —NR A1 C(═O) OR A1 . In certain embodiments, at least one R B is —NR A1 S (═O) 2 R A1 . In certain embodiments, at least one R B is —NHS(═O) 2 R A1 . In certain embodiments, at least one R B is —NHS(═O) 2 (C 1-6 alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R B is —NHS(═O) 2 Me. In certain embodiments, at least one R B is —S(═O) 2 R A1 . In certain embodiments, at least one R B is —S(═O) 2 N(R A1 ) 2 . In certain embodiments, at least one is —S(═O) 2 N( A1 ) 2 . In certain embodiments, at least one R B is —S(═O) 2 N(C 1-6 alkyl) 2 . In certain embodiments, at least one R B is —S(═O) 2 NH(C 1-6 alkyl). In certain embodiments, at least one R B is —S(═O) 2 NH(t-Bu). In certain embodiments, at least one R B is —S(═O) 2 NH 2 .

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

and l is 1. In certain embodiments, R B is

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

l is 1; and R B is para to the point of attachment of U. In certain embodiments, R B is substituted or unsubstituted —CH 2 -(piperazinyl); and l is 1. In cwrtain embodiments, R B is substitued to unsubstituted —CH 2 -(piperazinyl); l is 1; and R B is meta to the point of attachment of U. In certain embodiments, R B is substituted or unsubstituted —CH 2 -piperazinyl); l is 1; and R B is para to the point of attachment of U. In certain embodiments, R B is

and l is 1. In certain embodiments, R B is

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

l is 1; and R B is para to the point of attachment of U. In certain embodiments, R B is haloalkyl; and l is 1. In certain embodiments, R B is haloalkyl; l is 1; and R B is meta to the point of attachment of U. In certain embodiments, R B is haloalkyl; l is 1; and R B is para to the point of attachment of U. In certain embodiments, R B is —CF 3 ; and l is 1. In certain embodiments, R B is —CF 3 ; l is 1; and R B is meta to the point of attachment of U. In certain embodiments, R B is —CF 3 ; l is 1; and R B is para to the point of attachment of U. In certain embodiments, R B is substituted or unsubstituted imidazoyl and l is 1. In certain embodiments, R B is substituted or unsubstituted imidazoyl l is 1; and R B is meta to the point of attachment of U. In certain embodiments, R B is substituted or unsubstituted imidazoyl; l is 1; and R B is para to the point of attachment of U. In certain embodiments, R B is

and l is 1. In certain embodiments, R B is

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

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

and l is 1. In certain embodiments, R B is

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

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

In certain embodiments, at least one R B group is substituted or unsubstituted C 1-6 alkyl; and l is 2. In certain embodiments, at least one R B group is substituted or unsubstituted C 1-6 alkyl; l is 2; and at least one R B is meta to the point of attachment of U. In certain embodiments, at least one R B group is substituted or unsubstituted C 1-6 alkyl; l is 2; and one R B is para to the point of attachment of U. In certain embodiments, at least one R B group is C 1-6 alkyl substituted with one —CN group; and l is 2. In certain embodiments, at least one R B group is C 1-6 alkyl substituted with one —CN group; l is 2; and at least one R B is meta to the point of attachment of U. In certain embodiments, at least one R B group is C 1-6 alkyl substituted with one —CN group; l is 2; and one R B is para to the point of attachment of U. In certain embodiments, at least one R B group is

and l is 2. In certain embodiments, at least one R B group is

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

l is 2; and one R B is para to the point of attachment of U. In certain embodiments, at least one R B group is substituted or unsubstituted —CH 2 -(piperazinyl); and l is 2. In certain embodiments, at least one R B group is substituted or unsubstituted —CH 2 -(piperazinyl): l is 2; and at least one R B is meta to the point of attachment of U. In certain embodiments, at least one R B group is substituted or unsubstituted —CH 2 -(piperazinyl); l is 2; and one R B is para to the point of attachment of U. In certain embodiments, at least one R B group is

and l is 2. In certain embodiments, at least one R B group is

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

l is 2; and one R B is para to the point of attachment of U. In certain embodiments, at least one R B group is haloalkyl; and l is 2. In certain embodiments, at least one R B group is haloalkyl; l is 2; and at least one R B is meta to the point of attachment of U. In certain embodiments, at least one R B group is haloalkyl; l is 2; and one R B is para to the point of attachment of U. In certain embodiments, at least one R B group is —CF 3 ; and l is 2. In certain embodiments, at least one R B group is —CF 3 ; l is 2; and at least one R B is meta to the point of attachment of U. In certain embodiments, at least one R B group is —CF 3 ; l is 2; and one R B is para to the point of attachment of U. In certain embodiments, at least one R B group is substituted or unsubstituted imidazoyl; and l is 2. In certain embodiments, at least one R B group is substituted or unsubstituted imidazoyl; l is 2; and at least one R B is meta to the point of attachment of U. In certain embodiments, at least one R B group is substituted or unsubstituted imidazoyl; l is 2; and one R B is para to the point of attachment of U. In certain embodiments, at least one R B group is

and l is 2. In certain embodiments, at least one R B group is

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

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

l is 2. In certain embodiments, at least one R B group is

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

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

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

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

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

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

Formula (A) includes a pyridine or pyrimidine ring as Ring B. In certain embodiments, each instance of A included in Ring B is carbon. In certain embodiments, one instance of A included in Ring B is carbon, and the other instance of A included in Ring B is nitrogen. In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

In certain embodiments, Ring B is of the formula:

Formula (A) may include one or more R Y groups. When Formula (A) includes two instances of R Y , the two instances of R Y may be the same or different from each other. In certain embodiments, at least one instance of R Y is H. In certain embodiments, each instance of R Y is H. In certain embodiments, at least one instance of R Y is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of R Y is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, at least one instance of R Y is Me. In certain embodiments, at least one instance of R Y is substituted methyl (e. g., —CF 3 or Bn). In certain embodiments, at least one instance of R Y is Et, substituted ethyl (e.g., perfluoroethyl), Pr, substituted propyl (e.g., perfluoropropyl), Bu, or substituted butyl (e.g., perfluorobutyl).

In compounds of Formula (A), the pyridine or pyrimidine ring may be substituted with one or more R X groups. When Formula (A) includes two instances of R X , the two instances of R X may be the same or different from each other. In certain embodiments, at least one R X is substituted carbocyclyl. In certain embodiments, at least one R X is unsubstituted carbocyclyl. In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is substituted heterocyclyl. In certain embodiments, at least one R X is unbustituted hererocyclyl. In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is substituted aryl. In certain embodiments, at least one R X is unsubstituted aryl. In certain embodiments, at least one R X is substituted phenyl. In certain embodiments, at least one R X is unsubstituted phenyl. In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is substituted heteroaryl. In certain embodiments, at least one R X is unsubstituted heteroaryl. In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is —N(R A1 )(R Xa ). In certain embodiments, at least one R X is —NH 2 . In certain embodiments, at least one R X is —NH (3-6 membered cycloalkyl) where the cycloalkyl is substituted or unsubstituted. In certain embodiments, at least one R X is

In certain embodiments, at least one R X is —NH(C 1-6 alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R X is —N(C 1-6 alkyl) 2 where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R X is

In certain embodiments, at least one R X is —NH(acyl). In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is —NHC(═O)(3-6 membered cycloalkyl) where the cycloalkyl is ubtituted or unsubstituted. In certain embodiments, at least one R X is

In certain embodiments, at least one R X is —NHC(═O)(C 1-6 alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is

In certain embodiments, at least one R X is —N(R A1 )N(R A1 ) 2 . In certain embodiments, at least one R X is —NHN(R A1 ) 2 . In certain embodiments, at least one R X is —NHNH(acyl). In certain embodiments, at least one R X is —NHNHC(═O)Me. In certain embodiments, at least one R X is —NHN(C 1-6 alkyl) 2 where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R X is —NHNMe 2 .

In compounds of Formula (A), R X may be substituted with one or more R Xa groups. Each instance of R Xa is 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) 2 R A1 S(═O) 2 OR A , —S(═O) 2 R A1 , —S(═O) 2 N(R A1 ) 2 , —N(R A1 ) 2 , and a nitrogen protecting group; wherein each occurrence of R A1 is 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 A1 groups are joined to form an optionally substituted heterocyclic ring.

In certain embodiments, at least one R Xa is H. In certain embodiments, all R Xa groups are H. In certain embodiments, at least one R Xa is substituted alkyl. In certain embodiments, at least one R Xa is substituted C 1-6 alkyl. In certain embodiments, at least one R Xa is substituted methyl. In certain embodiments, at least one R Xa is unsubstituted alkyl. In certain embodiments, at least one R Xa is unsubstituted C 1-6 alkyl. In certain embodiments, at least one R Xa is methyl. In certain embodiments, at least one R Xa is ethyl. In certain embodiments, at least one R Xa is propyl. In certain embodiments, at least one R Xa is butyl. In certain embodiments, at least one R Xa is substituted alkenyl. In certain embodiments, at least one R Xa is unsubstituted alkenyl. In certain embodiments, at least one R Xa is substituted alkynyl. In certain embodiments, at least one R Xa is unsubstituted alkynyl. In certain embodiments, at least one R Xa is substituted carbocyclyl. In certain embodiments, at least one R Xa is unsubstituted carbocyclyl. In certain embodiments, at least one R Xa is substituted heterocyclyl. In certain embodiments, at least one R Xa is unsubstituted heterocyclyl. In certain embodiments, at least one R Xa is substituted aryl. In certain embodiments, at least one R Xa is unsubstituted aryl. In certain embodiments, at least one R Xa is substituted phenyl. In certain embodiments, at least one R Xa is unsubstituted phenyl. In certain embodiments, at least one R Xa is substituted heteroaryl. In certain embodiments, at least one R Xa is unsubstituted heteroaryl. In certain embodiments, at least one R Xa is —C(═O)R A1 . In certain embodiments, at least one R Xa —C(═O)H. In certain embodiments, at least one R Xa is acetyl. In certain embodiments, at least one R Xa is —C(═O)(C 1-6 alkyl). In certain embodiments, at least one R Xa —(═O)OR A1 . In certain embodiments, at least one R Xa is —C(═O)OH. In certain embodiments, at least one R Xa is —C(═O)O(C 1-6 alkyl). In certain embodiments, at least one R Xa is —C(═O)N(R A1 ) 2 . In certain embodiments, at least one R Xa is —C(═O)NHR A1 . In certain embodiments, at least one R Xa is —C(═O)N(C 1-6 alkyl) 2 . In certain embodiments, at least one R Xa is —C(═O)NH(C 1-6 alkyl). In certain embodiments, at least one R Xa is —C(═O)NH 2 . In certain embodiments, at least one R Xa is —S(═O)R A1 . In certain embodiments, at least one R Xa is —S(═O)(C 1-6 alkyl). In certain embodiments, at least one R Xa is —S(═O)N(R A1 ) 2 . In certain embodiments, at least one R Xa is —S(═O)NH(R A1 ). In certain embodiments, at least one R Xa is —S(═O)NH 2 . In certain embodiments, at least one R Xa is —S(═O)N(C 1-6 alkyl) 2 . In certain embodiments, at least one R Xa is —S(═O)NH(C 1-6 alkyl). In certain embodiments, at least one R Xa is —S(═O) 2 R A1 . In certain embodiments, at least one R Xa is —S(═O) 2 (C 1-6 alkyl). In certain embodiments, at least one R Xa is —S(═O) 2 OR A1 . In certain embodiments, at least one R Xa is —S(═O) 2 OH. In certain embodiments, at least one R Xa is —S(═O) 2 N(R A1 ) 2 . In certain embodiments, at least one R Xa is —S(═O) 2 NH (R A1 ). In certain embodiments, at least one R Xa is —S(═O) 2 NH 2 . In certain embodiments, at least one R Xa is —S(═O) 2 N(C 1-6 alkyl) 2 . In certain embodiments, at least one R Xa is —S(═O) 2 NH(C 1-6 alkyl). In certain embodiments, at least one R Xa is —N(R A1 ) 2 . In certain embodiments, at least one R Xa is —NH(R A1 ). In certain embodiments, at least one R Xa is —NH(acyl). In certain embodiments, at least one R Xa is —NHC(—O)Me. In certain embodiments, at least one R Xa is —N(C 1-6 alkyl) 2 where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R Xa is —NMe 2 .

In compounds of Formula (A), R X may be substituted with one or more R Xc groups. Each instance of R Xc is 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 , —NO 2 , —N 3 , —NR A1 C(═O)R A1 , —NR A1 C(═O)OR A1 , —NR A1 C(═O)N(R A1 ) 2 , —NR A1 S(═O) 2 R A1 , —NR A1 S(═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) 2 R A1 , —S(═O) 2 N(R A1 ) 2 ; wherein each occurrence of R A1 is 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 A1 groups are joined to form an optionally substituted heterocyclic ring.

In certain embodiments, at least one R Xc is H. In certain embodiments, all R Xc groups are H. In certain embodiments, at least one R Xc is substituted alkyl. In certain embodiments, at least one R Xc is substituted C 1-6 alkyl. In certain embodiments, at least one R Xc is substituted methyl. In certain embodiments, at least one R Xc is unsubstituted alkyl. In certain embodiments, at least one R Xc is unsubstituted C 1-6 alkyl. In certain embodiments, at least one R Xc is methyl. In certain embodiments, at least one R Xc is ethyl. In certain embodiments, at least one R Xc is propyl. In certain embodiments, at least one R Xc is butyl. In certain embodiments, at least one R Xc is substituted alkenyl. In certain embodiments, at least one R Xc is unsubstituted alkenyl. In certain embodiments, at least one R Xc is substituted alkynyl. In certain embodiments, at least one R Xc is unsubstituted alkynyl. In certain embodiments, at least one R Xc is substituted carbocyclyl. In certain embodiments, at least one R Xc is unsubstituted carbocyclyl. In certain embodiments, at least one R Xc is substituted heterocyclyl. In certain embodiments, at least one R Xc is unsubstituted heterocyclyl. In certain embodiments, at least one R Xc is substituted aryl. In certain embodiments, at least one R Xc is unsubstituted aryl. In certain embodiments, at least one R Xc is substituted phenyl. In certain embodiments, at least one R Xc is unsubstituted phenyl. In certain embodiments, at least one R Xc is substituted heteroaryl. In certain embodiments, at least one R Xc is unsubstituted heteroaryl. In certain embodiments, at least one R Xc is —OR A1 . In certain embodiments, at least one R Xc is —OH. In certain embodiments, at least one R Xc is —O(C 1-6 alkyl). In certain embodiments, at least one R Xc is —N(R A1 ) . In certain embodiments, at least one R Xc is —NH(R A1 ). In certain embodiments, at least one R Xc is —N(C 1-6 alkyl) 2 . In certain embodiments, at least one R Xc is —NH(C 1-6 alkyl). In certain embodiments, at least one R Xc is —NH 2 . In certain embodiments, at least one R Xc is —SR A1 . In certain embodiments, at least one R Xc is —SH. In certain embodiments, at least one R Xc is —S(C 1-6 alkyl). In certain embodiments, at least one R Xc is —CN. In certain embodiments, at least one R Xc is —NO 2 . In certain embodiments, at least one R Xc is —N 3 . In certain embodiments, at least one R Xc is —NR A1 C(═O)R A1 . In certain embodiments, at least one R Xc is —NHC(═O)R A1 . In certain embodiments, at least one R Xc is —NHC(═O)(C 1-6 alkyl). In certain embodiments, at least one R Xc is —NR A1 C(═O)OR A1 . In certain embodiments, at least one R Xa is —NHC(═O)OR A1 . In certain embodiments, at least one R Xc is —NR A1 C(═O)O(C 1-6 alkyl). In certain embodiments, at least one R Xc is —NR A1 C(═O)N(R A1 ) 2 . In certain embodiments, at least one R Xc is —NHC(═O)N(C 1-6 alkyl) 2 . In certain embodiments, at least one R Xc is —NHC(═O)NH 2 . In certain embodiments, at least one R Xc is —NR A1 S(═O) 2 R A1 . In certain embodiments, at least one R Xc is —NHS(═O) 2 R A1 . In certain embodiments, at least one R Xc is —NHS(═O) 2 (C 1-6 alkyl). In certain embodiments, at least one R Xc is —NR A1 S(═O)R A1 . In certain embodiments, at least one R Xc is —NR A1 S(═O)(C 1-6 alkyl). In certain embodiments, at least one R Xc is —NHS(═O)(C 1-6 alkyl). In certain embodiments, at least one R Xc is —OC(═O)R A1 . In certain embodiments, at least one R Xc is —OC(═O)(C 1-6 alkyl). In certain embodiments, at least one R Xc is —OC(═O)OR A1 In certain embodiments, at least one R Xc is —OC(═O)O(C 1-6 alkyl). In certain embodiments, at least one R Xc is —OC(═O)N(R A1 ) 2 . In certain embodiments, at least one R Xc is —OC(═O)NH(R A1 ). In certain embodiments, at least one R Xc is —OC(═O)N(C 1-6 alkyl) 2 . In certain embodiments, at least one R Xc is —C(═O)R A1 . In certain embodiments, at least one R Xc is —C(═O)H. In certain embodiments, at least one R Xc is acetyl. In certain embodiments, at least one R Xc is —C(═O)(C 1-6 alkyl). In certain embodiments, at least one R Xc is —C(═O)OR A1 In certain embodiments, at least one R Xc is —C(═O)OH. In certain embodiments, at least one R Xc is —C(═O)O(C 1-6 alkyl). In certain embodiments, at least one R Xc is —C(═O)N(R A1 ) 2 . In certain embodiments, at least one R Xc is —C(═)NHR A1 . In certain embodiments, at least one R Xc is —C(═O)N(C 1-6 alkyl) 2 . In certain embodiments, at least one R Xc is —C(═O)NH(C 1-6 alkyl). In certain embodiments, at least one R Xc is —C(═O)NH 2 . In certain embodiments, at least one R Xc is —S(═O)R A1 . In certain embodiments, at least one R Xc is —S(═O)(C 1-6 alkyl). In certain embodiments, at least one R Xc is —S(═O)N(R A1 ) 2 . In certain embodiments, at least one R Xc is —S(═O)NH(R A1 ). In certain embodiments, at least one R Xc is —S(═O)NH 2 . In certain embodiments, at least one R Xc is —S(═O)N(C 1-6 alkyl) 2 . In certain embodiments, at least one R Xc is —S(═O)NH(C 1-6 alkyl). In certain embodiments, at least one R Xc is —S(═O) 2 R A1 . In certain embodiments, at least one R Xc is —S(═O) 2 (C 1-6 alkyl). In certain embodiments, at least one R Xc is —S(═O) 2 OR A1 . In certain embodiments, at least one R Xc is —S(═O) 2 OH. In certain embodiments, at least one R Xc is —S(═O) 2 N(R A1 ) 2 . In certain embodiments, at least one R Xc is —S(═O) 2 NH(R A1 ). In certain embodiments, at least one R Xc is —S(═O) 2 NH 2 . In certain embodiments, at least one R Xc is —S(═O) 2 N(C 1-6 a 1 kyl) 2 . In certain embodiments, at least one R Xc is —S(═O) 2 NH(C 1-6 alkyl).

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

R D1 is 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, —NO 2 , —OR D1a , —N(R D1a ) 2 , —SR D1a , —CH 2 OR D1a , —CH 2 N(R D1a ) 2 , —CH 2 SR D1a , —C(═O)R D1a , —C(═ 0 )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 D1a is 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 D1a groups are joined to form an optionally substituted heterocyclic ring;

R D2 is 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, —NO 2 , —OR D2a , —N(R D2a ) 2 , —SR D2a , —CH 2 OR D2a , —CH 2 N(R D2a ) 2 , —CH 2 SR D2a , —C(═O)R D2a , —C(═ 0 )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 D2a is 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 D2a groups are joined to form an optionally substituted heterocyclic ring;

R D3 is 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, —NO 2 , —OR D3a , —N(R D3a ) 2 , —SR D3a , —CH 2 OR D3a , —CH 2 N(R D3a ) 2 , —CH 2 SR D3a , —C(═O)R D3a , —C(═ 0 )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 D3a is 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 D3a groups are joined to form an optionally substituted heterocyclic ring;

optionally R D1 and R D3 , or R D2 and R D3 , or R D1 and R D2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;

R D4 is a leaving group;

R D5 is hydrogen, C 1-6 alkyl, or a nitrogen protecting group;

Y Z is —O—, —S—, or —NR D6 —, wherein R D6 is hydrogen, C 1-6 alkyl, or a nitrogen protecting group;

a is 1 or 2;

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

optionally R D5 and one R C are joined to form an optionally substituted heterocyclic ring.

In certain embodiments, R D comprises 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 D is of Formula (i-1). In certain embodiments, R D is of Formula (i-2). In certain embodiments, R D is of Formula (i-3). In certain embodiments, R D is of Formula (i-4). In certain embodiments, R D is of Formula (i-5). In certain embodiments, R D is of Formula (i-6). In certain embodiments, R D is of Formula (i-7). In certain embodiments, R D is of Fomiula (i-8). In certain embodiments, R D is of Formula (i-9). In certain embodiments, R D is of Formula (i-10). In certain embodiments, R D is of Formula (i-11). In certain embodiments, R D is of Formula (i-12). In certain embodiments, R D is of Formula (i-13). In certain embodiments, R D is of Formula (i-14). In certain embodiments, R D is of Formula (i-15). In certain embodiments, R D is of Formula (i-16). In certain embodiments, R D is of Formula (i-17).

In compounds of Formula (A), R D may include a substituent R D1 . In certain embodiments, R D1 is H. In certain embodiments, R D1 is halogen. In certain embodiments, R D1 is F. In certain embodiments, R D1 is Cl. In certain embodiments, R D1 is Br. In certain embodiments, R D1 is I (iodine). In certain embodiments, R D1 is substituted acyl. In certain embodiments, R D1 is unsubstituted acyl. In certain embodiments, R D1 is acetyl. In certain embodiments, R D1 is substituted alkyl. In certain embodiments, R D1 is unsubstituted alkyl. In certain embodiments, R D1 is C 1-6 alkyl. In certain embodiments, R D1 is methyl. In certain embodiments, R D1 is ethyl. In certain embodiments, R D1 is propyl. In certain embodiments, R D1 is butyl. In certain embodiments, R D1 is substituted alkenyl. In certain embodiments, R D1 is unsubstituted alkenyl. In certain embodiments, R D1 is substituted alkynyl. In certain embodiments, R D1 is unsubstituted alkynyl. In certain embodiments, R D1 is substituted carbocyclyl. In certain embodiments, R D1 is unsubstituted carbocyclyl. In certain embodiments, R D1 is substituted heterocyclyl. In certain embodiments, R D1 is unsubstituted heterocyclyl. In certain embodiments, R D1 is substituted aryl. In certain embodiments, R D1 is unsubstituted aryl. In certain embodiments, R D1 is substituted phenyl. In certain embodiments, R D1 is unsubstituted phenyl. In certain embodiments, R D1 is substituted heteroaryl. In certain embodiments, R D1 is unsubstituted heteroaryl. In certain embodiments, R D1 is substituted pyridyl. In certain embodiments, R D1 is unsubstituted pyridyl. In certain embodiments, R D1 is —CN. In certain embodiments, R D1 is —NO 2 . In certain embodiments, R D1 is —OR D1a . In certain embodiments, R D1 is —N(R D1a ) 2 . In certain embodiments, R D1 is —SR D1a . In certain embodiments, R D1 is —CH 2 OR D1a . In certain embodiments, R D1 is —CH 2 N(R D1a ) 2 . In certain embodiments, R D1 is —CH 2 SR D1a .

In certain embodiments, at least one R D1a is H. In certain embodiments, at least one R D1a is substituted acyl. In certain embodiments, at least one R D1a is unsubstituted acyl. In certain embodiments, at least one R D1a is acetyl. In certain embodiments, at least one R D1a is substituted alkyl. In certain embodiments, at least one R D1a is unsubstituted alkyl. In certain embodiments, at least one R D1a is C 1-6 alkyl. In certain embodiments, at least one R D1a is methyl. In certain embodiments, at least one R D1a is ethyl. In certain embodiments, at least one R D1a is propyl. In certain embodiments, at least one R D1a is butyl. In certain embodiments, at least one R D1a is substituted alkenyl. In certain embodiments, at least one R D1a is unsubstituted alkenyl. In certain embodiments, at least one R D1a is substituted alkynyl. In certain embodiments, at least one R D1a is unsubstituted alkynyl. In certain embodiments, at least one R D1a is substituted carbocyclyl. In certain embodiments, at least one R D1a is unsubstituted carbocyclyl. In certain embodiments, at least one R D1a is substituted heterocyclyl. In certain embodiments, at least one R D1a is unsubstituted heterocyclyl. In certain embodiments, at least one R D1a is substituted aryl. In certain embodiments, at least one R D1a is unsubstituted aryl. In certain embodiments, at least one R D1a is substituted phenyl. In certain embodiments, at least one R D1a is unsubstituted phenyl. In certain embodiments, at least one R D1a is substituted heteroaryl. In certain embodiments, at least one R D1a is unsubstituted heteroaryl. In certain embodiments, at least one R D1a is substituted pyridyl. In certain embodiments, at least one R D1a is unsubstituted pyridyl. In certain embodiments, at least one R D1a is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R D1a is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R D1a is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R D1a is 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 D1a is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R D1a is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two R D1a groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R D1a groups are joined to form an unsubstituted heterocyclic ring.

In compounds of Formula (A), R D may include a substituent R D2 . In certain embodiments, R D2 is H. In certain embodiments, R D2 is halogen. In certain embodiments, R D2 is F. In certain embodiments, R D2 is Cl. In certain embodiments, R D2 is Br. In certain embodiments, R D2 is I (iodine). In certain embodiments, R D2 is substituted acyl. In certain embodiments, R D2 is unsubstituted acyl. In certain embodiments, R D2 is acetyl. In certain embodiments, R D2 is substituted alkyl. In certain embodiments, R D2 is unsubstituted alkyl. In certain embodiments, R D2 is C 1-6 alkyl. In certain embodiments, R D2 is methyl. In certain embodiments, R D2 is ethyl. In certain embodiments, R D2 is propyl. In certain embodiments, R D2 is butyl. In certain embodiments, R D2 is substituted alkenyl. In certain embodiments, R D2 is unsubstituted alkenyl. In certain embodiments, R D2 is substituted alkynyl. In certain embodiments, R D2 is unsubstituted alkynyl. In certain embodiments, R D2 is substituted carbocyclyl. In certain embodiments, R D2 is unsubstituted carbocyclyl. In certain embodiments, R D2 is substituted heterocyclyl. In certain embodiments, R D2 is unsubstituted heterocyclyl. In certain embodiments, R D2 is substituted aryl. In certain embodiments, R D2 is unsubstituted aryl. In certain embodiments, R D2 is substituted phenyl. In certain embodiments, R D2 is unsubstituted phenyl. In certain embodiments, R D2 is substituted heteroaryl. In certain embodiments, R D2 is unsubstituted heteroaryl. In certain embodiments, R D2 is substituted pyridyl. In certain embodiments, R D2 is unsubstituted pyridyl. In certain embodiments, R D2 is —CN. In certain embodiments, R D2 is —NO 2 . In certain embodiments, R D2 is —OR D2a . In certain embodiments, R D2 is —N(R D2a ) 2 . In certain embodiments, R D2 is —SR D2a . In certain embodiments, R D2 is —CH 2 OR D2a . In certain embodiments, R D2 is —CH 2 N(R D2a ) 2 . In certain embodiments, R D2 is —CH 2 SR D2a .

In certain embodiments, at least one R D2a is H. In certain embodiments, at least one R D2a is substituted acyl. In certain embodiments, at least one R D2a is unsubstituted acyl. In certain embodiments, at least one R D2a is acetyl. In certain embodiments, at least one R D2a is substituted alkyl. In certain embodiments, at least one R D2a is unsubstituted alkyl. In certain embodiments, at least one R D2a is C 1-6 alkyl. In certain embodiments, at least one R D2a is methyl. In certain embodiments, at least one R D2a is ethyl. In certain embodiments, at least one R D2a is propyl. In certain embodiments, at least one R D2a is butyl. In certain embodiments, at least one R D2a is substituted alkenyl. In certain embodiments, at least one R D2a is unsubstituted alkenyl. In certain embodiments, at least one R D2a is substituted alkynyl. In certain embodiments, at least one R D2a is unsubstituted alkynyl. In certain embodiments, at least one R D2a is substituted carbocyclyl. In certain embodiments, at least one R D2a is unsubstituted carbocyclyl. In certain embodiments, at least one R D2a is substituted heterocyclyl. In certain embodiments, at least one R D2a is unsubstituted heterocyclyl. In certain embodiments, at least one R D2a is substituted aryl. In certain embodiments, at least one R D2a is unsubstituted aryl. In certain embodiments, at least one R D2a is substituted phenyl. In certain embodiments, at least one R D2a is unsubstituted phenyl. In certain embodiments, at least one R D2a is substituted heteroaryl. In certain embodiments, at least one R D2a is unsubstituted heteroaryl. In certain embodiments, at least one R D2a is substituted pyridyl. In certain embodiments, at least one R D2a is unsubstituted pyridyl. In certain embodiments, at least one R D2a is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R D2a is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R D2a is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R D2a is 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 D2a is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R D2a is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two R D2a groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R D2a groups are joined to form an unsubstituted heterocyclic ring.

In compounds of Formula (A), R D may include a substituent R D3 . In certain embodiments, R D3 is H. In certain embodiments, R D3 is halogen. In certain embodiments, R D3 is F. In certain embodiments, R D3 is Cl. In certain embodiments, R D3 is Br. In certain embodiments, R D3 is I (iodine). In certain embodiments, R D3 is substituted acyl. In certain embodiments, R D3 is unsubstituted acyl. In certain embodiments, R D3 is acetyl. In certain embodiments, R D3 is substituted alkyl. In certain embodiments, R D3 is unsubstituted alkyl. In certain embodiments, R D3 is C 1-6 alkyl. In certain embodiments, R D3 is methyl. In certain embodiments, R D3 is ethyl. In certain embodiments, R D3 is propyl. In certain embodiments, R D3 is butyl. In certain embodiments, R D3 is substituted alkenyl. In certain embodiments, R D3 is unsubstituted alkenyl. In certain embodiments, R D3 is substituted alkynyl. In certain embodiments, R D3 is unsubstituted alkynyl. In certain embodiments, R D3 is substituted carbocyclyl. In certain embodiments, R D3 is unsubstituted carbocyclyl. In certain embodiments, R D3 is substituted heterocyclyl. In certain embodiments, R D3 is unsubstituted heterocyclyl. In certain embodiments, R D3 is substituted aryl. In certain embodiments, R D3 is unsubstituted aryl. In certain embodiments, R D3 is substituted phenyl. In certain embodiments, R D3 is unsubstituted phenyl. In certain embodiments, R D3 is substituted heteroaryl. In certain embodiments, R D3 is unsubstituted heteroaryl. In certain embodiments, R D3 is substituted pyridyl. In certain embodiments, R D3 is unsubstituted pyridyl. In certain embodiments, R D3 is —CN. In certain embodiments, R D3 is —NO 2 . In certain embodiments, R D3 is —OR D3a . In certain embodiments, R D3 is —N(R D3a ) 2 . In certain embodiments, R D3 is —SR D3a . In certain embodiments, R D3 is —CH 2 OR D3a . In certain embodiments, R D3 is —CH 2 N(R D3a ) 2 . In certain embodiments, R D3 is —CH 2 SR D3a .

In certain embodiments, at least one R D3a is H. In certain embodiments, at least one R D3a is substituted acyl. In certain embodiments, at least one R D3a is unsubstituted acyl. In certain embodiments, at least one R D3a is acetyl. In certain embodiments, at least one R D3a is substituted alkyl. In certain embodiments, at least one R D3a is unsubstituted alkyl. In certain embodiments, at least one R D3a is C 1-6 alkyl. In certain embodiments, at least one R D3a is methyl. In certain embodiments, at least one R D3a is ethyl. In certain embodiments, at least one R D3a is propyl. In certain embodiments, at least one R D3a is butyl. In certain embodiments, at least one R D3a is substituted alkenyl. In certain embodiments, at least one R D3a is unsubstituted alkenyl. In certain embodiments, at least one R D3a is substituted alkynyl. In certain embodiments, at least one R D3a is unsubstituted alkynyl. In certain embodiments, at least one R D3a is substituted carbocyclyl. In certain embodiments, at least one R D3a is unsubstituted carbocyclyl. In certain embodiments, at least one R D3a is substituted heterocyclyl. In certain embodiments, at least one R D3a is unsubstituted heterocyclyl. In certain embodiments, at least one R D3a is substituted aryl. In certain embodiments, at least one R D3a is unsubstituted aryl. In certain embodiments, at least one R D3a is substituted phenyl. In certain embodiments, at least one R D3a is unsubstituted phenyl. In certain embodiments, at least one R D3a is substituted heteroaryl. In certain embodiments, at least one R D3a is unsubstituted heteroaryl. In certain embodiments, at least one R D3a is substituted pyridyl. In certain embodiments, at least one R D3a is unsubstitrrted pyridyl. In certain embodiments, at least one R D3a is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R D3a is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R D3a is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R D3a is 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 D3a is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R D3a is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two R D3a groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R D3a groups are joined to form an unsubstituted heterocyclic ring.

In compounds of Formula (A), R D may include a substituent R D4 . In certain embodiments, R D4 is a leaving group. In certain embodiments, R D4 is halogen. In certain embodiments, R D4 is F. In certain embodiments, R D4 is Cl. In certain embodiments, R D4 is Br. In certain embodiments, R D4 is I (iodine). In certain embodiments, R D4 is —OS(═O) w R D4a . In certain embodiments, w is 1. In certain embodiments, w is 2. In certain embodiments, R D4 is —OMs. In certain embodiments, R D4 is —OTf. In certain embodiments, R D4 is —OTs. In certain embodiments, R D4 is —OBs. In certain embodiments, R D4 is 2-nitrobenzenesulfonyloxy. In certain embodiments, R D4 is —OR D4a . In certain embodiments, R D4 is —OMe. In certain embodiments, R D4 is —OCF 3 . In certain embodiments, R D4 is —OPh. In certain embodiments, R D4 is —OC(═O)R D4 . In certain embodiments, R D4 is —OC(═O)Me. In certain embodiments, R D4 is OC(═O)CF 3 . In certain embodiments, R D4 is —OC(═O)Ph. In certain embodiments, R D4 is —OC(═O)Cl. In certain embodiments, R D4 is —OC(═O)OR D4a . In certain embodiments, R D4 is —OC(═O)OMe. In certain embodiments, R D4 is —OC(═O)O(t-Bu).

In certain embodiments, R D4a is substituted alkyl. In certain embodiments, R D4a is unsubstituted alkyl. In certain embodiments, R D4a is C 1-6 alkyl. In certain embodiments, R D4a is methyl. In certain embodiments, R D4a is ethyl. In certain embodiments, R D4a is propyl. In certain embodiments, R D4a is butyl. In certain embodiments, R D4a is substituted alkenyl. In certain embodiments, R D4a is unsubstituted alkenyl. In certain embodiments, R D4a is vinyl. In certain embodiments, R D4a is substituted alkynyl. In certain embodiments, R D4a is unsubstituted alkynyl. In certain embodiments, R D4a is ethynyl. In certain embodiments, R D4a is substituted carbocyclyl. In certain embodiments, R D4a is unsubstituted carbocyclyl. In certain embodiments, R D4a is substituted heterocyclyl. In certain embodiments, R D4a is unsubstituted heterocyclyl. In certain embodiments, R D4a is substituted aryl. In certain embodiments, R D4a is unsubstituted aryl. In certain embodiments, R D4a is substituted phenyl. In certain embodiments, R D4a is unsubstituted phenyl. In certain embodiments, R D4a is substituted heteroaryl. In certain embodiments, R D4a is unsubstituted heteroaryl. In certain embodiments, R D4a is substituted pyridyl. In certain embodiments, R D4a is unsubstituted pyridyl.

In compounds of Formula (A), R D may include a substituent R D5 . In certain embodiments, R D5 is H. In certain embodiments, R D5 is substituted allyl. In certain embodiments, R D5 is unsubstituted alkyl. In certain embodiments, R D5 is C 1-6 alkyl. In certain embodiments, R D5 is methyl. In certain embodiments, R D5 is ethyl. In certain embodiments, R D5 is propyl. In certain embodiments, R D5 is butyl. In certain embodiments, R D5 is a nitrogen protecting group. In certain embodiments, R D5 is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts.

In certain embodiments, R D1 and R D2 are each hydrogen. In certain embodiments, R D1 and R D3 are each hydrogen. In certain embodiments, R D2 and R D3 are each hydrogen. In certain embodiments, R D1 , R D2 , and R D3 are each hydrogen. In certain embodiments, R D1 , R D2 , and R D3 , and R D5 are 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 D6 is hydrogen, C 1-6 alkyl, or a nitrogen protecting group. In certain embodiments, Y is —NH—. In certain embodiments, Y is —NCH 3 —. 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 D6 is hydrogen, C 1-6 alkyl, or a nitrogen protecting group. In certain embodiments, Y is —C(═NH)—. In certain embodiments, Y is —C(═NCH 3 )—. 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 D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

In certain embodiments, R D is of the formula:

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

For example, in certain embodiments, a compound of Formula (A) is a compound of Formula (A1) or (A2):

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

In certain embodiments, one R B group is substituted or unsubstituted —CH 2 -(piperazinyl). In certain embodiments, one R B group is

where the alkyl is optionally substituted. In certain embodiments, one R B group is

where the alkyl is unsubstituted. In certain embodiments, one R B group is

In certain embodiments, one R B groups is haloalkyl. In certain embodiments, one R B group is —CF 3 . In certain embodiments, one R B group is substituted or unsubstituted imidazoyl. In certain embodiments, one R B group is

where the alkyl is optionally substituted. In certain embodiments, one R B group is

where the alkyl is unsubstituted. In certain embodiments, one R B group is

In certain embodiments, one R B group is substituted or unsubstituted piperazinyl. In certain embodiments, one R B group is

where there alkyl is optionally substituted. In certain embodiments, one R B group is

where there alkyl is unsubstituted. In certain embodiments, one R B group is

In certain embodiments, one R B group is substituted or unsubstituted morpholine. In certain embodiments, two R B groups are substituted or unsubstituted morpholine. In certain embodiments, R X is —N(R A1 )N(R A1 ) 2 . In certain embodiments, R X is —N(R A1 )N(R A1 ) 2 ; and each instance of R A is hydrogen, methyl, or acetyl. In certain embodiments, R X is —NHNMe 2 or —NHNHAc. In certain embodiments, Rx is —NH 2 . In certain embodiments, R X is —NH(R A1 ). In certain embodiments, R X is —NH(R A1 ); and R A1 is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R X is —NH(R A1 ); and R A1 is substituted or unsubstituted methyl. In certain embodiments, R X is —NH(R A1 ); and R A1 is acyl. In certain embodiments, R X is —NH(R A1 ); and R A1 is substituted or unsubstituted —C(═O)—(C 1-6 alkyl). In certain embodiments, R X is —NH(R A1 ); and R A1 is acetyl or propionyl. In certain embodiments, R X is —NH(R A1 ); and R A1 is substituted or unsubstituted —C(═O)-(carbocyclyl). In certain embodiments, R X is —NH(R A ); and R A1 is substituted or unsubstituted —C(═O)-(cyclopropyl). In certain embodiments, R X is —NH(R A1 ); and R A1 is substituted or unsubstituted heteroaryl. In certain embodiments, R X is —NH(R A1 ); and R A1 is substituted or unsubstituted pyrazole. In certain embodiments, R X is —NH(R A1 ); and R A1 is substituted or unsubstituted isoxazole. In certain embodiments, R X is —NH(R A ); and R A1 is substituted or unsubstituted pyrimidine. In certain embodiments, R X is —NH(R A1 ); and R A1 is substituted or unsubstituted heterocyclyl. In certain embodiments, R X is —NH(R A1 ); and R A1 is substituted or unsubstituted azetidine. In certain embodiments, R X is —NH(R A1 ); and R A1 is substituted or unsubstituted oxetane.

In certain embodiments, a compound of Formula (A1) is a compound of Formula (A1-a), (A1-b), (A1-c), or (A1-d):

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

In certain embodiments, one R B group is substituted or unsubstituted —CH 2 -(piperazinyl). In certain embodiments, one R B group is

where the alkyl is optionally substituted. In certain embodiments, one R B group is

where the alkyl is unsubstituted. In certain embodiments, one R B group is

In certain embodiments, one R B group is haloalkyl. In certain embodiments, one R B group is —CF 3 . In certain embodiments, one R B group is substituted or unsubstituted imidazoyl. In certain embodiments, one R B group is

where the alkyl is optionally substituted. In certain embodiments, one R B group is

where the alkyl is unsubstituted. In certain embodiments, one R B group is

In certain embodiments, one R B group is substituted or unsubstituted piperazinyl. In certain embodiments, one R B group is

where there alkyl is optionally substituted. In certain embodiments, one R B group is

where there alkyl is unsubstituted. In certain embodiments, one R B group is

In certain embodiments, one R B group is substituted or unsubstituted morpholine. In certain embodiments, two R B groups are substituted or unsubstituted morpholine. In certain embodiments, all instances of R Xc are hydrogen. In certain embodiments, R Xa is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R Xa is methyl or ethyl.

In certain embodiments, a compound of Formula (A2) is a compound of Formula (A2-a), (A2-b), (A2-c), or (A2-d):

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

In certain embodiments, one R B group is substituted or unsubstituted —CH 2 -(piperazinyl). In certain embodiments, one R B group is

where the alkyl is optionally substituted. In certain embodiments, one R B group is

where the alkyl is unsubstituted. In certain embodiments, one R B group is

In certain embodiments, one R B group is haloalkyl. In certain embodiments, one R B group is —CF 3 . In certain embodiments, one R B group is substituted or unsubstituted imidazoyl. In certain embodiments, one R B group is

where the alkyl is optionally substituted. In certain embodiments, one R B group is

where the alkyl is unsubstituted. In certain embodiments, one R B group is

In certain embodiments, one R B group is substituted or unsubstituted piperazinyl. In certain embodiments one R B group is

where there alkyl is optionally substituted. In certain embodiments, one R B group is

where there alkyl is unsubstituted. In certain embodiments, one R B group is

In certain embodiments, one R B group is substituted or unsubstituted morpholine. In certain emodiments, two R B groups are substituted or unsubstituted morpholine. In certain embodiments, all instances of R Xc are hydrogen. In certain embodiments, R Xa is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R Xa is methyl or ethyl.

In certain embodiments, a compound of Formula (A1) is a compound of Formula (A1-e)-(A1-p):

where R Xa , R Xc , R A , and R B are defined herein. In certain embodiments R A is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R A is methyl. In certain embodiments, one R B group is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, one R B group is C 1-6 alkyl substituted with one —CN group. In certain embodiments, one R B group is

In certain embodiments, one R B group is substituted or unsubstituted —CH 2 -(piperazinyl). In certain embodiments, one R B group is

where the alkyl is optionally substituted. In certain embodiments, one R B group is

where the alkyl is unsubstituted. In certain embodiments, one R B group is

In certain embodiments, one R B group is haloalkyl. In certain embodiments, one R B group is —CF 3 . In certain embodiments, one R B group is substituted or unsubstituted imidazoyl. In certain embodiments, one R B group is

where the alkyl is optionally substituted. In certain embodiments, one R B group is

where the alkyl is unsubstituted. In certain embodiments, one R B group is

In certain embodiments, one R B group is substituted or unsubstituted piperazinyl. In certain embodiments, one R B group is

where the alkyl is optionally substituted. In certain embodiments, one R B group is

where the alkyl is unsubstituted. In certain embodiments, one R B group is

In certain embodiments, one R B group is substituted or unsubstituted morpholine. In certain embodiments, two R B groups are substituted or unsubstituted morpholine. In certain embodiments, all instances of R Xc are hydrogen. In certain embodiments, R Xa is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R Xa is methyl or ethyl.

In certain embodiments, a compound of Formula (A2) is a compound of Formula (A2-e)-(A2-p):

wherein R Xa , R Xc , R A , and R B are defined herein. In certain embodiments, R A is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R A is methyl. In certain embodiments, one R B group is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, one R B group is

C 1-6 alkyl substituted with one —CN group. In certain embodiments, one R B group is NC. In certain embodiments, one R B group is substituted or unsubstituted —CH 2 -(piperazinyl). In certain embodiments, one R B group is

where the alkyl is optionally substituted. In certain embodiments, one R B group is

where the alkyl is unsubstituted. In certain embodiments, one R B group is

In certain embodiments, one R B group is haloalkyl. In certain embodiments, one R B group is —CF 3 . In certain embodiments, one R B group is substituted or unsubstituted imidazoyl. In certain embodiments, one R B group is

where the alkyl optionally substituted. In certain embodiments, one R B group is

where the alkyl is unsubstituted. In certain embodiments, one R B group is

In certain embodiments, one R B group is substituted or unsubstituted piperazinyl. In certain embodiments, one R B group is

where there alkyl is optionally substituted. In certain embodiments, one R B group is

where there alkyl is unsubstituted. In certain embodiments, one R B group is

In certain embodiments, one R B group is substituted or unsubstituted morpholine. In certain embodiments, two R B groups are substituted or unsubstituted morpholine. In certain embodiments, all instances of R Xc are hydrogen. In certain embodiments, R Xa is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R Xa is methyl or ethyl.

In certain embodiments, a compound of Formula (A) is a compound of Formula (A3) or (A4):

wherein R D , R A , R B , and l are defined herein. In certain embodiments R A is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R A is methyl. In certain embodiments, l is 1. In certain embodiments, l is 1; and R B is 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 B groups are meta to the point of attachment of the amide linker. In certain embodiments, l is 2; one R B group is meta to the point of attachment of the amide linker; and the second R B group is para to the point of attachment of the amide linker. In certain embodiments, one R B group is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, one R B group is C 1-6 alkyl substituted with one —CN group. In certain embodiments, one R B group is

In certain embodiments, one R B group is substituted or unsubstituted —CH 2 -(piperazinyl). In certain embodiments, one R B group is

where the alkyl is optionally substituted. In certain embodiments, one R B group is

where the alkyl is unsubstituted. In certain embodiments, one R B group is

In certain embodiments, one R B group is haloalkyl. In certain embodiments, one R B group is —CF 3 . In certain embodiments, one R B group is substituted or unsubstituted imidazoyl. In certain embodiments, one R B group is

where the alkyl is optionally substituted. In certain embodiments, one R B group is

where the alkyl is unsubstituted. In certain embodiments, one R B group is

In certain embodiments, one R B group is substituted or unsubstituted piperazinyl. In certain embodiments, one R B group is

where there alkyl is optionally substituted. In certain embodiments, one R B group is

alkyl where there alkyl is unsubstituted. In certain embodiments, one R B group is

In certain embodiments, one R B group is substituted or unsubstituted morpholine. In certain embodiments, two R B groups are substituted or unsubstituted morpholine. In certain embodiments, R D is R D is

In certain embodiments, R D is

In certain embodiments, R D is

In certain embodiments, R D is

In certain embodiments, a compound of Formula (A3) is a compound of Formula (A3-a), (A3-b), or (A3-c).

wherein R D , R A , R B , and l are defined herein. In certain embodiments R A is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R A is methyl. In certain embodiments, l is 1. In certain embodiments, l is 1; and R B is 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 B groups are meta to the point of attachment of the amide linker. In certain embodiments, l is 2; one R B group is meta to the point of attachment of the amide linker; and the second R B group is para to the point of attachment of the amide linker. In certain embodiments, one R B group is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, one R B group is C 1-6 alkyl substituted with one —CN group. In certain embodiments, one R B group is

In certain embodiments, one R B group is substituted or unsubstituted —CH 2 -(piperazinyl). In certain embodiments, one R B group is

where the alkyl is optionally substituted. In certain embodiments, one R B group is

where the alkyl is unsubstituted. In certain embodiments, one R B group is

In certain embodiments, one R B group is haloalkyl. In certain embodiments, one R B group is —CF 3 . In certain embodiments, one R B group is substituted or unsubstituted imidazoyl. In certain embodiments, one R B group is

where the alkyl is optionally substituted. In certain embodiments, one R B group is

where the alkyl where the alkyl is unsubstituted. In certain embodiments, one R B group is

In certain embodiments, one R B group is substituted or unsubstituted piperazinyl. In certain embodiments, one R B group is

where there alkyl is optionally substituted. In certain embodiments, one R B group is

where there alkyl is unsubstituted. In certain embodiments, one R B group is

In certain embodiments, one R B group is substituted or unsubstituted morpholine. In certain embodiments, two R B groups are substituted or unsubstituted morpholine. In certain embodiments, R D is

In certain embodiments, R D is

In certain embodiments, R D is

In certain embodiments, R D is

In certain embodiments, a compound of Formula (A4) is a compound of Formula (A4-a), (A4-b), or (A4-c):

wherein R D , R A , R B , and l are defined herein. In certain embodiments R A is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R A is methyl. In certain embodiments, l is 1. In certain embodiments, l is 1; and R B is 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 B groups are meta to the point of attachment of the amide linker. In certain embodiments, l is 2; one R B group is meta to the point of attachment of the amide linker; and the second R B group is para to the point of attachment of the amide linker. In certain embodiments, one R B group is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, one R B group is C 1-6 alkyl substituted with one —CN group. In certain embodiments, one R B group is

In certain embodiments, one R B group is substituted or unsubstituted —CH 2 -(piperazinyl). In certain embodiments, one R B group is

where the alkyl is optionally substituted. In certain embodiments, one R B group is

where the alkyl is unsubstituted. In certain embodiments, one R B group is

In certain embodiments, one R B group is haloalkyl. In certain embodiments, one R B group is —CF 3 . In certain embodiments, one R B group is substituted or unsubstituted imidazoyl. In certain embodiments, one R B group is

where the alkyl is optionally substituted. In certain embodiments, one R B group is

where the alkyl is unsubstituted. In certain embodiments, one R B group is

In certain embodiments, one R B group is substituted or unsubstituted piperazinyl. In certain embodiments, one R B group is

where the alkyl is optionally substituted. In certain embodiments, one R B group is

where there alkyl is unsubstituted. In certain embodiments, one R B group is

In certain embodiments, one R B group is substituted or unsubstituted morpholine. In certain embodiments, two R B groups are substituted or unsubstituted morpholine. In certain embodiments, R D is

In certain embodiments, R D is

In certain embodiments, R D is

In certain embodiments, R D is

Another aspect of the invention relates to the compound of Formula (I-11):

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

In another aspect, provided are compounds of Formula (V):

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

each instance of each instance of R A ′, R B ′, and R X ′ are independently 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)SR A1 ′, —C(═O)N(R A1 ) 2 , —C(═S)R A1 ′, —C(═S)OR A1 ′, —C(═S)SR A1 ′, —C(═S)N(R A1 ′) 2 , —C(═NR A1 ′)R A1 ′, —C(═NR A1 ′)OR A1 ′, —C(═NR A1 ′)SR A1 ′, —C(═NR A1 ′)N(R A1 ′) 2 , —NO 2 , —N 3 , —N(R A1 ′) 3 + X′ − wherein X′ − is a counterion, —N(OR A1 ′)R A1 ′, —NR A1 ′C(═O)R A1 ′, —NR A1 ′C(═O)OR A1 ′, —NR A1 ′C(═O)SR A1 ′, —NR A1 ′C(═O)N(R A1 ′) 2 , —NR A1 ′C(═S)R A1 ′, —NR A1 C′(═S)OR A1 ′, —NR A1 C′(═S)SR A1 ′, —NR A1 ′C(═S)N(R A1 ′) 2 , —NR A1 ′C(═NR A1 ′)R A1 ′, —NR A1 ′C(═NR A1 ′)OR A1 ′, —NR A1 ′C(═NR A1 ′)SR A1 ′, —NR A1 ′C(═NR A1 ′)N(R A1 ′) 2 , —NR A1 ′S(═O) 2 R A1 ′, —NR A1 ′S(═O) 2 OR A1 ′, —NR A1 ′S(═O) 2 SR A1 ′, —NR A1 ′S(═O) 2 N(R A1 ′) 2 , —NR A1 ′S(═O)R A1 ′, —NR A1 ′S(═O)OR A1 ′, —NR A1 ′S(═O)SR A1 ′, —NR A1 ′S(═O)N(R A1 ′) 2 , —NR A1 ′P(═O), —NR A1 ′P(═O) 2 , —NR A1 ′P(═O)(R A1 ′) 2 , —NR A1 ′P(═O)R A1 ′(OR A1 ′, —NR A1 ′P(═O)(OR A1 ′) 2 , —OC(═O)R A1 ′, —OC(═O)OR A1 ′, —OC(═O)SR A1 ′, —OC(═O)N(R A1 ′) 2 , —OC(═NR A1 ′)R A1 ′, —OC(═NR A1 ′)OR A1 ′, —OC(═NR A1 ′)N(R A1 ′) 2 , —OC(═S)R A1 ′, —OC(═S)OR A1 ′, —OC(═S)SR A1 ′, —OC(═S)N(R A1 ′) 2 , —ON(R A1 ′) 2 , —OS(═O)R A1 ′, —OS(═O)OR A1 ′, —OS(═O)SR A1 ′, —OS(═O)N(R A1 ′) 2 , —OS(═O) 2 R A1 ′, —OS(═O) 2 OR A1 ′, —OS(═O) 2 SR A1 ′, —OS(═O) 2 N(R A1 ′) 2 , —OP(═O) 2 , —OP(═O)(R A1 ′) 2 , —OP(═O)R A1 ′(OR A1 ′), —OP(═O)(OR A1 ′) 2 , —OP(═O), —OP(R A1 ′) 2 , —OPR A1 ′(OR A1 ′), —OP(OR A1 ′) 2 , —OSi(R A1 ′) 3 , —OSi(R A1 ′) 2 OR A1 ′, —OSi(R A1 ′)(OR A1 ′) 2 , —OSi(OR A1 ′) 3 , —SSR A1 ′, —S(═O)R A1 ′, —S(═O)OR A1 ′, —S(═O)N(R A1 ′) 2 , —S(═O) 2 R A1 ′, —S(═O) 2 OR A1 ′, —S(═O) 2 N(R A1 ′) 2 , —SC(═O)R A1 ′, —SC(═O)OR A1 ′, —SC(═O)SR A1 ′, —SC(═O)N(R A1 ′) 2 , —SC(═S)R A1 ′, —SC(═S)OR A1 ′, —SC(═S)SR A1 ′, —SC(═S)N(R A1 ′) 2 , —P(R A1 ′) 2 , —PR A1 ′(OR A1 ′), —P(OR A1 ′) 2 , —P(═O), —P(═O)(R A1 ′) 2 , —P(═O)(OR A1 ′) 2 , —P(═O)R A1 ′(OR A1 ′), —P(═O) 2 , —B(R A1 ′) 2 , —B(OR A1 ′) 2 , —BR A1 ′(OR A1 ′), —Si(R A1 ′) 3 , —Si(R A1 ′) 2 OR A1 ′, —SiR A1 ′(OR A1 ′) 2 , and —Si(OR A1 ′) 3 , two R A ′ or R B ′ groups are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring, or R A ′ or R B′ forms an optional 5 to 8 membered ring with any one of X′, Y′, Z′, Q′, U′, or Cy; wherein each occurrence of R A1 ′ is 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 A1 ′ groups are joined to form an optionally substituted heterocyclic ring;

k′ and l′ are each independently 0, 1, 2, 3, 4, or 5;

X′, Y′, Z′ are each independently —CH 2 , —CHR A ′, —CH, —C(R A ′) 2 , —C, —N, —NR A ′, —O, —S or —C═O, or bond and may optionally form a 5 to 8 membered ring with R A ′ or R B ′;

Q′ and U′ are each independently —NR A ′, —O, —C═O, —NR A ′CO, or bond;

Ring A′ is an optionally substituted aryl. or optionally substituted heteroaryl ring

Ring C′ is an optionally substituted aryl ring; and

Cy is an optionally substituted aryl ring, optionally substituted heteroaryl ring, bond, or hydrogen.

Compounds of Formula (V) include an aryl group for Ring A′ optionally substituted with one or more R A ′ groups. In certain embodiments, when Ring A′ is naphthyl, the invention provides compounds of Formula (V-a):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R A ′, R B ′, R X ′, k′, and l′ are as defined herein.

Compounds of Formula (V) include an aryl group for Ring A′ optionally substituted with one or more R A ′ groups. In certain embodiments, Ring A′ is naphthyl, the invention provides compounds of Formula (V-b):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R A ′, R B ′, R X ′, k′, and l′ are as defined herein.

Compounds of Formula (V) include an aryl group for Ring A′ optionally substituted with one or more R A ′ groups. In certain embodiments, Ring A′ is phenyl, the invention provides compounds of Formula (V-c):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R A ′, R B ′, R X ′, k′, and l′ are as defined herein.

Compounds of Formula (V) include an aryl group for Ring A′ optionally substituted with one or more R A ′ groups. In certain embodiments, Ring A′ is phenyl, the invention provides compounds of Formula (V-d):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R A ′, R B ′, R X ′, k′, and l′ are as defined herein.

Compounds of Formula (V) include an heteroaryl group for Ring A′ optionally substituted with one or more R A ′ groups. In certain embodiments, when Ring A′ is pyrrolopyrimidine, the invention provides compounds of Formula (V-e):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R A ′, R B ′, R X ′, k′, and l′ are as defined herein.

Compounds of Formula (V) include an heteroaryl group for Ring A′ optionally substituted with one or more R A ′ groups. In certain embodiments, when Ring A′ is pyrimidine, the invention provides compounds of Formula (V-e A ):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R A ′, R B ′, R X ′, k′, and l′ are as defined herein.

Compounds of Formula (V) include an heteroaryl group for Ring A′ optionally substituted with one or more R A ′ groups. In certain embodiments, when Ring A′ is 1H-pyrazolo[3,4-d]pyrimidin-4-amine, the invention provides compounds of Formula (V-e B ):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R A ′, R B ′, R X ′, k′, and l′ are as defined herein.

Compounds of Formula (V) include an heteroaryl group for Ring A′ optionally substituted with one or more R A ′ groups. In certain embodiments, when Ring A′ is furo[2,3-c]pyridin-7-amine, the invention provides compounds of Formula (V-e C ):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R A ′, R B ′, R X ′, k′, and l′ are as defined herein.

Compounds of Formula (V) include an heteroaryl group for Ring A′ optionally substituted with one or more R A ′ groups. In certain embodiments, when Ring A′ is quinazoline, the invention provides compounds of Formula (V-e D ):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R A ′, R B ′, R X ′, k′, and l′ are as defined herein.

Compounds of Formula (V) include an heteroaryl group for Ring A′ optionally substituted with one or more R A ′ groups. In certain embodiments, when Ring A′ is phenyl, and at least one R A ′ group links to Cy forming an optional 5 to 8 membered ring, the invention provides compounds of Formula (V-f):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R A ′, R B ′, R X ′, k′, and l′ are as defined herein.

Compounds of Formula (V) include an heteroaryl group for Ring A′ optionally substituted with one or more R A ′ groups. In certain embodiments, when Ring A′ is phenyl, and at least one R A ′ group links to Cy forming an optional 5 to 8 membered ring, the invention provides compounds of Formula (V-g):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R A ′, R B ′, R X ′, k′, and l′ are as defined herein.

In another aspect, provided herein are copounds of Formula (II):

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

each instance of R D ′ is independently an optional electrophilic moiety that can be attached to Cy, Ring A′ , or Ring C′;

each instance of m′ is independently 0 or 1; and

Ring A′, Ring C′, Cy, Q′, U′, X′, Y′, Z′, R A ′, R B ′, R X ′, k′, and l′ are as defined herein.

In certain embodiments, R D ′ is an optional electrophilic moiety that can be atached to Cy, Ring A′, or Ring C′; and m′ is 0 or 1. In compounds of Formula (II), R D ′ is an optional electrophilic moiety that can be attached to Cy, Ring A′, or Ring C′. In certain embodiments, R D ′ is any one of Formulae (i-1)-(i-17):

wherein:

R D1′ is 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, —NO 2 , —OR D1a ′, —N(R D1a ′) 2 , —SR D1a ′, —CH 2 OR D1a ′, —CH 2 N(R D1a ′) 2 , —CH 2 SR 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 D1a ′ is 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 D1a ′ groups are joined to form an optionally substituted heterocyclic ring;

R D2 ′ is 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 heterycyclyl, optionally suubstituted aryl, optionally substituted heteroaryl, —CN, —NO 2 , —OR D2a ′, —N(R D2a ′) 2 , —SR D2a ′, —CH 2 OR D2a ′, —CH 2 N(R D2a ′) 2 , —CH 2 SR 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 D2a ′ is 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 D2a ′ groups are joined to form an optionally substituted heterocyclic ring;

R D3 ′ is 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, —NO 2 , —OR D3a ′, —N(R D3a ′) 2 , —SR D3a ′, —CH 2 OR D3a ′, —CH 2 N(R D3a ′) 2 , —CH 2 SR 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 D3a ′ is 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 D3a ′ groups are joined to form an optionally substituted heterocyclic ring;

optionally R D1 ′, and R D3 ′, or R D2 ′ and R D3 ′, or D D1 ′ and R D2 ′ are joined to form an optionally substituted carbocyclic or optionall ubstituted hereroyclic ring;

R D4 ′ is a leaving group;

R D5 ′ is hydrogen, C 1-6 alkyl, or a nitrogen protecting group;

Y Z ′ is —O, —S, or —NR D6 ′, wherein R D6 ′ is hydrogen, C 1-6 alkyl, or a nitrogen protecting group;

a′ is 1 or 2; and

z′ is 0, 1, 2, 3, 4, 5, or 6.

Compounds of Formula (II) include an aryl group for Ring A′ optionally substituted with one or more R A ′ groups. In certain embodiments, when Ring A′ is naphthyl, the invention provides compounds of Formula (II-a):

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

Compounds of Formula (II) include an aryl group for Ring A′ optionally substituted with one or more R A ′ groups. In certain embodiments, when Ring A′ is naphthyl, the invention provides compounds of Formula (II-b):

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

Compounds of Formula (II) include an aryl group for Ring A′ optionally substituted with one or more R A ′ groups. In certain embodiments, when Ring A′ is phenyl, the invention provides compounds of Formula (II-c):

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

Compounds of Formula (II) include an aryl group for Ring A′ optionally substituted with one or more R A ′ groups. In certain embodiments, when Ring A′ is phenyl, the invention provides compounds of Formula (II-d):

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

Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more R A ′ groups. In certain embodiments, when Ring A′ is pyrrolopyrimidine, the invention provides compounds of Formula (II-e):

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

Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more R A ′ groups. In certain embodiments, when Ring A′ is pyrimidine, the invention provides compounds of Formula (II-e A ):

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

Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more R A ′ groups. In certain embodiments, when Ring A′ is pyrimidine, the invention provides compounds of Formula (II-e B ):

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

Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more R A ′ groups. In certain embodiments, when Ring A′ is a furo[2,3-c]pyridin-7-amine, the invention provides compounds of Formula (II-e C ):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R A ′, R B ′, R X ′, k′, and l′ are as defined herein.

Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more R A ′ groups. In certain embodiments, when Ring A′ is quinazoline, the invention provides compounds of Formula (II-e D ):

wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, R A ′, R B ′, R X ′, k′, and l′ are as defined herein.

Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more R A ′ groups. In certain embodiments, when Ring A′ is phenyl, and at least one R A ′ group links to Cy forming an optional 5 to 8 membered ring, the invention provides copounds of Formula (II-f):

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

Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more R A ′ groups. In certain embodiments, when Ring A′ is phenyl, and at least one R A ′ group links to Cy forming an optional 5 to 8 membered ring, the invention provides copounds of Formula (II-g):

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

In compounds of Formula (II), R D ′ is a substituent on Ring A′, Ring C′, or Cy. In certain embodiments, R D ′ comprises a Michael acceptor moiety. This Michael aceptor moiety may reach 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 D ′ is of Formula (i-1). In certain embodiments, R D ′ is of Formula (i-2). In certain embodiments, R D ′ is of Formula (i-3). In certain embodiments, R D ′ is of Formula (I-4). In certain embodiments, R D ′ is of Formula (i-5). In certain embodiments, R D ′ is of Formula (i-6). In certain embodiments, R D ′ is of Fomrula (i-7). In certain embodiments, R D ′ is of Formula (i-8). In certain embodiments, R D ′ is of Formula (i-9). In certain embodiments, R D ′ is of Formula (i-10). In certain embodiments, R D ′ is of Formula (i-11). In certain embodiments, R D ′ is of Formula (i-12). In certain embodiments, R D ′ is of Formula (i-13). In certain embodiments, R D ′ is of Formula (i-14). In certain embodiments, R D ′ is of Formula (i-15). In certain embodiments, R D ′ is of Formula (i-16). In certain embodiments, R D ′ is of Formula (i-17).

In compounds of Formula (II), R D ′ may include a substituent R D1 ′. In certain embodiments, R D1 ′ is H. In certain embodiments, R D1 ′ is halogen. In certain embodiments, R D1 ′ is F. In certain embodiments, R D1 , is Cl. In certain embodiments, R D ′ is Br. In certain embodiments, R D1 ′ is I (iodine). In certain embodiments, R D1 , is substituted acyl. In certain embodiments, R D1 ′ is unsubstituted acyl. In certain embodiments, R D1 , is acetyl. In certain embodiments, R D1 ′ is substituted alkyl. In certain embodiments, R D1 , is unsubstituted alkyl. In certain embodiments, R D1 ′ is C 1-6 alkyl. In certain embodiments, R D1 ′ is methyl. In certain embodiments, R D1 ′ is ethyl. In certain embodiments, R D1 ′ is propyl. In certain embodiments, R D1 ′ is butyl. In certain embodiments, R D1 ′ is substituted alkenyl. In certain embodiments, R D1 ′ is unsubstituted alkenyl. In certain embodiments, R D1 ′ is substituted alkynyl. In certain embodiments, R D1 ′ is unsubstituted alkynyl. In certain embodiments, R D1′ is substituted carbocyclyl. In certain embodiments, R D1 ′ is unsubstituted carbocyclyl. In certain embodiments, R D1 ′ is substituted heterocyclyl. In certain embodiments, R D1 ′ is unsubstituted heterocyclyl. In certain embodiments, R D1 ′ is substituted aryl. In certain embodiments, R D1 ′ is unsubstituted aryl. In certain embodiments, R D1 ′ is substituted phenyl. In certain embodiments, R D1 ′ is unsubstituted phenyl. In certain embodiments, R D1 ′ is substituted heteroaryl. In certain embodiments, R D1 ′ is unsubstituted heteroaryl. In certain embodiments, R D1 ′ is substituted pyridyl. In certain embodiments, R D1 ′ is unsubstituted pyridyl. In certain embodiments, R D1 ′ is —CN. In certain embodiments, R D1 ′ is —NO 2 . In certain embodiments, R D1 ′ is —OR D1a . In certain embodiments, R D1 ′ is —N(R D1a ′) 2 . In certain embodiments, R D1 ′ is —SR D1a ′. In certain embodiments, R D1 ′, is —CH 2 OR D1a ′. In certain embodiments, R D1 ′ is —CH 2 N(R D1a ′) 2 . In certain embodiments, R D1 ′ is —CH 2 SR D1a ′.

In certain embodiments, at least one R D1a ′ is H. In certain embodiments, at least one R D1a ′ is substituted acyl. In certain embodiments, at least one R D1a ′ is unsubstituted acyl. In certain embodiments, at least one R D1a ′ is acetyl. In certain embodiments, at least one R D1a ′, is substituted alkyl. In certain embodiments, at least one R D1a ′ is unsubstituted alkyl. In certain embodiments, at least one R D1a ′ is C 1-6 alkyl. In certain embodiments, at least one R D1a ′ is methyl. In certain embodiments, at least one R D1a ′ is ethyl. In certain embodiments, at least one R D1a ′ is propyl. In certain embodiments, at least one R D1a ′ is butyl. In certain embodiments, at least one R D1a ′ is substituted alkenyl. In certain embodiments, at least one R D1a ′ is unsubstituted alkenyl. In certain embodiments, at least one R D1a ′ is substituted alkynyl. In certain embodiments, at least one R D1a ′ is unsubstituted alkynyl. In certain embodiments, at least one R D1a ′ is substituted carbocyclyl. In certain embodiments, at least one R D1a ′ is unsubstituted carbocyclyl. In certain embodiments, at least one R D1a ′ is substituted heterocyclyl. In certain embodiments, at least one R D1a ′ is unsubstituted heterocyclyl. In certain embodiments, at least one R D1a ′ is substituted aryl. In certain embodiments, at least one R D1a ′ is unsubstituted aryl. In certain embodiments, at least one R D1a ′ is substituted phenyl. In certain embodiments, at least one R D1a ′ is unsubstituted phenyl. In certain embodiments, at least one R D1a ′ is substituted heteroaryl. In certain embodiments, at least one R D1a ′ is unsubstituted heteroaryl. In certain embodiments, at least one R D1a ′ is substituted pyridyl. In certain embodiments, at least one R D1a ′ is unsubstituted pyridyl. In certain embodiments, at least one R D1a ′ is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R D1a ′ is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R D1a ′ is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R D1a ′ is 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 D1a ′ is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R D1a ′ is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two R D1a ′ groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R D1a ′ groups are joined to form an unsubstituted heterocyclic ring.

In compounds of Formula (II), R D ′ may include a substituent R D2 ′. In certain embodiments, R D2a ′ is H. In certain embodiments, R D2a ′ is halogen. In certain embodiments, R D2 , is F. In certain embodiments, R D2 ′ is Cl. In certain embodiments, R D2a ′ is Br. In certain embodiments, R D2a ′ is I (iodine). In certain embodiments, R D2a ′ is substituted acyl. In certain embodiments, R D2a ′ is unsubstituted acyl, In certain embodiments, R D2a ′ is acetyl. In certain embodiments, R D2a ′ is substituted alkyl. In certain embodiments, R D2a ′ is unsubstituted alkyl. In certain embodiments, R D2a ′ is C 1-6 alkyl. In certain embodiments, R D2a ′ is methyl. In certain embodiments, R D2a ′ is ethyl. In certain embodiments, R D2a ′ is propyl. In certain embodiments, R D2a ′ is butyl. In certain embodiments, R D2a ′ is substituted alkenyl. In certain embodiments, R D2a ′ is unsubstituted alkenyl. In certain embodiments, R D2a ′ is substituted alkynyl. In certain embodiments, R D2a ′ is unsubstituted alkynyl. In certain embodiments, R D2a ′ is substituted carbocyclyl. In certain embodiments, R D2a ′ is unsubstituted carbocyclyl. In certain embodiments, R D2a ′ is substituted heterocyclyl. In certain embodiments, R D2a ′ is unsubstituted heterocyclyl. In certain embodiments, R D2a ′ is substituted aryl. In certain embodiments, R D2a ′ is unsubstituted aryl. In certain embodiments, R D2a ′ is substituted phenyl. In certain embodiments, R D2a ′ is unsubstituted phenyl. In certain embodiments,R D2a ′ is substituted heteroaryl. In certain embodiments, R D2a ′ is unsubstituted heteroaryl. In certain embodiments, R D2a ′, is substituted pyridyl. In certain embodiments, R D2a ′ is unsubstituted pyridyl. In certain embodiments, R D2a ′ is —CN. In certain embodiments, R D2a ′ is —NO 2 . In certain embodiments, R D2a ′ is —OR D2a ′. In certain embodiments, R D2a ′ is —N(R D2a ′) 2 . In certain embodiments, R D2a ′ is —SR D2a ′. In certain embodiments, R D2a ′ is —CH 2 OR D2a ′. In certain embodiments, R D2a ′ is —CH 2 N(R D2a ′) 2 . In certain embodiments, R D2a ′ is —CH 2 SR D2a ′.

In certain embodiments, at least one R D2a ′ is H. In certain embodiments, at least one R D2a ′ is substituted acyl. In certain embodiments, at least one R D2a ′ is unsubstituted acyl. In certain embodiments, at least one R D2a ′ is acetyl. In certain embodiments, at least one R D2a ′ is substituted alkyl. In certain embodiments, at least one R D2a ′ is unsubstituted alkyl. In certain embodiments, at least one R D2a ′ is C 1-6 alkyl. In certain embodiments, at least one R D2a ′ is methyl. In certain embodiments, at least one R D2a ′ is ethyl. In certain embodiments, at least one R D2a ′ is propyl. In certain embodiments, at least one R D2a ′ is butyl. In certain embodiments, at least one R D2a ′ is substituted alkenyl. In certain embodiments, at least one R D2a ′ is unsubstituted alkenyl. In certain embodiments, at least one R D2a ′ is substituted alkynyl. In certain embodiments, at least one R D2a ′ is unsubstituted alkynyl. In certain embodiments, at least one R D2a ′ is substituted carbocyclyl. In certain embodiments, at least one R D2a ′ is unsubstituted carbocyclyl. In certain embodiments, at least one R D2a ′ is substituted heterocyclyl. In certain embodiments, at least one R D2a ′ is unsubstituted heterocyclyl. In certain embodiments, at least one R D2a ′ is substituted aryl. In certain embodiments, at least one R D2a ′ is unsubstituted aryl. In certain embodiments, at least one R D2a ′ is substituted phenyl. In certain embodiments, at least one R D2a ′ is unsubstituted phenyl. In certain embodiments, at least one R D2a ′ is substituted heteroaryl. In certain embodiments, at least one R D2a ′ is unsubstituted heteroaryl. In certain embodiments, at least one R D2a ′ is substituted pyridyl. In certain embodiments, at least one R D2a ′ is unsubstituted pyridyl. In certain embodiments, at least one R D2a ′ is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R D2a ′ is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R D2a ′ is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R D2a ′ is 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 D2a ′ is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R D2a ′ is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two R D2a ′ groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R D2a ′ groups are joined to form an unsubstituted heterocyclic ring.

In compounds of Formula (II), R D ′ may include a substituent R D3 ′. In certain embodiments, R D3 ′ is H. In certain embodiments, R D3 ′ is halogen. In certain embodiments, R D3 ′ is F. In certain embodiments, R D3 ′ is Cl. In certain embodiments, R D3 ′ is Br. In certain embodiments, R D3 ′ is I (iodine). In certain embodiments, R D3 ′ is substituted acyl. In certain embodiments, R D3 ′ is unsubstituted acyl. In certain embodiments, R D3 ′ is acetyl. In certain embodiments, R D3 ′ is substituted alkyl. In certain embodiments, R D3 ′ is unsubstituted alkyl. In certain embodiments, R D3 ′ is C 1-6 alkyl. In certain embodiments, R D3 ′ is methyl. In certain embodiments, R D3 ′ is ethyl. In certain embodiments, R D3 ′ is propyl. In certain embodiments, R D3 ′ is butyl. In certain embodiments, R D3 ′ is substituted alkenyl. In certain embodiments, R D3 ′ is unsubstituted alkenyl. In certain embodiments, R D3 ′ is substituted alkynyl. In certain embodiments, R D3 ′ is unsubstituted alkynyl. In certain embodiments, R D3 ′ is substituted carbocyclyl. In certain embodiments, R D3 ′ is unsubstituted carbocyclyl. In certain embodiments, R D3 ′ is substituted heterocyclyl. In certain embodiments, R D3 ′ is unsubstituted heterocyclyl. In certain embodiments, R D3a ′ is substituted aryl. In certain embodiments, R D3a ′ is unsubstituted aryl. In certain embodiments, R D3a ′ is substituted phenyl. In certain embodiments, R D3 ′ is unsubstituted phenyl. In certain embodiments, R D3 ′ is substituted heteroaryl. In certain embodiments, R D3 ′ is unsubstituted heteroaryl. In certain embodiments, R D3 ′ is substituted pyridyl. In certain embodiments, R D3a ′ is unsubstituted pyridyl. In certain embodiments, R D3a ′ is —CN. In certain embodiments, R D3a ′ is —NO 2 . In certain embodiments, R D3 ′ is —OR D3a ′. In certain embodiments, R D3a ′ is —N(R D3a ′) 2 . In certain embodiments, R D3 ′ is —SR D3a ′. In certain embodinrents, R D3 ′ is —CH 2 OR D3a ′. In certain embodiments, R D3 ′ is —CH 2 N(R D3a ′) 2 . In certain embodiments, R D3 ′ is —CH 2 SR D3a ′.

In certain embodiments, at least one R D3a ′ is H. In certain embodiments, at least one R D3a ′ is substituted acyl. In certain embodiments, at least one R D3a ′ is unsubstituted acyl. In certain embodiments, at least one R D3a ′ is acetyl. In certain embodiments, at least one R D3a ′ is substituted alkyl. In certain embodiments, at least one R D3a ′ is unsubstituted alkyl. In certain embodiments, at least one R D3a ′ is C 1-6 alkyl. In certain embodiments, at least one R D3a ′ is methyl. In certain embodiments, at least one R D3a ′ is ethyl. In certain embodiments, at least one R D3a ′ is propyl. In certain embodiments, at least one R D3a ′ is butyl. In certain embodiments, at least one R D3a ′ is substituted alkenyl. In certain embodiments, at least one R D3a ′ is unsubstituted alkenyl. In certain embodiments, at least one R D3a ′ is substituted alkynyl. In certain embodiments, at least one R D3a ′ is unsubstituted alkynyl. In certain embodiments, at least one R D3a ′ is substituted carbocyclyl. In certain embodiments, at least one R D3a ′ is unsubstituted carbocyclyl. In certain embodiments, at least one R D3a ′ is substituted heterocyclyl. In certain embodiments, at least one R D3a ′ is unsubstituted heterocyclyl. In certain embodiments, at least one R D3a ′ is substituted aryl. In certain embodiments, at least one R D3a ′ is unsubstituted aryl. In certain embodiments, at least one R D3a ′ is substituted phenyl. In certain embodiments, at least one R D3a ′ is unsubstituted phenyl. In certain embodiments, at least one R D3a ′, is substituted heteroaryl. In certain embodiments, at least one R D3a ′ is unsubstituted heteroaryl. In certain embodiments, at least one R D3a ′ is substituted pyridyl. In certain embodiments, at least one R D3a ′ is unsubstituted pyridyl. In certain embodiments, at least one R D3a ′ is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R D3a ′ is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R D3a ′ is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R D3a ′ is 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 D3a ′ is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R D3a ′ is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two R D3a ′ groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R D3a ′ groups are joined to form an unsubstituted heterocyclic ring.

In compounds of Fomrula (II), R D ′ may include a substituent R D4 ′. In certain embodiments, R D4 ′ is a leaving group. In certain embodiments, R D4 ′ is halogen. In certain embodiments, R D4 ′ is F. In certain embodiments, R D4 ′ is Cl. In certain embodiments, R D4 ′ is Br. In certain embodiments, R D4 ′ is I (iodine). In certain embodiments, R D4 ′ is —OS(═O) w′ R D4a ′. In certain embodiments, w′ is 1. In certain embodiments, w′ is 2. In certain embodiments, R D4 ′ is —OMs. In certain embodiments, R D4 ′ is —OTf. In certain embodiments, R D4 ′ is —OTs. In certain embodiments, R D4 ′ is —OBs. In certain embodiments, R D4 ′ is 2-nitrobenzene-sulfonyloxy. In certain embodiments, R D4 ′ is —OR D4a ′. In certain embodiments, R D4 ′ is —OMe. In certain embodiments, R D4 ′ is —OCF 3 . In certain embodiments, R D4 ′ is —OPh. In certain embodimentsR D4 ′ is —OC(═O)R D4a ′. In certain embodiments, R D4 ′ is —OC(═O)Me. In certain embodiments, R D4 ′ is —OC(═O)CF 3 . In certain embodiments, R D4 ′ is —OC(═O)Ph. In certain embodiments, R D4 ′ is —OC(═O)Cl. In certain embodiments, R D4 ′ is —OC(═O)OR D4a ′. In certain embodiments, R D4 ′ is —OC(═O)OMe. In certain embodiments, R D4 ′ is —OC(═O)O(t-Bu).

In certain embodiments, R D4a ′ is substituted alkyl. In certain embodiments, R D4a ′ is unsubstituted alkyl. In certain embodiments, R D4a ′ is C 1-6 alkyl. In certain embodiments, R D4a ′ is methyl. In certain embodiments, R D4a ′ is ethyl. In certain embodiments, R D4a ′ is propyl. In certain embodiments, R D4a ′ is butyl. In certain embodiments, R D4a′ is substituted alkenyl. In certain embodiments, R D4a ′ is unsubstituted alkenyl. In certain embodiments, R D4a ′ is vinyl. In certain embodiments, R D4a ′ is substituted alkynyl. In certain embodiments, R D4a ′ is unsubstituted alkynyl. In certain embodiments, R D4a ′ is ethynyl. In certain embodiments, R D4a ′ is substituted carbocyclyl. In certain embodiments, R D4a ′ is unsubstituted carbocyclyl. In certain embodiments, R D4a ′ is substituted heterocyclyl. In certain embodiments, R D4a ′ is unsubstituted heterocyclyl. In certain embodiments, R D4a ′ is substituted aryl. In certain embodiments, R D4a ′ is unsubstituted aryl. In certain embodiments, R D4a ′ is substituted phenyl. In certain embodiments, R D4a ′ is unsubstituted phenyl. In certain embodiments, R D4a ′ is substituted heteroaryl. In certain embodiments, R D4a ′ is unsubstituted heteroaryl. In certain embodiments, R D4a ′ is substituted pyridyl. In certain embodiments, R D4a ′ is unsubstituted pyridyl.

In compounds of Formula (II), R D ′ may include a substituent R D5 ′. In certain embodiments, R D5 ′ is H. In certain embodiments, R D5 ′ is substituted alkyl. In certain embodiments, R D5 ′ is unsubstituted alkyl. In certain embodiments, R D5 ′ is C 1-6 alkyl. In certain embodiments, R D5 ′ is methyl. In certain embodiments, R D5 ′ is ethyl. In certain embodiments R D5 ′ is propyl. In certain embodiments, R D5 ′ is butyl. In certain embodiments, R D5 ′ is a nitrogen protecting group. In certain embodiments, R D5 ′ is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts.

In certain embodiments, R D1 ′ and R D2 ′ are each hydrogen. In certain embodiments, R D1 ′ and R D3 ′ are each hydrogen. In certain embodiments, R D2 ′ and R D3 ′ are each hydrogen. In certain embodiments, R D1 ′, R D2′ , and R D3 ′ are each hydrogen. In certain embodiments, R D1 ′, R D2′ , and R D3′ , and R D5 ′ are 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 Z ′ is —O—. In certain embodiments, Y Z ′ is ═O. In certain embodiments, Y Z ′ is —S—. In certain embodiments Y Z ′ is ═S. In certain embodiments, Y Z ′ is 'NR D6 ′—, wherein R D6 ′ is hydrogen, C 1-6 alkyl, or a nitrogen protecting group. In certain embodiments, Y Z ′ is —NH—. In certain embodiments, Y Z ′ is —NCH 3 —. In certain embodiments, Y Z ′ is —N(BOC)—. In certain embodiments, Y Z ′ is —N(Fmoc)-. In certain embodiments, Y Z ′ is —N(Cbz)-. In certain embodiments, Y Z ′ is —N(Bn)-. In certain embodiments, Y Z ′ is —NR D6 ′, wherein R D6 ′ is hydrogen, C 1-6 alkyl, or a nitrogen protecting group. In certain embodiments, Y Z ′ is ═NH. In certain embodiments, Y Z ′ is ═NCH 3 . In certain embodiments, Y Z ′ is —NTs. In certain embodiments, Y Z ′ is ═NBn. In certain embodiments, Y Z ′ is ═NCH(Ph) 2 .

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

In certain embodiments, R D ′ is of the formula:

Compounds of Formula (II) or (V) include an aryl Ring A′ optionally substituted with one or more R A ′ groups. In certain embodiments, k′ is 0. In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, k′ is 1. In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

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

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

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

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

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

In certain embodiments, Ring A′ is of the formula:

Compounds of Formula (II) or (V) include an aryl Ring A′ optionally substituted with one or more R A ′ groups. In certain embodiments, X′, Y′, and Z′ are bonds, and Cy is hydrogen. In certain embodiments, k′ is 0. In certain embodiments, Ring A′ is of the formula:

In certain embodiments, k′ is 1. In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

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

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In certain embodiments, Ring A′ is of the formula:

In compounds of Formula (II) or (V), Ring A′ may be substituted with one or more R A ′ groups. In certain embodiments, at least one R A ′ is H. In certain embodiments, at least two R A ′ groups are H. In certain embodiments, at least three R A ′ groups are H. In certain embodiments, at least four R A ′ groups are H. In certain embodiments, at least one R A ′ is halogen. In certain embodiments, at least one R A ′ is F. In certain embodiments, at least one R A ′ is Cl. In certain embodiments, at least one R A ′ is Br. In certain embodiments, at least one R A ′ is I (iodine). In certain embodiments, at least one R A ′ is substituted acyl. In certain embodiments, at least one R A ′ is —C(═O)N(R A1 ′) 2 . In certain embodiments, at least one R A ′ is —C(═O)NHR A1 ′. In certain embodiments, at least one R A ′ is —C(═O)NH(C 1-6 alkyl). In certain embodiments, at least one R A ′ is —C(═O)NHMe. In certain embodiments, at least one R A ′ is —C(═O)NH 2 . In certain embodiments, at least one R A ′ is unsubstituted acyl. In certain embodiments, at least one R A ′ is acetyl. In certain embodiments, at least one R A ′ is substituted alkyl. In certain embodiments, at least one R A ′ is substituted methyl. In certain embodiments, at least one R A ′ is unsubstituted alkyl. In certain embodiments, at least one R A ′ is C 1-6 alkyl. In certain embodiments, at least one R A ′ is methyl. In certain embodiments, at least one R A ′ is ethyl. In certain embodiments, at least one R A ′ is propyl. In certain embodiments, at least one R A ′ is butyl. In certain embodiments, at least one R A ′ is substituted alkenyl. In certain embodiments, at least one R A ′ is unsubstituted alkenyl. In certain embodiments, at least one R A ′ is substituted alkynyl. In certain embodiments, at least one R A ′ is unsubstituted alkynyl. In certain embodiments, at least one R A ′ is substituted carbocyclyl. In certain embodiments, at least one R A ′ is unsubstituted carbocyclyl. In certain embodiments, at least one R A ′ is substituted heterocyclyl. In certain embodiments, at least one R A ′ is unsubstituted heterocyclyl. In certain embodiments, at least one R A ′ is

In certain embodiments, at least one R A ′ is substituted aryl. In certain embodiments, at least one R A ′ is unsubstituted aryl. In certain embodiments, at least one R A ′ is substituted phenyl. In certain embodiments, at least one R A ′ is unsubstituted phenyl. In certain embodiments, at least one R A ′ is substituted heteroaryl. In certain embodiments, at least one R A ′ is unsubstituted heteroaryl. In certain embodiments, at least one R A ′ is substituted pyridyl. In certain embodiments, at least one R A ′ is unsubstituted pyridyl. In certain embodiments, at least one R A ′ is —OR A1 ′. In certain embodiments, at least one R A ′ is —O(C 1-6 alkyl). In certain embodiments, at least one R A ′ is OMe. In certain embodiments, at least one R A ′ is —OH. In certain embodiments, at least one R A ′ is —N(R A1 ′) 2 . In certain embodiments, at least one R A ′ is —NH 2 . In certain embodiments, at least one R A ′ is —SR A1′ . In certain embodiments, at least one R A ′ is —SH. In certain embodiments, at least one R A ′ is —NR A1 ′C(═O)N(R A1 ′) 2 . In certain embodiments, at least one R A ′ is —NHC(═O)N(R A1 ′) 2 . In certain embodiments, at least one one R A ′ is —NHC(═O)NHR A1 ′. In certain embodiments, at least one R A ′ is —NHC(═O)NH(C 1-6 alkyl). In certain embodiments, at least one one R A ′ is —NHC(═O)NHMe. In certain embodiments, at least one R A ′ is —NHC(═O)NH 2 . In certain embodiments, at least one R A ′ is —NR A1 ′C(═O)NHR A1 ′. In certain embodiments, at least one R A ′ is —NR A1 ′C(═O)NH 2 . In certain embodiments, at least one one R A ′ is —NR A1 ′S(═O) 2 R A1 ′. In certain embodiments, at least one R A ′ is —NHS(═O) 2 R A1 ′. In certain embodiments, at least one R A ′ is —NHS(═O) 2 (C 1-6 alkyl). In certain embodiments, at least one R A ′ is —NHS(═O) 2 Me. In certain embodiments, at least one R A ′ is —S(═O) 2 N(R A1 ′) 2 . In certain embodiments, at least one R A ′ is —S(═O) 2 N(R A1 ′) 2 . In certain embodiments, at least one R A ′ is —S(═O) 2 N(C 1-6 alkyl) 2 . In certain embodiments, at least one R A ′ is —S(═O) 2 NH(C 1-6 alkyl). In certain embodiments, at least one R A ′ is —S(═O) 2 NH(t-Bu). In certain embodiments, at least one R A ′ is —S(═O) 2 NH 2 .

In compounds of Formula (II) or (V), Ring C′ may be substituted with one or more one R B ′ groups. In certain embodiments, at least one R B ′ is H. In certain embodiments, at least two R B ′ groups are H. In certain embodiments, at least three R B ′ groups are H. In certain embodiments, at least four R B ′ groups are H. In certain embodiments, at least one R B ′ is halogen. In certain embodiments, at least one R B ′ is F. In certain embodiments, at least one R B ′ is Cl. In certain embodiments, at least one R B ′ is Br. In certain embodiments, at least one R B ′ is I (iodine). In certain embodiments, at least one R B ′ is substituted acyl, In certain embodiments, at least one R B ′ is —C(═O)N(R A1 ′) 2 . In certain embodiments, at least one R B ′ is —C(═O)NHR A1 ′. In certain embodiments, at least one R B ′ is —C(═O)NH(C 1-6 alkyl). In certain embodiments, at least one R B ′ is —C(═O)NHMe. In certain embodiments, at least one R B ′ is —C(═O)NH 2 . In certain embodiments, at least one R B ′ is unsubstituted acyl. In certain embodiments, at least one R B ′ is acetyl. In certain embodiments, at least one R B ′ is substituted alkyl. In certain embodiments, at least one R B ′ is substituted methyl. In certain embodiments, at least one R B ′ is unsubstituted alkyl, In certain embodiments, at least one R B ′ is C 1-6 alkyl. In certain embodiments, at least one R B ′ is methyl. In certain embodiments, at least one R B ′ is ethyl. In certain embodiments, at least one R B ′ is propyl. In certain embodiments, at least one R B ′ is butyl. In certain embodiments, at least one R B ′ is —CF 3 . In certain embodiments, at least one R B ′ is substituted alkenyl. In certain embodiments, at least one R B ′ is unsubstituted alkenyl. In certain embodiments, at least one R B ′ is substituted alkynyl. In certain embodiments, at least one R B ′ is unsubstituted alkynyl. In certain embodiments, at least one R B ′ is substituted carbocyclyl. In certain embodiments, at least one R B ′ is unsubstituted carbocyclyl. In certain embodiments, at least one R B ′ is substituted heterocyclyl. In certain embodiments, at least one R B ′ is unsubstituted heterocyclyl. In certain embodiments, at least one R B ′ is substituted aryl. In certain embodiments, at least one R B ′ is unsubstituted aryl. In certain embodiments, at least one R B ′ is substituted phenyl. In certain embodiments, at least one R B ′ is unsubstituted phenyl. In certain embodiments, at least one R B ′ is substituted heteroaryl. In certain embodiments, at least one R B ′ is unsubstituted heteroaryl. In certain embodiments, at least one R B ′ is substituted pyridyl. In certain embodiments, at least one R B ′ is unsubstituted pyridyl. In certain embodiments, at least one R B ′ is —O A1 . In certain embodiments, at least one R B ′ is —O(C 1-6 alkyl). In certain embodiments, at least one R B ′ is —OMe. In certain embodiments, at least one R B ′ is —OH. In certain embodiments, at least one R B ′ is —N(R A1 ′) 2 . In certain embodiments, at least one R B ′ is —NH 2 . In certain embodiments, at least one R B ′ is —SR A1 ′. In certain embodiments, at least one R B ′ is —SH. In certain embodiments, at least one R B ′ is —NR A1 ′C(═O)N(R A1 ′) 2 . In certain embodiments, at least one R B ′ is —NHC(═O)N(R A1 ′) 2 . In certain embodiments, at least one R B ′ is —NHC(═O)NHR A1 ′. In certain embodiments, at least one R B ′ is —NHC(═O)NH(C 1-6 alkyl). In certain embodiments, at least one R B ′ is —NHC(═O)NHMe. In certain embodiments, at least one R B ′ is —NHC(═O)NH 2 . In certain embodiments, at least one R B ′ is —NR A1 ′C(═O)NHR A1 ′. In certain embodiments, at least one R B ′ is —NR A1 ′C(═O)NH 2 . In certain embodiments, at least one R B ′ is —NR A1 ′S(═O) 2 R A1 ′. In certain embodiments, at least one R B ′ is —NHS(═O) 2 R A1 ′. In certain embodiments, at least one R B ′ is —NHS(═O) 2 (C 1-6 alkyl). In certain embodiments, at least one R B ′ is —NHS(═O) 2 Me. In certain embodiments, at least one R B ′ is —S(═O) 2 N(R A1 ′) 2 . In certain embodiments, at least one R B ′ is —S(═O) 2 N(R A1 ′) 2 . In certain embodiments, at least one R B ′ is —S(═O) 2 N(C 1-6 alkyl) 2 . In certain embodiments, at least one R B ′ is —S(═O) 2 NH(C 1-6 alkyl). In certain embodiments, at least one R B ′ is —S(═O) 2 NH(t-Bu). In certain embodiments, at least one R B ′ is —S(═O) 2 NH 2 . In certain embodiments, at least one R B ′ is substituted imidazole. In certain embodiments, at least one R B ′ is substituted piperidine. In certain embodiments, at least one R B ′ substituted piperizine. In certain embodiments, at least one R B ′ substituted pyrrolidine. In certain embodiments, at least one R B ′ is substituted morpholine. In certain embodiments, at least one R B ′ is substituted diazepane. In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, at least one R B ′ is

In certain embodiments, two R B ′ groups are joined to form a 1,3 dioxolane. In certain embodiments, two R B ′ group are joined to form a 1,3 dioxolane which is fused to aryl Ring C′, together comprising an optionally substituted benzodioxolane. In certain embodiments, two R B ′ groups are joined to form a 1,2,3-thiadiazole. In certain embodiments, two R B ′ groups are joined to form a 1,2,3-thiadiazole which is fused to aryl Ring C′, together comprising an optionally substituted, benzo[d][1,2,3]thiadiazole.

In certain embodiments, at least one R A1 ′ is H. In certain embodiments, at least one R A1 ′ is substituted acyl. In certain embodiments, at least one R A1 ′ is unsubstituted acyl. In certain embodiments, at least one R A1 ′ is acetyl. In certain embodiments, at least one R A1 ′ is substituted alkyl. In certain embodiments, at least one R A1 ′ is unsubstituted alkyl. In certain embodiments, at least one R A1 ′ is C 1-6 alkyl. In certain embodiments, at least one R A1 ′ is methyl. In certain embodiments, at least one R A1 ′ is ethyl. In certain embodiments, at least one R A1 ′ is propyl. In certain embodiments, at least one R A1 ′ is butyl. In certain embodiments, at least one R A1 ′ is substituted alkenyl. In certain embodiments, at least one R A1 ′ is unsubstituted alkenyl. In certain embodiments, at least one R A1 ′ is substituted alkynyl. In certain embodiments, at least one R A1 ′ is unsubstituted alkynyl. In certain embodiments, at least one R A1 ′ is substituted carbocyclyl. In certain embodiments, at least one R A1 ′ is unsubstituted carbocyclyl. In certain embodiments, at least one R A1 ′ is substituted heterocyclyl. In certain embodiments, at least one R A1 ′ is unsubstituted heterocyclyl. In certain embodiments, at least one R A1 ′ is substituted aryl. In certain embodiments, at least one R A1 ′ is unsubstituted aryl. In certain embodiments, at least one R A1 ′ is substituted phenyl. In certain embodiments, at least one R A1 ′ is unsubstituted phenyl. In certain embodiments, at least one R A1 ′ is substituted heteroaryl. In certain embodiments, at least one R A1 ′ is unsubstituted heteroaryl. In certain embodiments, at least one R A1 ′ is substituted pyridyl. In certain embodiments, at least one R A1 ′ is unsubstituted pyridyl. In certain embodiments, at least one R A1 ′ is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R A1 ′ is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R A1 ′ is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, R A1 ′ is 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 A1 ′ is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, R A1 ′ is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom.

In compounds of Formula (II) or (V), two R A1 ′ groups 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 A1 ′ groups are joined to form a substituted carbocyclic ring. In certain embodiments, two R A1 ′ groups are joined to form an unsubstituted carbocyclic ring. In certain embodiments, two R A1 ′ groups are joined to form a substituted heterocyclic ring. In certain embodiments, two R A1 ′ groups are joined to form an unsubstituted heterocyclic ring. In certain embodiments, two R A1 ′ groups are joined to form a substituted aryl ring. In certain embodiments, two R A1 ′ groups are joined to form an unsubstituted aryl ring. In certain embodiments, two R A1 ′ groups are joined to form a substituted phenyl ring. In certain embodiments, two R A1 ′ groups are joined to form an unsubstituted phenyl ring. In certain embodiments, two R A1 ′ groups are joined to form a substituted heteroaryl ring. In certain embodiments, two R A1 ′ groups are joined to form an unsubstituted heteroaryl ring.

In certain embodiments, R A ′ is —OR A1 ′ and k′ is 1. In certain embodiments, R A ′ is —O(C 1-6 alkyl) and k′ is 1. In certain embodiments, R A ′ is —OMe and k′ is 1. In certain embodiments, R A ′ is —OH and k′ is 1.

In certain embodiments, R A ′ is substituted C 1-6 alkyl; and k′is 1. In certain embodiments, R A ′ is unsubstituted C 1-6 alkyl; and k′ is 1. In certain embodiments, R A ′ is methyl; and k′ is 1. In certain embodiments, R A ′ is —CF 3 ; and k′ is 1. In certain embodiments, R A , is ethyl; and k′is 1. In certain embodiments, R A ′ is propyl; and k′ is 1. In certain embodiments, R A ′ is butyl; and k′ is 1. In certain embodiments, R A ′ is propyl; and k′ is 1. In certain embodiments, R A ′ is butyl; and k′ is 1.

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

In certain embodiments, one instance of R A ′ is halogen, another instance of R A ′ is substituted C 1-6 alkyl; and k′ is 2. In certain embodiments, one instance of R A ′ is F, another instance of R A ′ is substituted C 1-6 alkyl; and k′ is 2. In certain embodiments, one instance of R A ′ is Cl, another instance of R A ′ is substituted C 1-6 alkyl; and k′ is 2. In certain embodiments, one instance of R A ′ is halogen, another instance of R A ′ is unsubstituted C 1-6 alkyl; and k′ is 2. In certain embodiments, one instance of R A ′ is F, another instance of R A ′ is unsubstituted C 1-6 ; alkyl; and k′ is 2. In certain embodiments, one instance of R A ′ is Cl, another instance of R A ′ is unsubstituted C 1-6 alkyl; and k′ is 2. In certain embodiments, one instance of R A ′ is halogen, another instance of R A ′ is methyl; and k′ is 2. In certain embodiments, one instance of R A ′ is F, another instance of R A ′ is methyl; and k′ is 2. In certain embodiments, one instance of R A′ is Cl, another instance of R A ′ is methyl; and k′ is 2. In certain embodiments, one instance of R A′ is halogen, another instance of R A ′ is —CF 3 ; and k′ is 2. In certain embodiments, one instance of R A ′ is F, another instance of R A ′ is —CF 3 ; and k′ is 2. In certain embodiments, one instance of R A ′ is Cl, another instance of R A ′ is —CF 3 ; and k′ is 2.

In compounds of Fomiula (II) or (V), linker X′, Y′, and Z′ are divalent linker moieties. In certain embodiments, X′ is a bond. In certain embodiments, X′ is a single bond. In certain embodiments, X′ is —CH 2 . In certain embodiments, X′ is —CHR A ′. In certain embodiments, X′ is —CH. In certain embodiments, X′ is —C(R A ′) 2 . In certain embodiments, X′ is —C. In certain embodiments, X′ is —N. In certain embodiments, X′is —NR A ′. In certain embodiments, X′ is —O. In certain embodiments, X′ is —C═O. In certain embodiments, X′ is —O. In certain embodiments, X′ is —S. In certain embodiments, X′ may optionally form a 5 to 8 membered ring with R A ′ or R B ′. In certain embodiments, Y′ is a bond. In certain embodiments, Y′ is a single bond. In certain embodiments, Y′ is —CH 2 . In certain embodiments, Y′ is —CHR A ′. In certain embodiments, Y′ is —CH. In certain embodiments, Y′ is —C(R A ′) 2 . In certain embodiments, Y′ is —C. In certain embodiments, Y′ is —N. In certain embodiments, Y′ is —NR A ′. In certain embodiments, Y′ is —O. In certain embodiments, Y′ is —C═O. In certain embodiments, Y′ is —S. In certain embodiments, Y′ may optionally form a 5 to 8 membered ring with R A ′ or R B ′. In certain embodiments, Z′ is a bond. In certain embodiments, Z′ is a single bond. In certain embodiments, Z′ is —CH 2 . In certain embodiments, Z′ is —CHR A ′. In certain embodiments, Z′ is —CH. In certain embodiments, Z′ is —C(R A ′) 2 . In certain embodiments, Z′ is —C. In certain embodiments, Z′ is —N. In certain embodiments, Z′ is —NR A ′. In certain embodiments, Z′ is —O. In certain embodiments, Z′ is —C═O. In certain embodiments, Z′ is —S. In certain embodiments, Z′ may optionally form a 5 to 8 membered ring with R A ′ or R B ′.

In compounds of Formula (II) or (V), linker X′, Y′, and Z′ can be taken together to represent specific linking groups. In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent

In certain embodiments, X′, Y′, and Z′ together represent a single bond.

In compounds of Formula (II) and (V), linker Q′ and U′ are divalent linker moieties. In certain embodiments, Q′ is —NR A ′. In certain embodiments, Q′ is —NH. In certain embodiments, Q′ is —C═O. In certain embodiments, Q′ —NR A ′CO. In certain embodiments, Q′ is a bond. In certain embodiments, X′ may optionally form a 5 to 8 membered ring with R A ′ or R B ′. In certain embodiments, U′ is —NR A ′. In certain embodiments, U′ is —NH. In certain embodiments, U′ is —C═O. In certain embodiments, U′ is —NR A ′CO. In certain embodiments, U′ is a bond. In certain embodiments, U′ may optionally form a 5 to 8 membered ring with R A ′ or R B .

In copounds of Formula (II) or (V), linker Q′ and U′ can be taken together to represent specific linking groups. In certain embodiments, Q′ and U′ together represent

In certain embodiments, Q′ and U′ together represent

In certain embodiments, Q′ and U′ together represent

In certain embodiments, Q′ and U′ together represent

In certain embodiments, Q′ and U′ together represent

In certain embodiments, Q′ and U′ together represent

In certain embodiments, Q′ and U′ together represent

In certain embodiments, Q′ and U′ together represent

In certain embodiments, Q′ and U′ together represent

In certain embodiments, Q′ and U′ together represent

In certain embodiments, Q′ and U′ together represent

In certain embodiments, Q′ and U′ together represent

Cy of Formula (II) or (V) may be an optionally substituted aryl ring. In certain embodiments, Ring Cy is a substituted aryl ring. In certain embodiments, Cy is an unsubstituted aryl ring. In certain embodiments, Cy is a monocyclic aryl ring. In certain embodiments, Cy is substituted phenyl. In certain embodiments, Cy is unsubstituted phenyl. In certain embodiments, Cy is a bicyclic aryl ring. In certain embodiments, Cy is substituted naphthyl. In certain embodiments, Cy is unsubstituted naphthyl. In certain embodiments, Cy is an optionally substituted aryl ring fused with one or more optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl groups wherein the point of attachment is on the aryl ring.

Cy of Formula (II) or (V) may also be an optionally substituted heteroaryl ring. In certain embodiments, Cy is a substituted heteroaryl ring. In certain embodiments, Cy is an unsubstituted heteroaryl ring. In certain embodiments, Cy is a monocyclic heteroaryl ring. In certain embodiments, Cy is a 5-membered monocyclic heteroaryl ring. In certain embodiments, Cy is a 5-membered monocyclic heteroaryl ring with one heteroatom selected from the group consisting of S, N, and O. In certain embodiments, Cy is a 5-membered monocyclic heteroaryl ring with two heteroatoms selected from the group consisting of S, N, and O. In certain embodiments, Cy is a 5-membered monocyclic heteroaryl ring with three heteroatoms selected from the group consisting of S, N, and O. In certain embodiments, Cy is substituted pyrrolyl. In certain embodiments, Cy is unsubstituted pyrrolyl. In certain embodiments, Cy is substituted furanyl. In certain embodiments, Cy is unsubstituted furanyl. In certain embodiments, Cy is substituted thienyl. In certain embodiments, Cy is unsubstituted thienyl. In certain embodiments, Cy is substituted pyrazolyl. In certain embodiments, Cy is unsubstituted pyrazolyl. In certain embodiments, Cy is substituted imidazolyl. In certain embodiments, Cy is unsubstituted imidazolyl. In certain embodiments, Cy is substituted oxazolyl. In certain embodiments, Cy is unsubstituted oxazolyl. In certain embodiments, Cy is substituted isoxazolyl. In certain embodiments, Cy is unsubstituted isoxazolyl. In certain embodiments, Cy is substituted thiazolyl. In certain embodiments, Cy is unsubstituted thiazoIyl. In certain embodiments, Cy is substituted isothiazolyl. In certain embodiments, Cy is unsubstituted isothiazolyl. In certain embodiments, Cy is substituted triazolyl. In certain embodiments, Cy is unsubstituted triazolyl. In certain embodiments, Cy is substituted oxadiazolyl. In certain embodiments, Cy is unsubstituted oxadiazolyl. In certain embodiments, Cy is substituted thiadiazolyl. In certain embodiments, Cy is unsubstituted thiadiazolyl. In certain embodiments, Cy is a 6-membered monocyclic heteroaryl ring. In certain embodiments, Cy is a 6-membered monocyclic heteroaryl ring with one heteroatom selected from the group consisting of S, N, and O. In certain embodiments, Cy is a 6-membered monocyclic heteroaryl ring with two heteroatoms selected from the group consisting of S, N, and O. In certain embodiments, Cy is a 6-membered monocyclic heteroaryl ring with three heteroatoms selected from the group consisting of S, N, and O. In certain embodiments, Cy is substituted pyridyl. In certain embodiments, Cy is unsubstituted pyridyl. In certain embodiments, Cy is substituted pyridazinyl. In certain embodiments, Cy is unsubstituted pyridazinyl. In certain embodiments, Cy is substituted pyrimidinyl. In certain embodiments, Cy is unsubstituted pyrimidinyl. In certain embodiments, Cy is substituted pyrazinyl. In certain embodiments, Cy is unsubstituted pyrazinyl. In certain embodiments, Cy is substituted triazinyl. In certain embodiments, Cy is unsubstituted triazinyl. In certain embodiments, Cy is an optionally substituted heteroaryl ring fused with one or more optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl groups wherein the point of attachment is on any one of the heteroaryl ring, or carbocyclic, heterocyclic, aryl, or heteroaryl groups, as valency permits. In certain embodiments, Cy is a bicyclic heteroaryl ring. In certain embodiments, Cy is an optionally substituted heteroaryl ring fused with an optionally substituted phenyl ring. In certain embodiments, Cy is substituted indolyl. In certain embodiments, Cy is unsubstituted indolyl. In certain embodiments, Cy is substituted isoindolyl. In certain embodiments, Cy is unsubstituted isoindolyl. In certain embodiments, Cy is substituted indazolyl. In certain embodiments, Cy is unsubstituted indazolyl. In certain embodiments, Cy is substituted benzothienyl. In certain embodiments, Cy is unsubstituted benzothienyl. In certain embodiments, Cy is substituted isobenzothienyl. In certain embodiments, Cy is unsubstituted isobenzothienyl. In certain embodiments, Cy is substituted benzofuranyl. In certain embodiments, Cy is unsubstituted benzofuranyl. In certain embodiments, Cy is substituted benzoisofuranyl. In certain embodiments, Cy is unsubstituted benzoisofuranyl. In certain embodiments, Cy is substituted benzimidazolyl. In certain embodiments, Cy is unsubstituted benzimidazolyl. In certain embodiments, Cy is substituted benzoxazolyl. In certain embodiments, Cy is unsubstituted benzoxazolyl. In certain embodiments, Cy is substituted benzisoxazolyl. In certain embodiments, Cy is unsubstituted benzisoxazolyl. In certain embodiments, Cy is substituted benzothiazolyl. In certain embodiments, Cy is unsubstituted benzothiazolyl. In certain embodiments, Cy is substituted benzisothiazolyl. In certain embodiments, Cy is unsubstituted benzisothiazolyl. In certain embodiments, Cy is substituted benzotriazolyl. In certain embodiments, Cy is unsubstituted benzotriazolyl. In certain embodiments, Cy is substituted benzoxadiazolyl. In certain embodiments, Cy is unsubstituted benzoxadiazolyl. In certain embodiments, Cy is substituted quinolinyl. In certain embodiments, Cy is unsubstituted quinolinyl. In certain embodiments, Cy is substituted isoquinolinyl. In certain embodiments, Cy is unsubstituted isoquinolinyl. In certain embodiments, Cy is substituted cinnolinyl. In certain embodiments, Cy is unsubstituted cinnolinyl. In certain embodiments, Cy is substituted quinoxalinyl. In certain embodiments, Cy is unsubstituted quinoxalinyl. In certain embodiments, Cy is substituted phthalazinyl. In certain embodiments, Cy is unsubstituted phthalazinyl. In certain embodiments, Cy is substituted quinazolinyl. In certain embodiments, Cy is unsubstituted quinazolinyl. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position. In certain embodiments, Cy is

wherein X′ may link to any freely valent position.

In compounds of Formula (II) or (V), Cy may be substituted with one or more R X ′ groups. In certain embodiments, at least one R X ′ is H. In certain embodiments, at least two R X ′ groups are H. In certain embodiments, at least three R X ′ groups are H. In certain embodiments, at least four R X ′ groups are H. In certain embodiments, at least one R X ′ is halogen. In certain embodiments, at least one R X ′ is F. In certain embodiments, at least one R X ′ is Cl. In certain embodiments, at least one R X ′ is Br. In certain embodiments, at least one R X ′ is I (iodine). In certain embodiments, at least one R X ′ is substituted acyl. In certain embodiments, at least one R X ′ is —C(═O)N(R A1 ′) 2 . In certain embodiments, at least one R X ′ is —C(═O)NHR A1 ′. In certain embodiments, at least one R X ′ is —C(═O)NH(C 1-6 alkyl). In certain embodiments, at least one R X ′ is —C(═O)NHMe. In certain embodiments, at least one R X ′ is —C(═O)NH 2 . In certain embodiments, at least one R X ′ is unsubstituted acyl. In certain embodiments, at least one R X ′ is acetyl. In certain embodiments, at least one R X ′ is substituted alkyl. In certain embodiments, at least one R X ′ is substituted methyl. In certain embodiments, at least one R X ′ is unsubstituted alkyl. In certain embodiments, at least one R X ′ is C 1-6 alkyl. In certain embodiments, at least one R X ′ is methyl. In certain embodiments, at least one R X ′ is ethyl. In certain embodiments, at least one R X ′ is propyl. In certain embodiments, at least one R X ′ is butyl. In certain embodiments, at least one R X ′ is substituted alkenyl. In certain embodiments, at least one R X ′ is unsubstituted alkenyl. In certain embodiments, at least one R X ′ is substituted alkynyl. In certain embodiments, at least one R X ′ is unsubstituted alkynyl. In certain embodiments, at least one R X ′ is substituted carbocyclyl. In certain embodiments, at least one R X ′ is unsubstituted carbocyclyl. In certain embodiments, at least one R X ′ is substituted heterocyclyl. In certain embodiments, at least one R X ′ is unsubstituted heterocyclyl. In certain embodiments, at least one R X ′ is substituted aryl. In certain embodiments, at least one R X ′ is unsubstituted aryl. In certain embodiments, at least one R X ′ is substituted phenyl. In certain embodiments, at least one R X ′ is unsubstituted phenyl. In certain embodiments, at least one R X ′ is substituted heteroaryl. In certain embodiments, at least one R X ′ is unsubstituted heteroaryl. In certain embodiments, at least one R X ′ is substituted pyridyl. In certain embodiments, at least one R X ′ is unsubstituted pyridyl. In certain embodiments, at least one R X ′ is —OR A1 ′. In certain embodiments, at least one R X ′ is —O(C 1-6 alkyl). In certain embodiments, at least one R X ′ is —OMe. In certain embodiments, at least one R X ′ is —OH. In certain embodiments, at least one R X ′ is —N(R A1 ′) 2 . In certain embodiments, at least one R X ′ is —NH 2 . In certain embodiments, at least one R X ′ is —SR A1 ′. In certain embodiments, at least one R X ′ is —SH. In certain embodiments, at least one R X ′ is —NR A1 ′C(═O)N(R A1 ′) 2 . In certain embodiments, at least one R X ′ is —NHC(═O)N(R A1 ′) 2 . In certain embodiments, at least one R X′ is —NHC(═O)NHR A1′ . In certain embodiments, at least one R X ′ is —NHC(═O)NH(C 1-6 alkyl). In certain embodiments, at least one R X ′ is —NHC(═O)NHMe. In certain embodiments, at least one R X ′ is —NHC(═O)NH 2 . In certain embodiments, at least one R X ′ is —NR A1 ′C(═O)NHR A1 ′. In certain embodiments, at least one R X ′ is —NR A1 ′C(═O)NH 2 . In certain embodiments, at least one R X ′ is —NR A1 ′S(═O) 2 R A1 ′. In certain embodiments, at least one R X ′ is —NHS(═O) 2 R A1 ′. In certain embodiments, at least one R X ′ is —NHS(═O) 2 (C 1-6 alkyl). In certain embodiments, at least one R X ′ is —NHS(═O) 2 Me. In certain embodiments, at least one R X ′ is —S(═O) 2 N(R A1 ′) 2 . In certain embodiments, at least one R X ′ is —S(═O) 2 N(R A1 ′) 2 . In certain embodiments, at least one R X ′ is —S(═O) 2 N(C 1-6 alkyl) 2 . In certain embodiments, at least one R X ′ is —S(═O) 2 NH(C 1-6 alkyl). In certain embodiments, at least one R X ′ is —S(═O) 2 NH(t-Bu). In certain embodiments, at least one R X ′ is —S(═O) 2 NH 2 . In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiments, at least one R X ′ is

In certain embodiment, a compound of the invention is a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiment, a compound of the invention is a compound of Formula (A), or a pharmaceutically acceptable salt thereof. In certain embodiment, a compound of the invention is a compound of Formula (I-11), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiment, a compound of the invention is a compound of Formula (I-11), or a pharmaceutically acceptable salt thereof. In certain embodiment, a compound of the invention is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer. isotopically labeled derivative, or prodrug thereof. In certain embodiment, a compound of the invention is a compound of Formula (II), or a pharmaceutically acceptable salt thereof. In certain embodiment, a compound of the invention is a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiment, a compound of the invention is a compound of Formula (V), or a pharmaceutically acceptable salt thereof.

In certain embodiments, compounds of the present invention include those which:

•

• exhibit kinase inhibitory activity, • exhibit the ability to inhibit transforming growth factor b-activated kinase-1 (TAK1), hemopoietic cell kinase (HCK) or both TAK1 and HCK, • exhibit the ability to inhibit hematopoietic progenitor kinase 1 (HPK1, also known as mitogen-activated protein kinase kinase kinase kinase 1 or MAP4K1), • exhibit the ability to inhibit Bruton's tyrosine kinase (BTK), v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (SRC) family of kinases or both BTK and SRC, • exhibit cytotoxic or growth inhibitory effect on WM cell lines maintained in vitro or in animal studies using a scientifically acceptable cancer cell xenograft model; and/or • exhibit a therapeutic profile (e.g., optimum safety and curative effect) that is superior to existing chemotherapeutic agents.

As used herein “kinase” refers to a large class of enzymes which catalyze the transfer of the γ-phosphate from ATP to the hydroxyl group on the side chain of Ser/Thr or Tyr in proteins and peptides and are intimately involved in the control of various important cell functions, perhaps most notably: signal transduction, differentiation and proliferation. There are estimated to be about 2,000 distinct protein kinases in the human body and although each of these phosphorylates particular protein/peptide substrates, they all bind the same second substrate ATP in a highly conserved pocket. About 50% of the known oncogene products are protein tyrosine kinases PTKs and their kinase activity has been shown to lead to cell transformation.

In certain embodiments, the kinase to be inhibited is involved in the myeloid differentiation primary response gene (88) (MYD88) signaling pathway. For example, the kinase is Transforming growth factor b-activated kinase-1 (TAK1) or Hemopoietic cell kinase (HCK). In certain embodiments, the compound of the invention inhibits TAK1, HCK, or both TAK1 and HCK.

Myeloid differentiation primary response gene (88) (MYD88) L265P is a widely expressed somatic mutation in WM patients that supports NF-NFκB signaling through stimulation of BTK, IRAK1/4, TAK1. MYD88 is an adaptor molecule for Toll-like receptors (TLR) with the exception of TLR-3 and interleukin-1 receptor (IL-1R) signaling. Following TLR or IL-1R stimulation, MYD88 is recruited to the activated receptor complex as a homodimer which then complexes with interleukin-1 receptor-associated kinase 4 (IRAK4) and activates IRAK1 and IRAK2. Tumor necrosis factor receptor associated factor 6 (TRAF6) is then activated by IRAK1 leading to NFκB activation via IκBα phosphorylation and TAK1 activation.

Transforming growth factor b-activated kinase-1 (TAK1; also known as MAP3K7) is a member of the serine/threonine protein kinase family. This kinase mediates the signaling transduction induced by TGF beta and morphogenetic protein (BMP), and controls a variety of cell functions including transcription regulation and apoptosis. TAK1 knockout is embryonic lethal to mice. Conditional knockdown of TAK1 in adult mice results in systemic inflammation, spenomegaly, degeneration in heart, kidneys and liver and increased proliferation and differentiation of myeloid progenitor cells. TAK1 is located downstream of Myd88, Bruton's tyrosine kinase (BTK), and interleukin-1 receptor-associated kinase (IRAK), and is being investigated for its role in innate immunity, inflammatory response, and Ras-dependent cancers.

Hemopoietic cell kinase (HCK) is a non-receptor tyrosine-protein kinase found in hematopoietic cells and is known to interact with Bruton's tyrosine kinase (BTK) upon activation by B cell receptors (Proc. Natl. Acad. Sci. USA. 1994, 91(17), 8152-55). HCK transmits signals from cell surface receptors and plays an important role in the regulation of innate immune responses, including neutrophil, monocyte, macrophage and mast cell functions, phagocytesis, cell survival and proliferation, cell adhesion and migration. It acts downstream of receptors that bind the Fc region of immunoglobulins, such as FCGR1A and FCGR2A, but also CSF3R, PLAUR, the receptors for IFNG, IL2, IL6 and IL8, and integrins, such as ITGB1 and ITGB2. During the phagocytic process, it mediates mobilization of secretory lysosomes, degranulation, and activation of NADPH oxidase to bring about the respiratory burst. It also plays a role in the release of inflammatory molecules, promotes reorganization of the actin cytoskeleton and actin polymerization, and formation of podosomes and cell protrusions.

Hematopoietic progenitor kinase 1 (HPK1) is a hematopoietic cell-restricted member of the Ste20 serine/threonine kinase super family. HPK1 is also known as mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1). HPK1 is a tissue-specific upstream activator of the MEKK/JNK/SAPK signaling pathway. HPK1 diminishes T cell receptor (TCR) signaling activity and T cell proliferation by phosphorylating the adaptor protein SLP-76. Cytosolic HPK1 is recruited to the TCR complex, and its kinase activity is induced upon the engagement of the TCR. Overexpression of HPK1 suppresses TCR-induced activation of AP-1-dependent gene transcription in a kinase-dependent manner, suggesting that the kinase activity of HPK1 is required to inhibit the Erk MAPK pathway. This blockage of the Erk MAPK pathway is thought to be the inhibitory mechanism that negatively regulates TCR-induced IL-2 gene transcription (Immunol. Res. 2012, 54(1-3), 262-65). In certain embodiments, the compounds of the invention, such as the compounds of Formula (A), (I-11), (II), or (V) (e.g., compounds of Formula (A-1)-(A-18)), inhibit HPK1.

In certain embodiments, the compounds of the invention are selective inhibitors of TAK1, HCK, or HPK1. The term “selective inhibitor” as used herein is understood to mean that in contrast to many kinase inhibitors of the prior art, the compounds do not act on a variety of kinases but act specifically on TAK1, HCK, or HPK1. In certain embodiments, the compounds of the invention inhibit one or more kinases in addition to TAK1, HCK, or HPK1 such as BTK or the SRC family of kinases. In certain embodiments of the invention, the specificity of the inhibitors is given by the IC 50 value. In some embodiments, the IC 50 value for a selective inhibitor is <100 μM for TAK1, HCK, or HPK1, but >100 μM for other kinases.

The IC 50 value is defined as the concentration of inhibitor required to inhibit 50% of the kinase activity. In certain embodiments, the compounds of the invention may exhibit IC 50 values<100 μM. In certain other embodiments, the compounds exhibit IC 50 values<50 μM. In certain other embodiments, the compounds exhibit IC 50 values<40 μM. In certain other embodiments, the compounds exhibit IC 50 values<30 μM. In certain other embodiments, the compounds exhibit IC 50 values<20 μM. In certain other embodiments, the compounds exhibit IC 50 values<10 μM. In certain other embodiments, the compounds exhibit IC 50 values<7.5 μM. In certain embodiments, the compounds exhibit IC 50 values<5 μM. In certain other embodiments, the compounds exhibit IC 50 values<2.5 μM. In certain embodiments, the compounds exhibit IC 50 values<1 μM. In certain embodiments, the compounds exhibit IC 50 values<0.75 μM. In certain embodiments, the compounds exhibit IC 50 values<0.5 μM. In certain embodiments, the compounds exhibit IC 50 values<0.25 μM. In certain embodiments, the compounds exhibit IC 50 values<0.1 μM. In certain other embodiments, the compounds exhibit IC 50 values<75 nM. In certain other embodiments, the compounds exhibit IC 50 values<50 nM. In certain other embodiments, the compounds exhibit IC 50 values<25 nM. In certain other embodiments, the compounds exhibit IC 50 values<10 nM. In other embodiments, the compounds exhibit IC 50 values<7.5 nM. In other embodiments, the compounds exhibit IC 50 values<5 nM.

In certain embodiments, the compounds of the invention (e.g., the compounds of Formula (A), (I-11), (II), or (V)) inhibit HCK selectively. In certain embodiments, the compounds of the invention (e.g., the compounds of Formula (A), (I-11), (II), or (V)) inhibit TAK1 selectively. A non-limiting example of a selective TAK1 inhibitor is:

In certain embodiments, the compounds of the invention (e.g., the compounds of Formula (A), (I-11), (II), or (V)) inhibit both TAK1 and HCK. A non-limiting example of a dual TAK1/HCK inhibitor is:

In certain embodiments, the compounds of the invention (e.g., the compounds of Formula (A), (I-11), (II), or (V)) inhibit HPK1 selectively. A non-limiting example of a selective HPK1 inhibitor is:

Also, provided are methods to treat 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 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.

Bruton's tyrosine kinase (BTK) is a key signaling enzyme expressed in all hematopoietic cells types except T lymphocytes and natural killer cells. BTK plays an essential role in the B cell signaling pathway linking cell surface B cell receptor BCR stimulation to downstream intracellular responses. BTK is a key regulator of B cell development activation signaling and survival (Kurosaki, Curr. Op. Imm, 2000, 276-281; Schaeffer and Schwartzberg, Curr. Op. Imm., 2000, 282-288). In addition BTK plays a role in a number of other hematopoietic cell signaling pathways, e.g., Toll like receptor (TLR) and cytokine receptor-mediated TNF-α production in macrophages, IgE receptor (FcepsilonRI) signaling in mast cells, inhibition of Fas/APO-1 apoptotic signaling in B-lineage lymphoid cells, and collagen stimulated platelet aggregation. See e.g., C. A. Jeffries, et al., J. Biol. Chem., 2003, 278, 26258-26264: N. J. Horwood, et al., J. Exp. Med., 2003, 197, 1603-1611; Iwaki et al., J. Biol. Chem., 2005, 280(48), 40261-40270; Vassilev et al., J. Biol. Chem., 1999, 274(3), 1646-1656; and Quek et al., Curr. Biol., 1998, 8(20), 1137-1140. Activated Btk interacts with MyD88 and TRIF, promoting the activation of MyD88-dependent and TRIF-dependent pathways (Nature Immunology, 2011, 12, 416-424).

BTK inhibitors are well-known in the art, and include, for example, ibrutinib and benzonaphthyridinones (see U.S. provisional patent application U.S. Ser. No. 61/716,273, filed Oct. 19, 2012), Additional non-limiting examples of BTK inhibitors are disclosed in WO 1999/054286, WO 2013/010380, WO 2009/137596, WO 2011/029043, WO 2010/056875, WO 2000/056737, and WO 2013/067277.

IRAK1 and 4 are serine/threonine-protein kinases that play a critical role in initiating innate immune response against foreign pathogens. They are involved in Toll-like receptor (TLR) and IL-1R signaling pathways, and are rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent auto-phosphorylation and kinase activation of IRAK1 (Immunity, 1997, 7(6), 837-47). IRAK4−/− mice have abolished cellular responses to various IL-1 and TLR ligands and are severely impaired in their response to viral and bacterial challenges. IRAK1−/− mice show a similar but partial response.

IRAK1 and lRAK4 inhibitors are well-known in the art, and include, for example, those disclosed in WO 2003/030902, WO 2012/007375, G. M. Buckely et al., Biorg. Med. Chem. Lett. 2008, 18, 3211-3214, and G. M. Buckely et al., Biorg. Med. Chem. Lett. 2008, 18, 3656-3660, WO2013/074986, and U.S. provisional patent application, U.S. Ser. No. 61/727,640, filed Nov. 16, 2012.

In certain embodiments, the IRAK4 inhibitor is of formula:

or an analog thereof.

“Bone Marrow on X chromosome” kinase (BMX, also termed ETK) is a non-receptor tyrosine kinase and is activated downstream of phosphatidylinositol-3 kinase (PI-3K) and v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (SRC), but its substrates are unknown. Positional scanning peptide library screening revealed a marked preference for a priming phosphotyrosine (pY) in the −1 position. Potential substrates include multiple tyrosine kinases with kinase domain pYpY sites required for full activity. BMX has been found to phosphorylate residue Y577 of focal adhesion kinase (FAK) subsequent to Y576 phosphorylation by SRC. In addition, BMX loss by RNA interference and mouse embryonic fibroblasts (MEFs) from Bmx negative (Bmx − ) mice displayed impaired FAK signaling. Insulin receptor (IR) phosphorylation similarly was decreased by BMX loss, as was hepatic IR phosphorylation in Bmx − mice. However, glucose tolerance was increased, reflecting a marked compensatory decrease in the activity of the AKT phosphatase PHLPP. These findings reveal a mechanism through which BMX functions as a central regulator of multiple kinase pathways.

BMX inhibitors are well-known in the art, and include, for example, those disclosed in U.S. Ser. No. 61/716,273 and 61/717,345, the contents of both of which are incorporated herein by reference. In certain embodiments, the BMX inhibitor is of formula:

or an analog thereof.

Phosphatidylinositol 3-kinases (PI3-kinases or PI3Ks) are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. PI3Ks are a family of related intracellular signal transducer enzymes capable of phosphorylating the 3 position hydroxyl group of the inositol ring of phosphatidylinositol (Ptdlns). Phosphatidylinositol 3-kinase is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by PI3KCA gene represents the catalytic subunit, which uses ATP to phosphorylate phosphatidylinositols (Ptdlns), Ptdlns4P and Ptdlns(4,5)P2. Of particular interest is the PI3K delta isoform, which is expressed in white blood cells and is mainly involved in the signaling, development, and survival of B cells.

PI3K inhibitors are well-known in the art, and include, for example, those disclosed in International PCT Publications WO 2013/088404, WO 2012/068096, and WO 2013/052699, which are incorporated herein by reference.

In certain embodiments, the PI3K inhibitor is

or its analogs.

Compounds of the invention may be combined with other kinase inhibitors to treat WM or other B cell neoplasms. In certain embodiments, a compound of the invention is administered with an inhibitor of Bruton's tyrosine kinase (BTK) to treat WM or other B cell neoplasm. In certain embodiments, a compound of the invention is administered with an inhibitor of interleukin-1 receptor-associated kinase 1 (IRAK1) to treat WM or otherB cell neoplasm. In certain embodiments, a compound of the invention is administered with an inhibitor of phosphoinositide 3-kinase (PI3K) to treat WM or other B cell neoplasm. In certain embodiments, a compound of of the invention is administered with an inhibitor of the phosphoinositide 3-kinase delta isoform (PI3Kδ) to treat WM or other B cell neoplasm. In certain embodiments, a compound of of the invention is administered with two of any inhibitors of BTK, IRAK1, or PI3K to treat WM or other B cell neoplasm. In certain embodiments, a compound of the invention is administered with more than two of any inhibitors of BTK, IRAK1, or PI3K to treat WM or other B cell neoplasm.

The BTK inhibitors, the IRAK1 inhibitors, the IRAK4 inhibitors, and/or the PI3K inhibitors can be administered to the subject simultaneously or sequentially.

A “subject” or “patient” to which administration is contemplated includes, any animal. In some embodiments, a subject includes but is not limited to, humans, commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs), birds (e.g., commercially relevant birds such as chickens, ducks, geese, and/or turkeys) and experimental animals (e.g., mice, rats, non-human primates). A subject in need of treatment is a subject identified as having a B cell neoplasm, i.e,. the subject has been diagnosed by a physician (e.g., using methods well known in the art) as having a B cell neoplasm. In certain embodiments, the subject in need of treatment is a subject suspected of having or developing a B cell neoplasm, such as a subject presenting one or more symptoms indicative of a B cell neoplasm. The term “subject in need of treatment” further includes people who once had a B cell neoplasm but whose signs and/or symptoms have been ameliorated (i.e., their cancer is in remission). The one or more symptoms or clinical features of B cell neoplasms include, but are not limited to, asymptomatic localized or generalized peripheral lymphadenopathy, plasmacytic difference, bone marrow involvement, autoimmune thrombocytopenia, peripheral blood villous lymphocytes, end organ damage (hypercalcemia, renal insufficiency, bone lesions), recurrent infections, elevated creatine, hyperuricemia, and hypoalbunemia.

In certain embodiments, the subject is diagnosed as having Waldenström's macroglobulinemia (WM). The subject may present one or more signs, symptoms, or clinical features of WM including anemia, hyper-viscosity, neuropathy, coagulopathies, splenomegaly, hepatomegaly, adenopathy, and an IgM serum paraprotein, In certain embodiments, the subject is diagnosed as having WM on the basis that the subject has a mutation at position 38182641 of chromosome 3p22.2. In some embodiments, the mutation results in a single nucleotide change from T to C in the MYD88 gene. In some embodiments, the mutation results in an amino acid change from leucine to proline at position 265 in the MYD88 gene. The mutation may be detected in a biological sample obtained from the subject using any suitable method known in the art, including but not limited to, direct sequencing of nucleic acid molecules, HPLC analysis, DNA chip technologies, and mass spectroscopy. Non-limiting examples of the biological sample include bone marrow, lymph node, spleen, or blood.

The terms “administer,” “administering,” or “administration,” as used he rein refers to implanting, absorbing, ingesting, injecting, or inhaling an inventive compound, or a pharmaceutical composition thereof.

As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a B cell neoplasm. In certain embodiments, treatment may be administered after one or more signs or symptoms have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the B cell neoplasm. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.

An “effective amount” of compounds of the invention refers to an amount sufficient to elicit the desired biological response, i.e., treating the B cell neoplasm. As will be appreciated by those of ordinary skill in this art, the effective amount of compounds of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. An eifective amount includes, but is not limited to, that amount necessary to slow, reduce, inhibit, ameliorate or reverse one or more signs and/or symptoms associated with a B cell neoplasm. In the treatment of Waldenström's macroglobulinemia, this may refer to a reduction in the levels of IgM serum paraprotein, reduction in anemia, reduction in hyper-viscosity, reduction in neuropathy, reduction in coagulopathies, reduction in splenomegaly, reduction in hepatomegaly, and reduction in adenopathy.

An effective amount of a compound may vary from about 0.001 mg/kg to about 1000 mg/kg in one or more dose administrations, for one or several days (depending on the mode of administration). In certain embodiments, the effective amount varies from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kg to about 750 mg/kg, from about 0.1 mg/kg to about 500 mg/kg, from about 1.0 mg/kg to about 250 mg/kg, from about 1.0 mg/kg to about 100 mg/kg, and from about 10.0 mg/kg to about 150 mg/kg.

One or more additional pharmaceutical agents, such as anti-cancer agents (e.g., chemotherapeutics), anti-inflammatory agents, steroids, immunosuppressants, radiation therapy, or other agents, can be used in combination with the compounds of of the invention in the treatment of a B cell neoplasm. The one or more additional pharmaceutical agents can be administered to the subject simultaneously or sequentially.

Exemplary chemotherapeutic agents include alkylating agents such as nitrogen mustards, ethylenimines, methylmelamines, alkyl sulfonates, nitrosuoureas, and triazenes; antimetabolites such as folic acid analogs, pyrimidine analogs, in particular fluorouracil and cytosine arabinoside, and purine analogs; natural products such as vinca alkaloids epi-podophyllotoxins, antibiotics, enzymes, and biological response modifiers; and miscellaneous products such as platinum coordination complexes, anthracenedione, substituted urea such as hydroxyurea, methyl hydrazine derivatives, and adrenocorticoid suppressant.

Exemplary chemotherapeutic agents also include anthracycline antibiotic, actinomycin D, plicamycin, puromycin, gramicidin D, paclitaxel, colchicine, cytochalasin B, emetine, maytansine, amsacrine, cisplatin, carboplatin, mitomycin, altretamine, cyclophosphamide, lomustine, and carmustine.

In yet another aspect, the present invention provides pharmaceutical compositions comprising an effective amount of a compound of of the invention, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs, and optionally a pharmaceutically acceptable excipient, for use in the treatment of a B cell neoplasm. In certain embodiments, provided by the invention are the compounds of of the invention, and pharmaceutically acceptable salts and compositions thereof, for use in the treatment of a B cell neoplasm. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the therapeutically effective amount is an amount useful for the treatment and/or prevention of a B cell neoplasm. In certain embodiments, the B cell neoplasm is, but is not limited to, Hodgkin's lymphomas and most non-Hodgkins 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, Waldenström's macroglobulinemia, Nodal marginal zone B cell lymphoma (NMZL), Splenic marginal zone lymphoma (SMZL), Intravascular large B-cell lymphoma, Primary effusion lymphoma and Lymphomatoid granulomatosis. An etfective amount of a compound may vary from about 0.001 mg/kg to about 1000 mg/kg in one or more dose administrations, for one or several days (depending on the mode of administration). In certain embodiments, the effective amount varies from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kg to about 750 mg/kg, from about 0.1 mg/kg to about 500 mg/kg, from about 1.0 mg/kg to about 250 mg/kg, and from about 10.0 mg/kg to about 150 mg/kg.

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

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

The pharmaceutical preparations of the present invention may include or be diluted into a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” as used herein means one or more compatible fillers, diluents or other such substances, which are suitable for administration to a human or other mammal, such as a dog, cat, rat, mouse, or horse. The term “carrier” denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The carriers are capable of being commingled with the preparations of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy or stability. Carriers suitable for oral, subcutaneous, intravenous, intramuscular, etc. formulations can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa.

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

The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. The desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., two, thR ee , four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

In certain embodiments, the compound of the invention is administered at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

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

The present invention is further illustrated by the following Example, which in no way should be construed as further limiting. The entire contents of all of the references (including literature references, issued patents, published patent applications, and co pending patent applications) cited throughout this application are hereby expressly incorporated by reference.

EXAMPLES

In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope.

Example 1. Preparation of the Compounds

Preparation of I-11

4-methyl-3-((7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzoic acid

4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (284 mg, 1.0 mmol), 3-hydroxy-4-methylbenzoic acid (152 mg, 1.0 mmol) and K 2 CO 3 (414 mg, 3.0 mmol) were combined in DMSO (5 mL) and stirred overnight at 100° C. The reaction mixture was then cooled to room temperature. The mixture was acidified with 1N HCl solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na 2 SO 4 , filtered and concentrated. The crude product was purified by column chromatography to yield 296 mg of product as a colorless oil. Ms (ESI) m/z 400 (M+H) + .

3-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)-N-(3-(2-cyanopropan-2-yl)phenyl)-4-methylbenzamide (I-11)

To a solution of 4-methyl -3-((7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzoic acid (200 mg, 0.5 mmol), HATU (230 mg, 0.6 mmol), DMAP (73 mg, 0.6 mmol) and iPr 2 NEt (220 uL, 1.25 mmol) in CH 2 Cl 2 (3 mL) was added 2-(3-aminophenyl)-2-methyl-propanenitrile (80 mg, 0.5 mmol) and the resulting mixture was stirred at room temperature for 24 hours. The solution was filtered to remove solids, concentrated and purified with column chromatography (dichloromethane:methanol=10:1) to afford 455 mg of product as a colorless oil. To the solution of the obtained oil in CH 2 Cl 2 (5 mL) was added TFA (0.5 mL) and the resulting mixture was stirred at room temperature for 5 hours. The solution was concentrated and dried with vacuum, then dissolved in THF (4 mL) and 1 N NaOH solution (4 mL). The reaction mixture was stirred for 24 h and extracted with ethyl acetate. The combined organic phase was washed with brine and dried with Na 2 SO 4 , then filtered and concentrated, and purified by reverse phase HPLC to give 185 mg (90%) of title compound as a white solid.

Preparation of A-17

3-((6-chloropyrimidin-4-yl)oxy)-4-methylbenzoic acid

Sodium hydroxide (2 ml of 1N solution) was added to a solution of 4,6-dichloropyrimidine (150 mg, 1.0 mmol) and 3-hydroxy-4-methylbenzoic acid (152 mg, 1.0 mmol) in acetone (2 mL) and the reaction mixture as stirred at room temperature for 1 hour at which point LC-MS analysis indicated complete consumption of starting material. The reaction mixture was extracted with ethyl acetate. The combined organic phase was washed with brine and dried with Na 2 SO 4 , then filtered and concentrated, and purified by colunm chromatography to yield 250 mg of product as a white solid. MS (ESI) m/z 265 (M+H) + .

3-((6-chloropyrimidin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide

To a solution of 3-((6 -chloropyrimidin-4-yl)oxy)-4-methylbenzoic acid (210 mg, 0.8 mmol), HATU (365 mg 0.96 mmol), DMAP (117 mg, 0.96 mmol) and iPr 2 NEt (350 uL, 2.0 mmol) in CH 2 Cl 2 (4 mL) was added 4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (230 mg, 0.8 mmol) and the resulting mixture was stirred at room temperature for 24 hours The solution was filtered to remove solids, concentrated and purified column chromatography to yield 360 mg (84%) of product as a pale yellow oil. MS (ESI) m/z 534 (M+H) + .

3-((6-aminopyrimidin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide

10 mL of a 2N solution of NH 3 in i-PrOH was added to 3-((6-chloropyrimidin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide (270 mg, 0.5 mmol) and the reaction mixture was stirred for 48 hours at 75° C. then cooled to room temperature and concentrated. The crude product was purified by column chromatography to yield 120 mg of product as a colorless oil. MS (ESI) m/z 515 (M+H) + .

3-((6-acrylamidopyrimidin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide (A-17)

To a solution of 3-((6-aminopyrimidin-4-yl)oxy)-N-(4((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide (51 mg, 0.1 mmol) in DMF cooled in a dry ice/SOLVENT bath was added acryloyl chloride (8.9 uL, 0.11 mmol). The cooling bath was removed allowing the mixture to warm to room temperature and continue stirring for an half hour. The solution was then diluted in DMSO and purified by reverse phase HPLC to afford 45 mg (80%) of A-17 as a white solid.

Compounds (A-1)-(A-16) and (A-18) were prepared similarly to A-17.

Characterization data for all final compounds is in the table below.

ID # Structure Name 1 H NMR and or MS (m/z)

A-1 N-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl) phenyl)-4-methyl- 3-((6-(methylamino) pyrimidin-4-yl)oxy) benzamide 1 H NMR (400 MHz, DMSO) δ 10.39 (s, 1H), 8.11 (s, 1H), 9.00 (d, J = 8.4) Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.33 (bs, 1H), 3.60 (s, 2H), 3.38 (m, 2H), 2.97-2.79 (m, 6H), 2.71 (bs, 3H), 2.37-2.22 (m, 2H), 2.09 (s, 3H), 1.12 (t, J = 6.8 Hz, 3H). MS (ESI) m/z 529 (M + H) + .

A-2 N-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl) phenyl)-4-methyl- 3-((6-(propionamido- pyrimidin)-4-yl)oxy) benzamide 1 H NMR (600 MHz, TFA salt, DMSO) δ 10.89 (s, 1H), 10.42 (s, 1H), 9.36 (br, 1H), 8.42 (s, 1H), 8.13 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.71 (s, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.57 (s, 1H), 7.46 (d, J = 7.8 Hz, 1H), 3.61 (s, 2H), 3.38 (m, 2H), 3.07 (m, 2H), 2.92 (m, 2H), 2.85 (m, 2H), 2.37 (q, J = 7.2 Hz, 2H), 2.32 (m, 2H), 2.10 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H), 0.98 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 571 (M + H) + .

A-3 3-((6-(cyclopropane- carboxamido) pyrimidin-4-yl)oxy)- N-(4-((4-ethylpiperazin- 1-yl)methyl)-3- (trifluoromethyl) phenyl)-4-methyl- benzamide 1 H NMR (600 MHz, DMSO) δ 11.25 (s, 1H), 10.36 (s, 1H), 8.43 (s, 1H), 8.11 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.70 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 3.49 (s, 2H), 2.32 (m, 8H), 2.24 (m, 2H), 2.09 (s, 3H), 1.97 (m, 1H), 0.91 (t, J = 7.2 Hz, 3H), 0.79 (m, 4H). MS (ESI) m/z 583 (M + H) + .

A-4 3-((6-aminopyrimidin- 4-yl)oxy)-N-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl) phenyl)-4-methyl- benzamide 1 H NMR (600 MHz, TFA salt, DMSO) δ 8.06 (s, 1H), 8.03 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.63 (s, 1H), 7.43 (d, J = 7.2 Hz, 1H), 5.78 (s, 1H), 3.70 (s, 2H), 3.47 (m, 2H), 3.15 (q, J = 7.2 Hz, 2H), 3.01 (m, 4H), 2.42 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 515 (M + H) + .

A-5 N-(4-((4-ethylpiperazin- 1-yl)methyl)-3-(trifluoro- methyl)phenyl)-4- methyl-3-((6-((1- methyl-1H-pyrazol- 4-yl)amino)pyrimidin- 4-yl)oxy)benzamide 1 H NMR (600 MHz, DMSO) δ 10.36 (s, 1H), 9.37 (br, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 5.94 (s, 1H), 3.74 (s, 3H), 3.50 (s, 2H), 2.18-2.42 (m, 10H), 2.12 (s, 3H), 0.92 (m, 3H). MS (ESI) m/z 595 (M + H) + .

A-6 3-((6-((1H-pyrazol-5-yl) amino)pyrimidin-4-yl) oxy)-N-(4-((4-ethyl- piperazin-1-yl)methyl)- 3-(trifluoromethyl) phenyl)-4-methyl- benzamide 1 H NMR (600 MHz, TFA salt, DMSO) δ 10.45 (s, 1H), 9.92 (s, 1H), 9.33 (br, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.74 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.62 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 3.66 (s, 2H), 3.44 (m, 2H), 3.12 (m, 2H), 2.97 (m, 2H), 2.91 (m, 2H), 2.37 (m, 2H), 2.17 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 581 (M + H) + .

A-7 3-((6-((1H-pyrazol-4- yl)amino)pyrimidin-4- yl)oxy)-N-(4-((4- ethylpiperazin-1-yl) methyl)-3-(trifluoro- methyl)phenyl)-4- methylbenzamide 1 H NMR (600 MHz, DMSO) δ 12.63 (br, 1H), 10.44 (s, 1H), 9.42 (br, 1H), 8.26 (br, 1H), 8.19 (s, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.90 (br, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.76 (s, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.53 (br, 1H), 7.51 (d, J = 8.4 Hz, 1H), 6.00 (s, 1H), 3.60 (s, 2H), 2.25-2.86 (m, 10H), 2.19 (s, 3H), 1.05, (m, 3H). MS (ESI) m/z 581 (M + H) + .

A-8 N-(4-((4-ethylpiperazin- 1-yl)methyl)-3-(tri- fluoromethyl)phenyl)- 4-methyl-3-((6- (pyrimidin-5-ylamino) pyrimidin-4-yl)oxy) benzamide 1 H NMR (600 MHz, TFA salt, DMSO) δ 10.49 (s, 1H), 10.02 (s, 1H), 9.44 (br, 1H), 9.08 (s, 2H), 8.82 (s, 1H), 8.42 (s, 1H), 8.19 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.79 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 6.27 (s, 1H), 3.66 (s, 2H), 3.44 (m, 2H), 3.13 (m, 2H), 2.98 (m, 2H), 2.91 (m, 2H), 2.38 (m, 2H), 2.20 (s, 3H), 1.20 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 593 (M + H) + .

A-9 3-((6-(2-acetylhydra- zinyl)pyrimidin-4- yl)oxy)-N-(4-((4- ethylpiperazin-1-yl) methyl)-3-(trifluoro- methyl)phenyl)-4- methylbenzamide 1 H NMR (600 MHz, DMSO) δ 10.43 (s, 1H), 9.88 (s, 1H), 9.20 (s, 1H), 8.19 (s, 1H), 8.17 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.73 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 5.99 (s, 1H), 3.56 (s, 2H), 3.32 (m, 4H), 2.29-2.48 (m, 4H), 2.32 (q, J = 7.2 Hz, 2H), 2.17 (s, 3H), 1.92 (s, 3H), 0.97 (J = 7.2 Hz, 3H). MS (ESI) m/z 572 (M + H) + .

A-10 3-((6-(azetidin-3- ylamino)pyrimidin- 4-yl)oxy)-N-(4-((4- ethylpiperazin-1-yl) methyl)-3-(trifluoro- methyl)phenyl)-4- methylbenzamide 1 H NMR (600 MHz, TFA salt, DMSO) δ 10.56 (s, 1H), 10.05 (s, 1H), 9.47 (br, 1H), 8.76 (s, 1H), 8.20 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 7.77 (s, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 6.35 (s, 1H), 4.60 (m, 1H), 4.38 (m, 2H), 3.68 (s, 2H), 3.57 (m, 2H), 3.46 (m, 2H), 3.12 (m, 2H), 2.98 (m, 2H), 2.92 (m, 2H), 2.39 (m, 2H), 2.21 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 570 (M + H) + .

A-11 3-((6-(2,2-dimethyl- hydrazinyl)pyrimidin- 4-yl)oxy)-N-(4-((4- ethylpiperazin-1-yl) methyl)-3-(trifluoro- methyl)phenyl)-4- methylbenzamide 1 H NMR (600 MHz, TFA salt, DMSO) δ 10.58 (s, 1H), 9.48 (br, 1H), 8.95 (s, 1H), 8.20 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.79 (s, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 6.84 (br, 2H), 3.71 (s, 6H), 3.68 (s, 2H), 3.46 (m, 2H), 3.15 (m, 2H), 2.98 (m, 2H), 2.92 (m, 2H), 2.39 (m, 2H), 2.21 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 558 (M + H) + .

A-12 N-(4-((4-ethylpiperazin- 1-yl)methyl)-3-(tri- fluoromethyl)phenyl)- 4-methyl-3-((6-((1- methyl-1H-pyrazol- 3-yl)amino)pyrimidin- 4-yl)oxy)benzamide 1 H NMR (600 MHz, TFA salt, DMSO) δ 10.47 (s, 1H), 9.94 (s, 1H), 9.36 (br, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.76 (s, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.58 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 6.16 (br, 1H), 3.75 (s, 3H), 3.68 (s, 2H), 3.45 (m, 2H), 3.14 (m, 2H), 2.99 (m, 2H), 2.94 (m, 2H), 2.37 (m, 2H), 2.19 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 595 (M + H) + .

A-13 N-(4-((4-ethylpiperazin- 1-yl)methyl)-3-(tri- fluoromethyl)phenyl)- 4-methyl-3-((6- (oxetan-3-ylamino) pyrimidin-4-yl) oxy)benzamide 1 H NMR (600 MHz, TFA salt, DMSO) δ 10.46 (s, 1H), 9.32 (br, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 8.15 (br, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 6.6 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.72 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 5.88 (br, 1H), 4.15 (m, 2H), 3.70 (m, 2H), 3.68 (s, 2H), 3.46 (m, 2H), 3.14 (m, 2H), 2.99 (m, 2H), 2.93 (m, 2H), 2.38 (m, 2H), 2.17 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 571 (M + H) + .

A-14 N-(4-((4-ethylpiperazin- 1-yl)methyl)-3-(tri- fluoromethyl)phenyl)- 4-methyl-3-((2-((1- methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)oxy)benzamide 1 H NMR (600 MHz, DMSO) δ 10.45 (s, 1H), 9.60 (br, 1H), 8.33 (s, 1H), 8.17 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.98 (m, 1H), 7.88 (m, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.61 (m, 1H), 7.05 (m, 1H), 6.73 (m, 1H), 6.46 (m, 1H), 3.55 (s, 3H), 3.49 (br, 2H), 2.20-2.58 (m, 10H), 2.18 (s, 3H), 0.97 (t, J = 7.2 Hz, 3H), MS (ESI) m/z 595 (M + H) + .

A-15 N-(4-((4-ethylpiperazin- 1-yl)methyl)-3- (trifluoromethyl) phenyl)-3-((2-(isoxazol- 4-ylamino)pyrimidin- 4-yl)oxy)-4- methylbenzamide 1 H NMR (600 MHz, TFA salt, DMSO) δ 10.51 (s,1H), 9.90 (m, 1H), 9.31 (br, 1H), 8.44 (d, J = 5.4 Hz, 1H), 8.32 (m, 1H), 8.20 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.97 (m, 1H), 7.87 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 6.62 (s, 1H), 3.69 (s, 2H), 3.46 (m, 2H), 3.15 (m, 2H), 2.99 (m, 2H), 2.94 (m, 2H), 2.39 (m, 2H), 2.19 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 582 (M + H) + .

A-16 N-(4-((4-ethylpiperazin- 1-yl)methyl)-3- (trifluoromethyl) phenyl)-3-((6-(isoxazol- 4-ylamino)pyrimidin- 4-yl)oxy)-4- methylbenzamide MS (ESI) m/z 582 (M + H)+.

A-17 3-((6-acrylamido- pyrimidin-4-yl)oxy)- N-(4-((4-ethyl-piperazin- 1-yl)methyl)-3-(tri- fluoromethyl)phenyl)- 4-methylbenzamide 1 H NMR (600 MHz, DMSO) δ 11.16 (s, 1H), 10.37 (s, 1H), 8.46 (s, 1H), 8.11 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.73 (s, 1H), 7.68 (s, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 6.54 (dd, J = 16.8, 10.8 Hz, 1H), 6.30 (d, J = 16.8 Hz, 1H), 5.81 (d, J = 10.8 Hz, 1H), 3.49 (s, 2H), 2.32 (m, 8H), 2.23 (q, J = 7.2 Hz, 2H), 2.11 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 569 (M + H) + .

I-11 3-((7H-pyrrolo[2,3-d] pyrimidin-4-yl)oxy)-N- (3-(2-cyanopropan-2-yl) phenyl)-4-methyl- benzamide 1 H NMR (400 MHz, DMSO) δ 10.23 (s, 1H), 8.22 (s, 1H), 7.86 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0, 1H), 7.43 (d, J = 3.2 Hz, 1H), 7.33 (dd, J = 8.0, 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.48 (d, J = 3.2 Hz, 1H), 2.10 (s, 3H), 1.61 (s, 6H). MS (ESI) m/z 412 (M + H) + .

Example 2. Biological Assays of the Compounds

In Vitro Activity Assays

The in vitro activity of the compounds described herein in inhibiting TAK1, HCK and other kinases were obtained using an Invitrogen Select Screening assay as known in the art. The IC50 values determined from this assay are shown below.

Cell Proliferation Analysis

CellTiter-Glo® Luminescent cell viability assay (Pro-mega) was used to assess cell survival following treatment with the compounds described. Cells were seeded into 384 well plates with the EL406 Combination Washer Dispenser (BioTek Instruments, Inc.) and the compounds were injected into the cells culture media with the JANUS Automated Workstation (PerkinElmer Inc.). Cells were treated with a series diluted inhibitors (20-0.04 μM) for 72 hours at 37° C. Luminescent measurement is performed using the 2104 Envision® Multilabel Reader (PerkinElmer Inc.).

Apoptosis Analysis for Primary Patient Bone Marrow Tumor Cells

WM cells were treated with and without the compounds described herein. Cells were incubated at 37° C. with 0.01-4 uM of the compounds described herein. Apoptosis analysis was performed using Annexin V/Propidium iodide staining with the Apoptosis Detection Kit I (BD Pharmingen). 1×106/well cells were treated in 24 well plates for ˜24 hours with inhibitors or corresponding controls. A minimum of 10,000 events were acquired using a BD™ FACSCanto II flow cytometer and analyzed with BD FACS DIVA Software.

Results

A number ofcompounds described herein show inhibitory activity against TAK1, HCK, BTK and other kinases. Shown in Table 1 and 1a are exemplary in vitro IC 50 data of these compounds. Table 2 and 2a shows the in vitro EC 50 values of these compounds.

TABLE 1

HCK

Com- BTK IC 50 TAK1 GCK

pound IC 50 (nM) IC 50 IC 50

Structure ID (nM) Inv (nM) (nM)

(A-1) — 275 364 31

(A-17) 3380 28 45 17

(A-2) — 253 100 28

(A-3) — 185 92 —

(A-4) — 382 591 —

(I-11) — — — —

TABLE 1a

HCK

BTK IC 50 TAK1

Cpd. IC 50 (nM) IC 50

Structure ID (nM) Inv (nM)

(A-5) >10000 61.8 100

(A-6) — 38.4 63.5

(A-7) — 33.8 71.7

(A-8) — 889 487

(A-9) — >10000 7310

(A-10) — >10000 >10000

(A-18) — 6980 1750

(A-11) — >10000 >10000

(A-12) — 18 76.2

(A-13) — 392 400

(A-14) — 27.4 53.8

(A-15) — 116 136

(A-16) — — —

TABLE 2

BCWM.1 MWCL-1 RPCIWM-1 OCI-Ly3 Ramos OCI-Ly19 Mec1 EC 50

Cpd. ID EC 50 (nM) EC 50 (nM) EC 50 (nM) EC 50 (nM) EC 50 (nM) EC 50 (nM) (nM)

(A-1) 1720 3990 — 11500 9480 4980 —

(A-2) 42 1350 — 2960 5340 1750 —

(A-3) 50 910 — 480 2680 600 —

(A-4) 3010 1150 — 31900 21100 9430 14300

(A-17) 8 202 — 247 389 188 —

TABLE 2a

BCWM.1 MWCL-1 TMD8 OCI-Ly7 OCI-Ly3 Ramos OCI-Ly19

Cpd. ID EC 50 (nM) EC 50 (nM) EC 50 (nM) EC 50 (nM) EC 50 (nM) EC 50 (nM) EC 50 (nM)

(A-5) 51 73 132 655 4710 3000 173

72 242 6060 417

(A-6) 86 118 — — 4770 3080 302

(A-7) 48 71 — — 4000 3020 192

(A-8) 980 2660 — — >10000 6180 1700

(A-9) 10800 18700 — — 19600 >20000 >20000

6460 >20000 >20000

(A-10) 8250 24800 — — 8370 >20000 >20000

>20000 >20000 >20000

(A-11) 19700 >20000 — — >20000 >20000 >20000

(A-12) 38 75 — — 156 2960 209

71 71 472

(A-13) 361 1760 — — 1200 3260 2280

964 2860 1730

(A-14) 33 128 45 173 — 2090 179

(A-15) 185 718 392 786 — 4680 307

(A-16) 610 1710 856 1030 — 1310 777

(A-18) 1980 4090 — — 1860 7240 2780

3750 6740 5030

(I-11) 4950 1440 3460 1120 9690 3890 —

Kinome Scan

Compounds (A-2) and (A-17) were run in the Kinome Scan™ (DiscoverRx) assay to determine the inhibition against a broad panel of known kinases.

Results

Table 3 shows the KinomeScan (an active site-directed competition binding assay to measure interactions between test compounds and individual kinases) data of each compound, II-1 and I-13. Lower values indicate a greater inhibition for a given kinase by the test compound. As is shown, II-1 and I-13 inhibited several other kinases include LOK, DDR1, JNK2, ZAK, IKK-alpha, BLK, p38-alpha, ABL1, LYN, and STK36 along with the key target HCK.

TABLE 3

Kinases A-2 (1 μM) A-17 (1 μM)

TAOK1 0.45 0.05

LOK 0.05 0.1

TAOK3 0.45 0.1

DDR1 0.35 0.25

HCK 1.5 0.3

JNK2 0.15 0.3

ZAK 1.6 0.4

IKK-alpha 13 0.55

BLK 0.65 0.6

p38-alpha 0 0.75

ABL1-nonphosphorylated 1 0.8

LYN 3.6 0.8

STK36 1 0.9

LCK 1.6 1

FLT3 1.8 1.2

MKK7 11 1.2

MAP4K2 2.8 1.4

p38-beta 1.8 2.1

PDGFRB 5.1 2.5

CSF1R 3.2 2.6

RET(M918T) 7.4 2.8

ABL2 2.9 2.9

ABL1(E255K)-phosphorylated 3.3 3

CDC2L1 0.45 3.2

EPHA8 5.4 3.6

RET 9.9 3.6

CDC2L2 0.4 3.8

KIT(L576P) 2.2 3.9

CDK8 12 4

MAP4K4 6.4 4

KIT(V559D) 3.4 4.2

MINK 18 4.6

MAP3K3 21 4.8

TAOK2 0.15 4.8

JAK3(JH1domain-catalytic) 47 4.9

JNK1 6.8 5

KIT 5.6 5.1

FES 4.1 5.2

CDKL2 1.4 5.5

TIE1 5.5 5.5

ULK3 71 6

HPK1 30 6.2

CDK11 1.6 6.6

CDKL3 1.6 6.8

FGR 13 7.7

TNIK 20 9

CDC2L5 19 10

MST3 36 10

ABL1(M351T)-phosphorylated 6 11

DDR2 3 11

FGFR1 21 12

FLT3(N841I) 14 12

HIPK2 29 12

NLK 29 12

SRC 5.9 12

HIPK3 13 13

MAP4K5 29 14

p38-gamma 6.6 14

RSK2(Kin. Dom. 2-C-terminal) 97 15

KIT(A829P) 32 16

KIT(V559D, T670I) 11 16

OSR1 79 16

TNK1 33 16

EPHB2 69 17

YSK1 21 17

EGFR(L747-E749del, A750P) 21 18

EPHA3 32 18

FRK 19 18

MST4 38 18

PCTK1 45 18

RET(V804M) 26 18

TIE2 13 18

PCTK2 10 20

ULK1 100 20

FGFR4 32 21

BRAF(V600E) 23 22

HIPK1 32 22

EGFR(L747-S752del, P753S) 19 23

FLT3(D835Y) 23 23

JNK3 15 23

p38-delta 15 23

FLT3(D835H) 23 24

CAMK1 38 26

CTK 40 26

FLT1 38 26

MYO3A 59 26

SGK3 97 26

YES 24 27

FGFR2 34 28

NEK4 59 30

SBK1 89 31

ABL1(F317L)-phosphorylated 3.9 33

AURKA 95 33

MEK3 84 33

CAMK1D 73 34

HIPK4 14 34

ZAP70 69 35

MUSK 43 37

ASK2 65 38

EGFR(E746-A750del) 28 38

FLT4 54 38

STK39 23 38

TTK 39 38

FLT3(R834Q) 64 39

PAK3 61 39

SLK 17 39

ABL1(T315I)-phosphorylated 37 40

CDK3 58 40

CSK 69 40

PFTK1 27 40

BRAF 42 41

FER 30 42

IKK-beta 48 42

PIK3CA(Q546K) 85 42

ABL1(T315I)-nonphosphorylated 0 44

MYLK2 63 44

PRKCD 39 44

ROCK1 97 44

CDKL1 45 45

TYK2(JH1domain-catalytic) 90 45

GRK7 68 46

PLK4 78 46

ROCK2 100 46

CDK2 43 47

MAST1 59 47

ABL1(F317I)-nonphosphorylated 0 48

EIF2AK1 62 48

AURKB 77 50

MEK6 77 50

ERBB2 46 51

ERN1 58 51

RET(V804L) 62 51

RPS6KA5(Kin. Dom. 1-N-terminal) 78 51

KIT(V559D, V654A) 50 52

PCTK3 32 52

EGFR(L747-T751del, Sins) 18 53

EPHA2 40 53

EGFR(L861Q) 56 54

MAP3K15 100 54

SGK 100 54

FYN 52 55

PDGFRA 25 55

PIK3CA(C420R) 100 55

SRMS 66 55

CDK5 67 56

IRAK1 97 56

PIK3C2G 81 56

PKNB(M. tuberculosis) 100 56

QSK 69 56

YSK4 89 57

CIT 56 58

EGFR(T790M) 83 58

JAK2(JH1domain-catalytic) 74 58

MAP3K1 60 58

PIK3CA(E545A) 89 58

PIK3CG 94 58

NDR1 87 59

PFPK5(P. falciparum) 100 59

SRPK1 70 59

DYRK2 99 60

EGFR 55 60

GSK3A 40 60

ABL1(F317L)-nonphosphorylated 0 61

CLK1 85 61

PRKCQ 55 61

PAK1 96 62

STK35 80 62

ABL1(F317I)-phosphorylated 7.9 63

CAMK1G 61 64

CAMK4 100 64

CDKL5 93 64

CDK7 33 66

PLK3 100 66

PRKD1 87 66

IRAK4 99 67

PIK3CA(E545K) 88 67

EGFR(S752-I759del) 37 68

INSRR 71 68

PFTAIRE2 100 68

MYLK 100 69

PIK3CA(I800L) 83 70

SYK 21 70

AURKC 100 71

CASK 60 71

CDK9 46 71

CSNK1A1 83 71

EPHB6 92 71

PIK3CA 100 71

BMPR1B 99 72

FLT3-autoinhibited 68 72

PIK3CA(E542K) 87 72

PRKCI 65 73

ANKK1 100 74

EPHA4 64 75

EGFR(G719C) 60 76

EPHA5 86 76

JAK1(JH1domain-catalytic) 86 76

MST2 82 76

PRKCH 94 76

ARK5 96 77

CLK4 66 77

FGFR3 80 77

GAK 77 77

MEK1 100 77

MYO3B 76 77

WNK3 95 77

DCAMKL1 77 78

EPHA6 68 78

FGFR3(G697C) 81 78

KIT(D816H) 82 78

RIPK5 90 78

SNRK 68 78

ERBB4 88 79

EGFR(L858R) 83 80

IKK-epsilon 100 80

TLK1 100 80

TRKC 100 80

ERK2 100 81

PRKD2 73 81

ACVRL1 83 82

BMPR2 86 82

NEK10 100 82

PAK2 78 82

S6K1 54 82

SIK 73 82

GSK3B 83 83

HUNK 100 83

MERTK 100 83

NIK 62 83

PIP5K2B 100 83

RIOK1 100 83

VRK2 96 83

CAMK2D 92 84

PAK6 100 84

TBK1 95 84

GCN2(Kin. Dom. 2, S808G) 84 85

PKN1 100 85

SGK2 100 85

TGFBR2 100 85

WNK1 100 85

ALK 92 86

DCAMKL3 97 86

MEK2 83 86

PIM1 100 86

PRKCE 92 86

TAK1 3.2 86

YANK2 100 86

AXL 68 87

MKNK2 72 87

NEK6 91 87

PIP5K1A 100 87

ADCK3 100 88

CLK2 100 88

ERK8 100 88

PIK3CB 66 88

PIM3 93 88

RAF1 75 88

AKT1 82 89

BUB1 80 89

MAP4K3 100 89

BTK 65 90

ICK 65 90

PAK7 100 90

PIK3CD 100 90

RIOK3 83 90

BMX 79 91

CDK4-cyclinD1 94 91

SNARK 100 91

TRKA 90 91

ALK(L1196M) 90 92

LATS2 100 92

PRKG2 74 92

NEK2 98 93

TRKB 85 93

AAK1 94 94

EGFR(L858R, T790M) 80 94

ERK3 93 94

LRRK2(G2019S) 100 94

PAK4 95 94

PIK3CA(H1047L) 97 94

RIPK4 88 94

RPS6KA4(Kin. Dom. 1-N-terminal) 96 94

TESK1 81 94

CSF1R-autoinhibited 96 95

LIMK2 94 95

LRRK2 95 95

PIK3CA(M1043I) 83 95

RPS6KA4(Kin. Dom. 2-C-terminal) 100 95

TNNI3K 64 95

HASPIN 84 96

MAP3K4 80 96

PRP4 94 96

YANK1 73 96

ABL1(Y253F)-phosphorylated 4.8 97

EGFR(G719S) 65 97

MLK1 91 97

NEK1 93 97

PIK4CB 98 97

BIKE 92 98

RSK2(Kin. Dom. 1-N-terminal) 100 98

SRPK2 100 98

STK16 100 98

AMPK-alpha2 95 99

CAMKK2 79 99

EPHB4 87 99

RSK4(Kin. Dom. 1-N-terminal) 92 99

ABL1(Q252H)-phosphorylated 11 100

ACVR1 100 100

ACVR1B 100 100

ACVR2A 100 100

ACVR2B 95 100

ADCK4 100 100

AKT2 90 100

AKT3 100 100

ALK(C1156Y) 49 100

AMPK-alpha1 85 100

ASK1 96 100

BMPR1A 100 100

BRK 100 100

BRSK1 100 100

BRSK2 100 100

CAMK2A 92 100

CAMK2B 100 100

CAMK2G 86 100

CAMKK1 100 100

CDK4-cyclinD3 100 100

CHEK1 100 100

CHEK2 100 100

CLK3 100 100

CSNK1A1L 99 100

CSNK1D 100 100

CSNK1E 100 100

CSNK1G1 100 100

CSNK1G2 100 100

CSNK1G3 93 100

CSNK2A1 100 100

CSNK2A2 100 100

DAPK1 100 100

DAPK2 93 100

DAPK3 100 100

DCAMKL2 74 100

DLK 100 100

DMPK 100 100

DMPK2 88 100

DRAK1 100 100

DRAK2 85 100

DYRK1A 92 100

DYRK1B 77 100

EPHA1 90 100

EPHA7 75 100

EPHB1 78 100

EPHB3 100 100

ERBB3 100 100

ERK1 100 100

ERK4 96 100

ERK5 98 100

FAK 100 100

GRK1 77 100

GRK4 100 100

IGF1R 100 100

INSR 100 100

IRAK3 100 100

ITK 95 100

JAK1(JH2domain-pseudokinase) 90 100

KIT(D816V) 96 100

KIT-autoinhibited 65 100

LATS1 100 100

LIMK1 100 100

LKB1 100 100

LTK 100 100

LZK 100 100

MAK 93 100

MAP3K2 90 100

MAPKAPK2 100 100

MAPKAPK5 94 100

MARK1 83 100

MARK2 100 100

MARK3 94 100

MARK4 92 100

MEK4 82 100

MEK5 37 100

MELK 89 100

MET 100 100

MET(M1250T) 89 100

MET(Y1235D) 100 100

MKNK1 94 100

MLCK 100 100

MLK2 100 100

MLK3 62 100

MRCKA 100 100

MRCKB 100 100

MST1 80 100

MST1R 100 100

MTOR 86 100

MYLK4 100 100

NDR2 100 100

NEK11 100 100

NEK3 65 100

NEK5 85 100

NEK7 100 100

NEK9 100 100

NIM1 100 100

PDPK1 69 100

PHKG1 100 100

PHKG2 100 100

PIK3C2B 100 100

PIK3CA(H1047Y) 79 100

PIM2 71 100

PIP5K1C 50 100

PIP5K2C 82 100

PKAC-alpha 72 100

PKAC-beta 100 100

PKMYT1 100 100

PKN2 89 100

PLK1 100 100

PLK2 100 100

PRKD3 100 100

PRKG1 100 100

PRKR 100 100

PRKX 100 100

PYK2 97 100

RIOK2 100 100

RIPK1 54 100

RIPK2 86 100

ROS1 75 100

RPS6KA5(Kin. Dom. 2-C-terminal) 100 100

RSK1(Kin. Dom. 1-N-terminal) 100 100

RSK1(Kin. Dom. 2-C-terminal) 100 100

RSK3(Kin. Dom. 1-N-terminal) 100 100

RSK3(Kin. Dom. 2-C-terminal) 100 100

RSK4(Kin. Dom. 2-C-terminal) 100 100

SgK110 100 100

SIK2 100 100

SRPK3 100 100

STK33 97 100

TEC 82 100

TGFBR1 100 100

TLK2 100 100

TNK2 100 100

TRPM6 58 100

TSSK1B 83 100

TXK 89 100

TYK2(JH2domain-pseudokinase) 87 100

TYRO3 92 100

ULK2 81 100

VEGFR2 28 100

WEE1 100 100

WEE2 100 100

YANK3 88 100

Kinative

The kinase selectivity of compounds (A-5) and (A-14) were evaluated using a chemical proteomic approach named KiNativ which detects 260 kinases in A375 cells (ActivX Biosciences). To probe the intracellular targets of the compounds, A375 cells were incubated with the inhibitor at 1 μM final concentration and then looked for protection of labeling by an ATP-biotin probe that non-specifically labels conserved lysines on kinases and other nucleotide-dependent enzymes.

Results

Table 4 shows that compound (A-5) inhibits a number of kinases at 1 μM, including Ab1 (>90%), FYN (71.2%), LYN (87.8%), and ZAK (75.7%). Table 5 shows that compound (A-14) inhibits a number of kinases at 1 μM, including Ab1 (>90%), FYN (88.2%), LYN (85.7%), and ZAK (75.8%).

TABLE 4

SEQ Compound

ID Labeling A-4

Kinase Reference Sequence NO: Site (1.0 μM)

ABL, ARG UniRef100_P00519, LMTGDTYTAHAGAKFPIK 1 Activation 95.5

UniRef100_P42684 Loop

ACK UniRef100_Q07912 TVSVAVKCLKPDVLSQPEA 2 Lys1 4.9

MDDFIR

AGK UniRef100_Q53H12 ATVFLNPAACKGK 3 ATP −31.4

AMPKa1, UniRef100_P54646, DLKPENVLLDAHMNAK 4 Lys2 16.3

AMPKa2 UniRef100_Q13131

ARAF UniRef100_P10398 DLKSNNIFLHEGLTVK 5 Lys2 12.2

ATR UniRef100_Q13535 FYIMMCKPK 6 ATP 23.0

AurA UniRef100_O14965 FILALKVLFK 7 Lys1 −16.0

AurB UniRef100_Q96GD4 SHFIVALKVLFK 8 Lys1 −51.1

BARK1 UniRef100_P25098 DLKPANILLDEHGHVR 9 Lys2 −13.4

BRAF UniRef100_P15056 DLKSNNIFLHEDLTVK 10 Lys2 18.9

BTK UniRef100_Q06187 YVLDDEYTSSVGSKFPVR 11 Activation −18.8

Loop

CaMK1a UniRef100_Q14012 LVAIKCIAK 12 Lys1 12.4

CaMK1d UniRef100_Q8IU85 LFAVKCIPK 13 Lys1 −6.0

CaMK2d UniRef100_Q13557 IPTGQEYAAKIINTKK 14 Lys1 −8.1

CaMK2g UniRef100_Q13555 TSTQEYAAKIINTK 15 Lys1 −23.1

CaMK4 UniRef100_Q16566 DLKPENLLYATPAPDAPLK 16 Lys2 5.9

CaMKK2 UniRef100_Q96RR4 DIKPSNLLVGEDGHIK 17 Lys2 6.2

CASK UniRef100_O14936, ETGQQFAVKIVDVAK 18 Lys1 −28.1

UniRef100_C9JGY0

CDC2 UniRef100_P06493 DLKPQNLLIDDKGTIK 19 Lys2 −2.3

CDK11, UniRef100_P49336, DLKPANILVMGEGPER 20 Lys2 50.0

CDK8 UniRef100_Q9BWU1

CDK2 UniRef100_P24941 DLKPQNLLINTEGAIK 21 Lys2 −3.5

CDK4 UniRef100_P11802 DLKPENILVTSGGTVK 22 Lys2 17.4

CDK5 UniRef100_Q00535 DLKPQNLLINR 23 Lys2 −27.3

CDK6 UniRef100_Q00534 DLKPQNILVTSSGQIK 24 Lys2 13.1

CDK7 UniRef100_P50613 DLKPNNLLLDENGVLK 25 Lys2 3.9

CDK9 UniRef100_P50750 DMKAANVLITR 26 Lys2 −16.2

CHK1 UniRef100_B5BTY6, DIKPENLLLDER 27 Lys2 −5.0

UniRef100_O14757

CHK2 UniRef100_O96017 DLKPENVLLSSQEEDCLIK 28 Lys2 −7.8

CK1a UniRef100_P48729, DIKPDNFLMGIGR 29 Lys2 −0.6

UniRef100_B4E1D9

CK1g2 UniRef100_P78368 DVKPENFLVGRPGTK 30 Lys2 −9.1

CK2a2 UniRef100_P19784 DVKPHNVMIDHQQK 31 Lys2 −18.2

CLK3 UniRef100_P49761 YEIVGNLGEGTFGKVVECL 32 ATP Loop −52.8

DHAR

CSK UniRef100_P41240 VSDFGLTKEASSTQDTGKL 33 Activation 15.3

PVK Loop

DGKA UniRef100_P23743 IDPVPNTHPLLVFVNPKSG 34 ATP −4.8

GK

DGKH UniRef100_Q86XP1 ATFSFCVSPLLVFVNSKSG 35 ATP −6.3

DNQGVK

DGKQ UniRef100_P52824 GRLLTALVLPDLLHAKLPP 36 ATP 11.0

DSCPLLVFVNPKSGGLK

DNAPK UniRef100_P78527 KGGSWIQEINVAEK 37 ATP −61.5

DNAPK UniRef100_P78527 EHPFLVKGGEDLR 38 ATP −64.6

eEF2K UniRef100_O00418 YIKYNSNSGFVR 39 ATP −30.5

EphB1 UniRef100_P54762 YLQDDTSDPTYTSSLGGKI 40 Activation −1.7

PVR Loop

EphB2 UniRef100_P29323 FLEDDTSDPTYTSALGGKI 41 Activation −12.8

PIR Loop

Erk1 UniRef100_P27361 DLKPSNLLINTTCDLK 42 Lys2 −9.0

Erk2 UniRef100_P28482 DLKPSNLLLNTTCDLK 43 Lys2 −3.8

Erk5 UniRef100_Q13164 DLKPSNLLVNENCELK 44 Lys2 25.9

FER UniRef100_P16591 TSVAVKTCKEDLPQELK 45 Lys1 91.4

FES UniRef100_P07332 LRADNTLVAVKSCR 46 Lys1 89.1

FGR UniRef100_P09769 LIKDDEYNPCQGSKFPIK 47 Activation 31.9

Loop

FRAP UniRef100_P42345 IQSIAPSLQVITSKQRPR 48 ATP −7.5

FRK UniRef100_P42685 HEIKLPVK 49 Activation 91.1

Loop

FYN, SRC, UniRef100_P12931, QGAKFPIKWTAPEAALYG 50 Activation 71.2

YES UniRef100_P07947, R Loop

UniRef100_P06241

GCK UniRef100_Q12851 DIKGANLLLTLQGDVK 51 Lys2 94.9

GCN2 UniRef100_Q9P2K8 DLKPVNIFLDSDDHVK 52 Lys2 20.8

GSK3A UniRef100_P49840 DIKPQNLLVDPDTAVLK 53 Lys2 36.0

GSK3B UniRef100_P49841 DIKPQNLLLDPDTAVLK 54 Lys2 0.5

HPK1 UniRef100_Q92918 DIKGANILINDAGEVR 55 Lys2 68.1

IKKa UniRef100_O15111 DLKPENIVLQDVGGK 56 Lys2 −17.0

IKKb UniRef100_O14920 DLKPENIVLQQGEQR 57 Lys2 −12.6

IKKe UniRef100_Q14164 SGELVAVKVFNTTSYLRPR 58 Lys1 −9.9

ILK UniRef100_Q13418 WQGNDIVVKVLK 59 Lys1 5.2

IRAK1 UniRef100_P51617 AIQFLHQDSPSLIHGDIKSS 60 Lys2 −3.5

NVLLDER

IRAK4 UniRef100_Q9NWZ3 DIKSANILLDEAFTAK 61 Lys2 1.9

IRE1 UniRef100_O75460 DLKPHNILISMPNAHGK 62 Lys2 −2.2

ITPK1 UniRef100_Q13572 ESIFFNSHNVSKPESSSVLT 63 ATP 1.2

ELDKIEGVFERPSDEVIR

JAK1 UniRef100_P23458 QLASALSYLEDKDLVHGN 64 Protein 4.3

VCTKNLLLAR Kinase

Domain

JAK1 UniRef100_P23458 IGDFGLTKAIETDKEYYTVK 65 Activation −6.2

domain2 Loop

JAK3 UniRef100_P52333 IADFGLAKLLPLDKDYYVV 66 Activation 7.7

domain2 R Loop

JNK1, UniRef100_P45983, DLKPSNIVVK 67 Lys2 77.2

JNK2, UniRef100_P53779,

JNK3 UniRef100_P45984

KHS1 UniRef100_Q9Y4K4 NVHTGELAAVKIIK 68 Lys1 15.8

KSR1 UniRef100_Q8IVT5 SKNVFYDNGKVVITDFGLF 69 Activation −22.0

GISGVVR Loop

KSR1, UniRef100_Q6VAB6, SKNVFYDNGK 70 Activation −10.0

KSR2 UniRef100_Q8IVT5 Loop

LATS1 UniRef100_095835 ALYATKTLR 71 Lys1 5.4

LATS2 UniRef100_Q9NRM7 DIKPDNILIDLDGHIK 72 Lys2 −1.9

LCK UniRef100_P06239 EGAKFPIKWTAPEAINYGT 73 Activation 92.3

FTIK Loop

LKB1 UniRef100_Q15831 DIKPGNLLLTTGGTLK 74 Lys2 −6.0

LOK UniRef100_O94804 DLKAGNVLMTLEGDIR 75 Lys2 19.9

LRRK2 UniRef100_Q5S007 DLKPHNVLLLYPNAAIIA 76 Lys2 −15.9

K

LYN UniRef100_P07948 VAVKTLKPGTMSVQAFLE 77 Lys1 87.8

EANLMK

MAP2K1 UniRef100_Q02750 IMHRDVKPSNILVNSR 78 Lys2 11.4

MAP2K1, UniRef100_P36507, DVKPSNILVNSR 79 Lys2 −16.3

MAP2K2 UniRef100_Q02750

MAP2K3 UniRef100_P46734 DVKPSNVLINK 80 Lys2 −1.0

MAP2K4 UniRef100_P45985 DIKPSNILLDR 81 Lys2 −14.1

MAP2K5 UniRef100_Q13163 DVKPSNMLVNTR 82 Lys2 20.5

MAP2K6 UniRef100_P52564 DVKPSNVLINALGQVK 83 Lys2 0.5

MAP2K7 UniRef100_O14733 DVKPSNILLDER 84 Lys2 −38.2

MAP3K1 UniRef100_Q13233 DVKGANLLIDSTGQR 85 Lys2 26.9

MAP3K2 UniRef100_Q9Y2U5 ELAVKQVQFDPDSPETSK 86 Lys1 4.2

EVNALECEIQLLK

MAP3K2, UniRef100_Q9Y2U5, DIKGANILR 87 Lys2 3.2

MAP3K3 UniRef100_Q99759

MAP3K3 UniRef100_Q99759 ELASKQVQFDPDSPETSKE 88 Lys1 3.7

VSALECEIQLLK

MAP3K4 UniRef100_Q9Y6R4 DIKGANIFLTSSGLIK 89 Lys2 19.2

MAP3K5 UniRef100_Q99683 DIKGDNVLINTYSGVLK 90 Lys2 −30.4

MAP3K6 UniRef100_O95382 DIKGDNVLINTFSGLLK 91 Lys2 −25.0

MARK2, UniRef100_P27448, DLKAENLLLDADMNIK 92 Lys2 4.6

MARK3 UniRef100_Q7KZI7

MARK3 UniRef100_P27448 EVAIKIIDKTQLNPTSLQK 93 Lys1 −26.1

MARK3, UniRef100_Q96L34, EVAIKIIDK 94 Lys1 −16.2

MARK4 UniRef100_P27448

MARK4 UniRef100_Q96L34 DLKAENLLLDAEANIK 95 Lys2 2.9

MAST1, UniRef100_Q6P0Q8, DLKPDNLLITSMGHIK 96 Lys2 35.6

MAST2 UniRef100_Q9Y2H9

MAST3 UniRef100_O60307 DLKPDNLLITSLGHIK 97 Lys2 −8.1

MASTL UniRef100_Q96GX5 GAFGKVYLGQK 98 ATP Loop 12.8

MASTL UniRef100_Q96GX5 LYAVKVVK 99 Lys1 3.3

MELK UniRef100_Q14680 DLKPENLLFDEYHK 100 Lys2 −19.6

MER UniRef100_Q12866 NCMLRDDMTVCVADFGL 101 Activation 49.8

SKK Loop

MER, UniRef100_Q06418, KIYSGDYYR 102 Activation 1.6

TYRO3 UniRef100_Q12866 Loop

MET UniRef100_P08581 DMYDKEYYSVHNK 103 Activation −21.0

Loop

MLK3 UniRef100_Q16584 DLKSNNILLLQPIESDDME 104 Lys2 20.7

HK

MLK4 UniRef100_Q5TCX8 DLKSSNILLLEK 105 Lys2 −1.7

MLKL UniRef100_Q8NB16 APVAIKVFK 106 Lys1 −14.9

MPSK1 UniRef100_O75716 DLKPTNILLGDEGQPVLM 107 Lys2 16.1

DLGSMNQACIHVEGSR

MSK1 UniRef100_O75582 DIKLENILLDSNGHVVLTD 108 Lys2 5.7

domain1 FGLSK

MSK2 UniRef100_O75676 DLKLENVLLDSEGHIVLTD 109 Lys2 −64.9

domain1 FGLSK

MST1 UniRef100_Q13043 ETGQIVAIKQVPVESDLQE 110 Lys1 −4.7

IIK

MST2 UniRef100_Q13188 ESGQVVAIKQVPVESDLQ 111 Lys1 −6.2

EIIK

MST3 UniRef100_Q9Y6E0 DIKAANVLLSEHGEVK 112 Lys2 −3.7

MST4 UniRef100_Q9P289 TQQVVAIKIIDLEEAEDEIE 113 Lys1 6.2

DIQQEITVLSQCDSSYVTK

MST4, UniRef100_000506, DIKAANVLLSEQGDVK 114 Lys2 4.6

YSK1 UniRef100_Q9P289

MYO3A, UniRef100_Q8NEV4, DVKGNNILLTTEGGVK 115 Lys2 −15.3

MYO3B UniRef100_Q8WXR4

NDR1 UniRef100_Q15208 DIKPDNLLLDSK 116 Lys2 9.3

NDR2 UniRef100_Q9Y2H1 DIKPDNLLLDAK 117 Lys2 −10.9

NEK1 UniRef100_Q96PY6 DIKSQNIFLTK 118 Lys2 −3.0

NEK2 UniRef100_P51955 DLKPANVFLDGK 119 Lys2 −22.7

NEK3 UniRef100_P51956 SKNIFLTQNGK 120 Activation 13.1

Loop

NEK4 UniRef100_P51957 DLKTQNVFLTR 121 Lys2 1.5

NEK6, UniRef100_Q8TDX7, DIKPANVFITATGVVK 122 Lys2 −12.5

NEK7 UniRef100_Q9HC98

NEK7 UniRef100_Q8TDX7 AACLLDGVPVALKK 123 Lys1 −7.2

NEK8 UniRef100_Q86SG6 DLKTQNILLDK 124 Lys2 −11.4

NEK9 UniRef100_Q8TD19 DIKTLNIFLTK 125 Lys2 −1.2

OSR1 UniRef100_C9JIG9, DVKAGNILLGEDGSVQIA 126 Lys2 −11.1

UniRef100_O95747 DFGVSAFLATGGDITR

p38a UniRef100_Q16539 DLKPSNLAVNEDCELK 127 Lys2 61.4

p38a UniRef100_Q16539 QELNKTIWEVPER 128 Protein 92.2

Kinase

Domain

p38b UniRef100_015759 QELNKTVWEVPQR 129 Protein 51.4

Kinase

Domain

p38d, UniRef100_O15264, DLKPGNLAVNEDCELK 130 Lys2 62.5

p38g UniRef100_P53778

70SEK UniRef100_P23443 DLKPENIMLNHQGHVK 131 Lys2 −2.3

p70S6Kb UniRef100_Q9UBS0 DLKPENIMLSSQGHIK 132 Lys2 8.2

PAN3 UniRef100_Q58A45 VMDPTKILITGK 133 ATP 12.1

PCTAIRE1 UniRef100_Q00536 SKLTDNLVALKEIR 134 Lys1 −3.5

PCTAIRE2, UniRef100_Q00537, SKLTENLVALKEIR 135 Lys1 11.7

PCTAIRE3 UniRef100_Q07002

PDK1 UniRef100_O15530 EYAIKILEK 136 Lys1 18.8

PEK UniRef100_Q9N2J5 DLKPSNIFFTMDDVVK 137 Lys2 9.4

PFTAIRE1 UniRef100_O94921 LVALKVIR 138 Lys1 4.3

PHKg1 UniRef100_Q16816 DLKPENILLDDNMNIK 139 Protein −49.0

Kinase

Domain

PHKg2 UniRef100_P15735 ATGHEFAVKIMEVTAER 140 Lys1 15.2

PI4KA, UniRef100_A4QPH2, SGTPMQSAAKAPYLAK 141 ATP 19.3

PI4KAP2 UniRef100_P42356

PI4KB UniRef100_Q9UBF8 VPHTQAVVLNSKDK 142 ATP −0.2

PIK3C2B UniRef100_O00750 VIFKCGDDLRQDMLTLQ 143 ATP 24.0

MIR

PIK3C3 UniRef100_Q8NEB9 TEDGGKYPVIFKHGDDLR 144 ATP −5.1

PIK3CB UniRef100_Q9BTS4, VFGEDSVGVIFKNGDDLR 145 ATP 27.8

UniRef100_P42338 QDMLTLQMLR

PIK3CD UniRef100_O00329 VNWLAHNVSKDNRQ 146 ATP 2.2

PIK3CG UniRef100_P48736 KKPLWLEFK 147 ATP −21.1

PIP4K2A UniRef100_P48426 AKELPTLKDNDFINEGQK 148 ATP −26.7

PIP4K2B UniRef100_P78356 AKDLPTFKDNDFLNEGQK 149 ATP −44.7

PIP4K2C UniRef100_Q8TBX8 TLVIKEVSSEDIADMHSNL 150 ATP 5.2

SNYHQYIVK

PIP5K3 UniRef100_Q9Y217 GGKSGAAFYATEDDRFILK 151 ATP 0.9

PITSLRE UniRef100_P21127 DLKTSNLLLSHAGILK 152 Lys2 −10.4

PKCa, UniRef100_P17252, DLKLDNVMLDSEGHIK 153 Lys2 2.3

PKCb UniRef100_P05771,

UniRef100_B5BU22

PKD2 UniRef100_Q9BZL6 DVAVKVIDK 154 Lys1 −6.9

PKN1 UniRef100_Q16512 VLLSEFRPSGELFAIKALK 155 Lys1 −32.1

PKR UniRef100_P19525 DLKPSNIFLVDTK 156 Lys2 −28.4

PLK1 UniRef100_P53350 CFEISDADTEVFAGKIVP 157 Lys1 −9.1

K

PRP4 UniRef100_Q13523 CNILHADIKPDNILVNESK 158 Lys2 −20.1

PRPK UniRef100_Q96S44 FLSGLELVKQGAEAR 159 ATP Loop −13.7

PYK2 UniRef100_Q14289 YIEDEDYYKASVTR 160 Activation 10.9

Loop

RAF1 UniRef100_P04049 DMKSNNIFLHEGLTVK 161 Lys2 36.6

RIPK3 UniRef100_Q9Y572 DLKPSNVLLDPELHVK 162 Lys2 32.6

ROCK1, UniRef100_O75116, DVKPDNMLLDK 163 Lys2 22.0

ROCK2 UniRef100_Q13464

RSK1 UniRef100_Q15418 DLKPENILLDEEGHIKLTDF 164 Lys2 −20.9

domain1 GLSKEAIDHEK

RSK1 UniRef100_Q15418, DLKPENILLDEEGHIK 165 Lys2 −17.7

domain1, UniRef100_P51812,

RSK2 UniRef100_Q15349

domain1,

RSK3

domain1

RSK1 UniRef100_Q15418 DLKPSNILYVDESGNPECL 166 Lys2 −16.3

domain1 R

RSK2 UniRef100_P51812 DLKPENILLDEEGHIKLTDF 167 Lys2 −3.3

domain1 GLSKESIDHEK

RSK2 UniRef100_P51812 DLKPSNILYVDESGNPESIR 168 Lys2 −24.1

domain2

RSK3 UniRef100_015349 DLKPENILLDEEGHIKITDF 169 Lys2 −32.6

domain1 GLSK

RSK4 UniRef100_Q9UK32 DLKPENILLDEIGHIK 170 Lys2 27.6

domain1

RSKL1 UniRef100_Q96S38 VLGVIDKVLLVMDTR 171 ATP 31.5

SGK3 UniRef100_Q96BR1 FYAVKVLQK 172 Lys1 −10.2

SLK UniRef100_Q9H2G2 DLKAGNILFTLDGDIK 173 Lys2 −14.3

SMG1 UniRef100_Q96Q15 DTVTIHSVTITILPTKTK 174 ATP −4.0

PK

SNRK UniRef100_Q9NRH2 DLKPENVVFFEK 175 Lys2 18.0

SRC UniRef100_P12931 VAIKTLKPGTMSPEAFLQE 176 Lys1 76.1

AQVMKK

SRPK1 UniRef100_Q96SB4 IIHTDIKPENILLSVNEQYIR 177 Lys2 −34.1

STK33 UniRef100_Q9BYT3 DLKLENIMVK 178 Lys2 12.9

STLK5 UniRef100_Q7RTN6 YSVKVLPWLSPEVLQQNL 179 Activation 5.0

QGYDAK Loop

SYK UniRef100_P43405 ISDFGLSKALR 180 Activation 17.4

Loop

TAK1 UniRef100_043318 DLKPPNLLLVAGGTVLK 181 Lys2 32.0

TAO1, UniRef100_Q9H2K8, DIKAGNILLTEPGQVK 182 Lys2 76.5

TAO3 UniRef100_Q7L7X3

TAO2 UniRef100_Q9UL54 DVKAGNILLSEPGLVK 183 Lys2 86.0

TBK1 UniRef100_Q9UHD2 TGDLFAIKVFNNISFLRPV 184 Lys1 18.2

DVQMR

TEC UniRef100_P42680 YVLDDQYTSSSGAKFPVK 185 Activation −12.8

Loop

TLK1 UniRef100_Q9UKI8 YLNEIKPPIIHYDLKPGNILL 186 Lys2 4.9

VDGTACG

TLK2 UniRef100_Q86UE8 YLNEIKPPIIHYDLKPGNILL 187 Lys2 7.1

VNGTACGEIK

TYK2 UniRef100_P29597 IGDFGLAKAVPEGHEYYR 188 Activation −18.1

domain2 Loop

ULK1 UniRef100_075385 DLKPQNILLSNPAGR 189 Lys2 −6.0

ULK3 UniRef100_D3DW67, NISHLDLKPQNILLSSLEKP 190 Lys2 −4.4

UniRef100_Q6PHR2 HLK

VRK2 UniRef100_Q86Y07 MLDVLEYIHENEYVHGDIK 191 Lys2 27.9

AANLLLGYK

Wee1 UniRef100_P30291 YIHSMSLVHDIKPSNIFIS 192 Lys2 23.2

R

Wnk1, UniRef100_Q9Y3S1, GSFKTVYK 193 ATP Loop 24.2

Wnk2 UniRef100_D3DUP1,

UniRef100_Q9H4A3

Wnk1, UniRef100_Q9Y3S1, DLKCDNIFITGPTGSVK 194 Lys2 0.2

Wnk2, UniRef100_D3DUP1,

Wnk3 UniRef100_Q9BYP7,

UniRef100_Q9H4A3

YANK3 UniRef100_Q86UX6 DVKPDNILLDER 195 Lys2 27.7

ZAK UniRef100_Q9NYL2 WISQDKEVAVKK 196 Lys1 75.7

ZAP70 UniRef100_P43403 ISDFGLSKALGADDSYYTA 197 Activation 49.2

R Loop

ZC1/HGK, UniRef100_O95819, DIKGQNVLLTENAEVK 198 Lys2 19.2

ZC2/TNIK, UniRef100_Q9UKE5,

ZC3/MINK UniRef100_Q8N4C8

ZC2/TNIK UniRef100_Q9UKE5 TGQLAAIKVMDVTGDEEE 199 Lys1 23.9

EIKQEINMLKK

TABLE 5

SEQ Cmpd.

ID Labeling A-14

Kinase Reference Sequence NO: Site (1.0 μM)

ABL, ARG UniRef100_P00519, LMTGDTYTAHAGAKFPIK 200 Activation 98.4

UniRef100_P42684 Loop

ACK UniRef100_Q07912 TVSVAVKCLKPDVLSQPEA 201 Lys1 8.5

MDDFIR

AGK UniRef100_Q53H12 ATVFLNPAACKGK 202 ATP 5.9

AKT1 UniRef100_P31749 GTFGKVILVK 203 ATP Loop −23.9

AKT2, UniRef100_Q9Y243, GTFGKVILVR 204 ATP Loop −19.7

AKT3 UniRef100_P31751

AMPKa1, UniRef100_P54646, DLKPENVLLDAHMNAK 205 Lys2 −17.5

AMPKa2 UniRef100_Q96E92

ANPa UniRef100_P16066 GMLFLHNGAICSHGNLKS 206 Lys2 −5.3

SNCVVDGR

ARAF UniRef100_P10398 DLKSNNIFLHEGLTVK 207 Lys2 2.0

ATR UniRef100_Q13535 FYIMMCKPK 208 ATP −20.3

AurA UniRef100_O14965 FILALKVLFK 209 Lys1 14.6

AurA UniRef100_O14965 DIKPENLLLGSAGELK 210 Lys2 6.1

AurA, UniRef100_O14965, GKFGNVYLAR 211 ATP Loop −2.4

AurB, UniRef100_Q9UQB9,

AurC UniRef100_Q96GD4

AurB UniRef100_Q96GD4 SHFIVALKVLFK 212 Lys1 3.3

BARK1 UniRef100_P25098 DLKPANILLDEHGHVR 213 Lys2 −13.6

BRAF UniRef100_P15056 DLKSNNIFLHEDLTVK 214 Lys2 18.9

BTK UniRef100_006187 YVLDDEYTSSVGSKFPVR 215 Activation −10.2

Loop

CaMK1a UniRef100_Q14012 LVAIKCIAK 216 Lys1 −5.4

CaMK1d UniRef100_Q8IU85 LFAVKCIPK 217 Lys1 −1.8

CaMK2d UniRef100_Q13557 IPTGQEYAAKIINTKK 218 Lys1 −7.3

CaMK2g UniRef100_Q13555 TSTQEYAAKIINTK 219 Lys1 2.0

CaMK4 UniRef100_Q16566 DLKPENLLYATPAPDAPLK 220 Lys2 −2.0

CaMKK2 UniRef100_Q96RR4 DIKPSNLLVGEDGHIK 221 Lys2 16.2

CASK UniRef100_014936 ETGQQFAVKIVDVAK 222 Lys1 7.1

CDC2 UniRef100_Q5H9N4 DLKPQNLLIDDKGTIK 223 Lys2 9.0

CDK11, UniRef100_P49336, DLKPANILVMGEGPER 224 Lys2 49.2

CDK8 UniRef100_Q9BWU1

CDK2 UniRef100_P24941 DLKPQNLLINTEGAIK 225 Lys2 34.5

CDK4 UniRef100_P11802 DLKPENILVTSGGTVK 226 Lys2 11.4

CDKS UniRef100_Q00535 DLKPQNLLINR 227 Lys2 11.3

CDK6 UniRef100_Q00534 DLKPQNILVTSSGQIK 228 Lys2 13.6

CDK7 UniRef100_P50613 DLKPNNLLLDENGVLK 229 Lys2 −7.3

CDK9 UniRef100_P50750 DMKAANVLITR 230 Lys2 −13.1

CHK1 UniRef100_B4DT73 DIKPENLLLDER 231 Lys2 12.2

CHK2 UniRef100_O96017 DLKPENVLLSSQEEDCLIK 232 Lys2 −1.6

CK1a UniRef100_P48729 DIKPDNFLMGIGR 233 Lys2 −19.6

CK1d, UniRef100_P49674, DVKPDNFLMGLGKK 234 Lys2 −9.3

CK1e UniRef100_P48730

CK1g1, UniRef100_Q9Y6M4, KIGCGNFGELR 235 ATP Loop 1.3

CK1g2, UniRef100_P78368,

CK1g3 UniRef100_Q9HCP0

CK1g2 UniRef100_P78368 DVKPENFLVGRPGTK 236 Lys2 −23.3

CLK2 UniRef100_P49760 LTHTDLKPENILFVNSDYEL 237 Lys2 −30.3

TYNLEK

CLK3 UniRef100_P49761 YEIVGNLGEGTFGKVVECL 238 ATP Loop −4.0

DHAR

CSK UniRef100_P41240 VSDFGLTKEASSTQDTGKL 239 Activation 20.0

PVK Loop

DGKA UniRef100_P23743 IDPVPNTHPLLVFVNPKSG 240 ATP −16.3

GK

DGKH UniRef100_Q86XP1 ATFSFCVSPLLVFVNSKSG 241 ATP 32.6

DNQGVK

DGKQ UniRef100_P52824 GRLLTALVLPDLLHAKLPP 242 ATP −23.2

DSCPLLVFVNPKSGGLK

DNAPK UniRef100_P78527 KGGSWIQEINVAEK 243 ATP −35.9

DNAPK UniRef100_P78527 EHPFLVKGGEDLR 244 ATP −63.7

eEF2K UniRef100_O00418 YIKYNSNSGFVR 245 ATP −22.0

Erk1 UniRef100_P27361 DLKPSNLLINTTCDLK 246 Lys2 −16.3

Erk2 UniRef100_P28482 DLKPSNLLLNTTCDLK 247 Lys2 −2.7

Erk3 UniRef100_Q16659 DLKPANLFINTEDLVLK 248 Lys2 31.8

ErkS UniRef100_Q13164 DLKPSNLLVNENCELK 249 Lys2 −42.7

FER UniRef100_P16591 TSVAVKTCKEDLPQELK 250 Lys1 74.0

FES UniRef100_P07332 LRADNTLVAVKSCR 251 Lys1 36.1

FGR UniRef100_P09769 LIKDDEYNPCQGSKFPIK 252 Activation 70.3

Loop

FRAP UniRef100_P42345 IQSIAPSLQVITSKQRPR 253 ATP −3.3

FRK UniRef100_P42685 HEIKLPVK 254 Activation 98.0

Loop

FYN, SRC, UniRef100_P12931, QGAKFPIKWTAPEAALYG 255 Activation 88.2

YES UniRef100_P07947, R Loop

UniRef100_P06241

GCK UniRef100_Q12851 DIKGANLLLTLQGDVK 256 Lys2 96.3

GCN2 UniRef100_Q9P2K8 DLKPVNIFLDSDDHVK 257 Lys2 5.4

GPRK6 UniRef100_P43250 DLKPENILLDDHGHIR 258 Lys2 −1.9

GSK3A UniRef100_P49840 DIKPQNLLVDPDTAVLK 259 Lys2 25.5

GSK3B UniRef100_P49841 DIKPQNLLLDPDTAVLK 260 Lys2 −3.5

HPK1 UniRef100_Q92918 DIKGANILINDAGEVR 261 Lys2 88.2

IKKa UniRef100_O15111 DLKPENIVLQDVGGK 262 Lys2 −3.1

IKKb UniRef100_O14920 DLKPENIVLQQGEQR 263 Lys2 −12.2

IKKe UniRef100_Q14164 SGELVAVKVFNTTSYLRPR 264 Lys1 −3.9

ILK UniRef100_Q13418 WQGNDIVVKVLK 265 Lys1 −0.4

ILK UniRef100_Q13418 ISMADVKFSFQCPGR 266 Protein 6.8

Kinase

Domain

IRAK1 UniRef100_P51617 AIQFLHQDSPSLIHGDIKSS 267 Lys2 7.6

NVLLDER

IRAK3 UniRef100_Q9Y616 VEIQNLTYAVKLFK 268 Lys1 −7.1

IRAK4 UniRef100_Q9NWZ3 DIKSANILLDEAFTAK 269 Lys2 6.3

IRE1 UniRef100_O75460 DLKPHNILISMPNAHGK 270 Lys2 −0.6

ITPK1 UniRef100_Q13572 ESIFFNSHNVSKPESSSVLT 271 ATP −16.2

ELDKIEGVFERPSDEVIR

JAK1 UniRef100_P23458 QLASALSYLEDKDLVHGN 272 Protein 9.0

domain1 VCTKNLLLAR Kinase

Domain

JAK1 UniRef100_P23458 IGDFGLTKAIETDKEYYTVK 273 Activation 29.3

domain2 Loop

JAK1 UniRef100_P23458 YDPEGDNTGEQVAVKSLK 274 Lys1 24.0

domain2 PESGGNHIADLKK

JAK3 UniRef100_P52333 IADFGLAKLLPLDKDYYVV 275 Activation −4.3

domain2 R Loop

JNK1, UniRef100_P45983, DLKPSNIVVK 276 Lys2 31.5

JNK2, UniRef100_P53779,

JNK3 UniRef100_P45984

KHS1 UniRef100_Q9Y4K4 NVHTGELAAVKIIK 277 Lys1 33.9

KHS2 UniRef100_Q8IVH8 NVNTGELAAIKVIK 278 Lys1 3.8

KSR1 UniRef100_Q8IVT5 SKNVFYDNGKVVITDFGLF 279 Activation −0.2

GISGVVR Loop

KSR1, UniRef100_Q6VAB6, SKNVFYDNGK 280 Activation 1.4

KSR2 UniRef100_Q8IVT5 Loop

LATS1 UniRef100_O95835 ALYATKTLR 281 Lys1 15.8

LATS2 UniRef100_Q9NRM7 DIKPDNILIDLDGHIK 282 Lys2 0.8

LCK UniRef100_P06239 EGAKFPIKWTAPEAINYGT 283 Activation 83.8

FTIK Loop

LKB1 UniRef100_Q15831 DIKPGNLLLTTGGTLK 284 Lys2 3.6

LOK UniRef100_O94804 DLKAGNVLMTLEGDIR 285 Lys2 28.8

LRRK2 UniRef100_Q5S007 DLKPHNVLLLYPNAAIIA 286 Lys2 −11.8

K

LYN UniRef100_P07948 VAVKTLKPGTMSVQAFLE 287 Lys1 85.7

EANLMK

MAP2K1 UniRef100_Q02750 IMHRDVKPSNILVNSR 288 Lys2 6.6

MAP2K1, UniRef100_P36507, KLIHLEIKPAIR 289 Lys1 9.4

MAP2K2 UniRef100_Q02750

MAP2K1, UniRef100_P36507, DVKPSNILVNSR 290 Lys2 2.2

MAP2K2 UniRef100_Q02750

MAP2K2 UniRef100_P36507 HQIMHRDVKPSNILVNSR 291 Lys2 3.9

MAP2K3 UniRef100_P46734 DVKPSNVLINK 292 Lys2 −1.0

MAP2K4 UniRef100_P45985 DIKPSNILLDR 293 Lys2 0.4

MAP2K5 UniRef100_Q13163 DVKPSNMLVNTR 294 Lys2 −46.0

MAP2K6 UniRef100_P52564 DVKPSNVLINALGQVK 295 Lys2 2.0

MAP2K7 UniRef100_O14733 DVKPSNILLDER 296 Lys2 19.3

MAP3K1 UniRef100_Q13233 DVKGANLLIDSTGQR 297 Lys2 27.5

MAP3K2 UniRef100_Q9Y2U5 ELAVKQVQFDPDSPETSK 298 Lys1 −1.1

EVNALECEIQLLK

MAP3K2, UniRef100_Q9Y2U5, DIKGANILR 299 Lys2 8.4

MAP3K3 UniRef100_Q99759

MAP3K3 UniRef100_Q99759 ELASKQVQFDPDSPETSKE 300 Lys1 10.0

VSALECEIQLLK

MAP3K4 UniRef100_Q9Y6R4 DIKGANIFLTSSGLIK 301 Lys2 17.3

MAP3K5 UniRef100_Q99683 DIKGDNVLINTYSGVLK 302 Lys2 −10.2

MAP3K6 UniRef100_095382 DIKGDNVLINTFSGLLK 303 Lys2 2.1

MARK2, UniRef100_P27448, DLKAENLLLDADMNIK 304 Lys2 −15.6

MARK3 UniRef100_Q7KZI7

MARK3 UniRef100_P27448 EVAIKIIDKTQLNPTSLQK 305 Lys1 2.6

MARK3, UniRef100_Q96L34, EVAIKIIDK 306 Lys1 −7.5

MARK4 UniRef100_P27448

MARK4 UniRef100_Q96L34 DLKAENLLLDAEANIK 307 Lys2 −28.5

MAST1, UniRef100_Q6P0Q8, DLKPDNLLITSMGHIK 308 Lys2 −24.8

MAST2 UniRef100_Q9Y2H9

MAST3 UniRef100_O60307 DLKPDNLLITSLGHIK 309 Lys2 −4.7

MASTL UniRef100_Q96GX5 GAFGKVYLGQK 310 ATP Loop 1.1

MASTL UniRef100_Q96GX5 LYAVKVVK 311 Lys1 −7.6

MELK UniRef100_Q14680 DLKPENLLFDEYHK 312 Lys2 −3.0

MER, UniRef100_Q06418, KIYSGDYYR 313 Activation 21.2

TYRO3 UniRef100_Q12866 Loop

MET UniRef100_P08581 DMYDKEYYSVHNK 314 Activation 5.7

Loop

MLK3 UniRef100_Q16584 DLKSNNILLLQPIESDDME 315 Lys2 −0.2

IIK

MLK4 UniRef100_Q5TCX8 DLKSSNILLLEK 316 Lys2 1.5

MLKL UniRef100_Q8NB16 APVAIKVFK 317 Lys1 −5.5

MPSK1 UniRef100_O75716 DLKPTNILLGDEGQPVLM 318 Lys2 −2.3

DLGSMNQACIHVEGSR

MSK1 UniRef100_O75582 DIKLENILLDSNGHVVLTD 319 Lys2 −21.5

domain1 FGLSK

MSK2 UniRef100_O75676 DLKLENVLLDSEGHIVLTD 320 Lys2 −8.1

domain1 FGLSK

MST1 UniRef100_Q13043 ETGQIVAIKQPVESDLQE 321 Lys1 7.5

IIK

MST2 UniRef100_Q13188 ESGQVVAIKQVPVESDLQ 322 Lys1 8.6

EIIK

MST3 UniRef100_Q9Y6E0 DIKAANVLLSEHGEVK 323 Lys2 −8.9

MST4 UniRef100_Q9P289 TQQVVAIKIIDLEEAEDEIE 324 Lys1 −37.3

DIQQEITVLSQCDSSYVTK

MST4, UniRef100_O00506, DIKAANVLLSEQGDVK 325 Lys2 −2.4

YSK1 UniRef100_Q9P289

MYO3A, UniRef100_Q8NEV4, DVKGNNILLTTEGGVK 326 Lys2 22.9

MYO3B UniRef100_Q8WXR4

NDR1 UniRef100_Q15208 DIKPDNLLLDSK 327 Lys2 2.3

NDR2 UniRef100_Q9Y2H1 DIKPDNLLLDAK 328 Lys2 9.8

NEK1 UniRef100_Q96PY6 DIKSQNIFLTK 329 Lys2 −7.1

NEK2 UniRef100_P51955 DLKPANVFLDGK 330 Lys2 12.5

NEK3 UniRef100_P51956 SKNIFLTQNGK 331 Activation −8.6

Loop

NEK4 UniRef100_P51957 DLKTQNVFLTR 332 Lys2 2.8

NEK6, UniRef100_Q8TDX7, DIKPANVFITATGVVK 333 Lys2 −1.8

NEK7 UniRef100_Q9HC98

NEK7 UniRef100_Q8TDX7 AACLLDGVPVALKK 334 Lys1 2.7

NEK8 UniRef100_Q86SG6 DLKTQNILLDK 335 Lys2 −7.8

NEK9 UniRef100_Q8TD19 DIKTLNIFLTK 336 Lys2 −10.7

NLK UniRef100_Q9UBE8 DIKPGNLLVNSNCVLK 337 Lys2 22.3

OSR1 UniRef100_C9JIG9, DVKAGNILLGEDGSVQIA 338 Lys2 32.2

UniRef100_095747 DFGVSAFLATGGDITR

p38a UniRef100_Q16539 DLKPSNLAVNEDCELK 339 Lys2 76.1

p38a UniRef100_Q16539 QELNKTIWEVPER 340 Protein 88.4

Kinase

Domain

p38d, UniRef100_O15264, DLKPGNLAVNEDCELK 341 Lys2 51.5

p38g UniRef100_P53778

p70S6K UniRef100_P23443 DLKPENIMLNHQGHVK 342 Lys2 −74.1

p70S6Kb UniRef100_Q9UBS0 DLKPENIMLSSQGHIK 343 Lys2 3.5

PAN3 UniRef100_Q58A45 VMDPTKILITGK 344 ATP 7.3

PCTAIRE1 UniRef100_Q00536 SKLTDNLVALKEIR 345 Lys1 53.3

PCTAIRE2, UniRef100_Q00537, SKLTENLVALKEIR 346 Lys1 72.9

PCTAIRE3 UniRef100_Q07002

PDHK1 UniRef100_Q15118 SPGQPIQVVYVPSHLYHM 347 ATP −23.7

VFELFKNAMR

PEK UniRef100_Q9NZJ5 DLKPSNIFFTMDDVVK 348 Lys2 −21.9

PFTAIRE1 UniRef100_O94921 LVALKVIR 349 Lys1 64.0

PHKg1 UniRef100_Q16816 DLKPENILLDDNMNIK 350 Protein −0.9

Kinase

Domain

PHKg2 UniRef100_P15735 ATGHEFAVKIMEVTAER 351 Lys1 7.1

PI4K2B UniRef100_Q8TCG2 SEEPYGQLNPKWTK 352 ATP 33.4

PI4KA, UniRef100_A4QPH2, SGTPMQSAAKAPYLAK 353 ATP 2.1

PI4KAP2 UniRef100_P42356

P14KB UniRef100_Q9UBF8 VPHTQAVVLNSKDK 354 ATP 23.7

PIK3C2B UniRef100_O00750 VIFKCGDDLRQDMLTLQ 355 ATP −15.7

MIR

PIK3C3 UniRef100_Q8NEB9 TEDGGKYPVIFKHGDDLR 356 ATP −29.7

PIK3CB UniRef100_P42338 VFGEDSVGVIFKNGDDLR 357 ATP −3.9

QDMLTLQMLR

PIK3CD UniRef100_O00329 VNWLAHNVSKDNRQ 358 ATP −22.8

PIK3CG UniRef100_P48736 KKPLWLEFK 359 ATP −20.1

PIP4K2A UniRef100_P48426 AKELPTLKDNDFINEGQK 360 ATP −19.5

PIP4K2C UniRef100_Q8TBX8 TLVIKEVSSEDIADMHSNL 361 ATP −7.3

SNYHQYIVK

PIP5K3 UniRef100_Q9Y217 GGKSGAAFYATEDDRFILK 362 ATP 21.7

PITSLRE UniRef100_P21127 DLKTSNLLLSHAGILK 363 Lys2 10.2

PKCa, UniRef100_P05771, DLKLDNVMLDSEGHIK 364 Lys2 −86.4

PKCb UniRef100_P17252

PKCe UniRef100_Q02156 DLKLDNILLDAEGHCK 365 Lys2 27.7

PKCi UniRef100_P41743 IYAMKVVK 366 Lys1 −54.3

PKD2 UniRef100_Q9BZL6 DVAVKVIDK 367 Lys1 −5.4

PKN1 UniRef100_Q16512 VLLSEFRPSGELFAIKALK 368 Lys1 1.8

PKR UniRef100_P19525 DLKPSNIFLVDTK 369 Lys2 −1.7

K

PLK1 UniRef100_P53350 CFEISDADTKEVFAGKIVP 370 Lys1 18.8

K

PLK4 UniRef100_O00444 AESIHTGLEVAIKMIDKK 371 Lys1 −17.3

PRP4 UniRef100_Q13523 CNILHADIKPDNILVNESK 372 Lys2 −5.5

PRPK UniRef100_Q96544 FLSGLELVKQGAEAR 373 ATP Loop −16.0

PYK2 UniRef100_Q14289 YIEDEDYYKASVTR 374 Activation 30.5

Loop

RIPK1 UniRef100_Q13546 DLKPENILVDNDFHIK 375 Lys2 23.1

RIPK3 UniRef100_Q9Y572 DLKPSNVLLDPELHVK 376 Lys2 70.2

ROCK1, UniRef100_O75116, DVKPDNMLLDK 377 Lys2 −0.2

ROCK2 UniRef100_Q13464

RSK1 UniRef100_Q15418 DLKPENILLDEEGHIKLTDF 378 Lys2 −29.6

domain1 GLSKEAIDHEK

RSK1 UniRef100_P51812, DLKPENILLDEEGHIK 379 Lys2 −25.1

domain1, UniRef100_Q15418,

RSK2 UniRef100_Q15349

domain1,

RSK3

domain1

RSK1 UniRef100_Q15418 DLKPSNILYVDESGNPECL 380 Lys2 1.0

domain2 R

RSK2 UniRef100_P51812 DLKPENILLDEEGHIKLTDF 381 Lys2 −36.7

domain1 GLSKESIDHEK

RSK2 UniRef100_P51812 DLKPSNILYVDESGNPESIR 382 Lys2 2.8

domain2

RSK3 UniRef100_015349 DLKPENILLDEEGHIKITDF 383 Lys2 −37.8

domain1 GLSK

RSKL1 UniRef100_Q96S38 VLGVIDKVLLVMDTR 384 ATP 21.8

SGK3 UniRef100_Q96BR1 FYAVKVLQK 385 Lys1 16.6

SLK UniRef100_Q9H2G2 DLKAGNILFTLDGDIK 386 Lys2 13.8

SMG1 UniRef100_Q96Q15 DTVTIHSVTITILPTKTK 387 ATP −3.6

PK

SNRK UniRef100_Q9NRH2 DLKPENVVFFEK 388 Lys2 24.5

SRC UniRef100_P12931 VAIKTLKPGTMSPEAFLQE 389 Lys1 82.7

AQVMKK

SRPK1 UniRef100_Q96SB4 IIHTDIKPENILLSVNEQYIR 390 Lys2 −9.1

SRPK1, UniRef100_P78362, FVAMKVVK 391 Lys1 −38.7

SRPK2 UniRef100_Q96SB4

STK33 UniRef100_Q9BYT3 DLKLENIMVK 392 Lys2 −8.0

STLK5 UniRef100_Q7RTN6 YSVKVLPWLSPEVLQQNL 393 Activation 12.0

QGYDAK Loop

SYK UniRef100_P43405 ISDFGLSKALR 394 Activation 6.6

Loop

TAK1 UniRef100_043318 DLKPPNLLLVAGGTVLK 395 Lys2 0.4

TAO1, UniRef100_Q7L7X3, DIKAGNILLTEPGQVK 396 Lys2 87.1

TAO3 UniRef100_Q9H2K8

TAO2 UniRef100_Q9UL54 DVKAGNILLSEPGLVK 397 Lys2 92.0

TBK1 UniRef100_Q9UHD2 TGDLFAIKVFNNISFLRPV 398 Lys1 −18.0

DVQMR

TEC UniRef100_P42680 YVLDDQYTSSSGAKFPVK 399 Activation 20.6

Loop

TLK1 UniRef100_Q9UKI8 YLNEIKPPIIHYDLKPGNILL 400 Lys2 11.5

VDGTACGEIK

TLK2 UniRef100_Q86UE8 YLNEIKPPIIHYDLKPGNILL 401 Lys2 10.2

VNGTACGEIK

ULK1 UniRef100_O75385 DLKPQNILLSNPAGR 402 Lys2 8.8

ULK3 UniRef100_D3DW67 NISHLDLKPQNILLSSLEKP 403 Lys2 27.1

HLK

VRK2 UniRef100_Q86Y07 MLDVLEYIHENEYVHGDIK 404 Lys2 −1.2

AANLLLGYK

Wnk1, UniRef100_Q9Y3S1, GSFKTVYK 405 ATP Loop 11.2

Wnk2 UniRef100_D3DUP1

Wnk1, UniRef100_Q9Y3S1, DLKCDNIFITGPTGSVK 406 Lys2 −1.1

Wnk2, UniRef100_D3DUP1,

Wnk3 UniRef100_Q9BYP7

YANK3 UniRef100_Q86UX6 DVKPDNILLDER 407 Lys2 −43.1

ZAK UniRef100_Q9NYL2 WISQDKEVAVKK 408 Lys1 75.8

ZAP70 UniRef100_P43403 ISDFGLSKALGADDSYYTA 409 Activation 10.7

R Loop

ZC1/HGK, UniRef100_095819, DIKGQNVLLTENAEVK 410 Lys2 57.5

ZC2/TNIK, UniRef100_Q9UKE5,

ZC3/MINK UniRef100_Q8N4C8

ZC2/TNIK UniRef100_Q9UKE5 TGQLAAIKVMDVTGDEEE 411 Lys1 46.0

EIKQEINMLKK

Example 3. p-BTK and p-Hck Inhibition

Protocol for PhosFlow Studies

PhosFlow was performed to detect levels of phosphorylation for BTK-pY223 (BD Biosciences) and Hck-pY410 (Abcam) in BCWM.1 cells, in BCWM cells that stably overexpress HCK (BCWM.1_HCK-wt) and in BCWM.1 cells that stably overexpress the T338M mutant of HCK (BCWM.1_HCK-mu). Cells were fixed with BD Phosflow Fix Buffer I (BD Biosciences) at 37° C. for 10 min, then washed twice with BD Phosflow Perm/Wash Buffer I (BD Biosciences). Cells were suspended in BD Phosflow Perm/Wash Buffer I at 10 million/ml and antibodies aliquoted to flow tubes with 100 μl cells. Cells were incubated at room temperature for 30 min in the dark. Cells were washed twice with ED Phosflow Perm/Wash Buffer I before performing flow analysis using a BD™ FACSCanto II flow cytometer.

Protocol for Apoptosis Analysis

Apoptosis analysis of WM patient primary lymphoplasmacytic cells (LPCs) was preformed following A-5 and A-14 treatment of Bone marrow mononuclear cells (BMMC) from WM patients for 24 hours. Apoptosis analysis was performed using Annexin V/Propidium iodide staining with the Apoptosis Detection Kit I (BD Pharmingen) in CD19-APC-cy7 antibody (BD Pharmingen) gated LPCs population.

Results

PhosFlow studies indicate both A-5 and A-14 inhibit Hck and BTK phosphorylation in BCWM.1 cells and BCWM.1 cells with genetic engineered expression of Hck wild type (-wt) and T338M gatekeeper mutant (-mu) with both 0.5 μuM and 0.1 μM doses (shown by Table 6 and Table 7, respectively). In addition, the expression of Hck-wt or Hck-mu increased the resistance to the inhibition of both Hck and BTK phosphorylations by A-5 and A-14, with more resistance presented in Hck-mu expressing BCWM.1 cells. Both A-5 and A-14 induced significant apoptosis in WM patient primary LPCs compared with DMSO control, as shown in Table 8.

TABLE 6

Relative p-BTK p-Hck

MFI % _Hck- _Hck- _Hck- _Hck-

(0.5 μM BCW M.1 BCWM.1 wt BCWM.1 mu BCW M.1 BCWM.1 wt BCWM.1 mu

drugs) 15 min 90 min 15 min 90 min 15 min 90 min 15 min 90 min 15 min 90 min 15 min 90 min

DMSO 100 100 100 100 100 100 100 100 100 100 100 100

A-5 56.3 42.3 73.6 69.9 100.7 90.4 68.2 49 80.4 77.7 102.2 81.1

A-14 51.5 27.4 65.6 29.7 112.1 83.9 59.3 35.6 68.6 41.5 89.7 52.3

TABLE 7

Relative p-BTK p-Hck

MFI % _Hck- _Hck- _Hck- _Hck-

(0.1 μM BCW M.1 BCWM.1 wt BCWM.1 mu BCW M.1 BCWM.1 wt BCWM.1 mu

drugs) 15 min 90 min 15 min 90 min 15 min 90 min 15 min 90 min 15 min 90 min 15 min 90 min

DMSO 100 100 100 100 100 100 100 100 100 100 100 100

A-5 68.1 52.7 82.1 78.3 70.9 70.4 76.3 50.5 76 80.6 95.3 69.6

A-14 81.8 50.1 76.3 72 75.3 61.2 73.6 57.8 75.8 78.9 83.1 63.7

TABLE 8

Dose (1.0 μM) Dose (0.5 μM) Dose (0.2 μM)

Apoptosis Apoptosis Relative Apoptosis Apoptosis Relative Apoptosis Apoptosis Relative

Treatments (%) to DMSO (%) to DMSO (%) to DMSO

Patient 1 Untreated 40.9 114.30%

DMSO 39.2 100%

A-5 57.7 147.20%

Patient 2 N 14.2 97.30%

DMSO 14.6 100%

A-5 28.9 197.90%

Patient 3 N 14.529 95.49%

DMSO 15.216 100.00%

A-5 29.48 193.70%

Patient 4 N 29.83 103.00%

DMSO 29.75 100.00%

A-5 48.56 163.20%

Patient 5 N 18.69 110.70%

DMSO 16.89 100%

A-5 30.5 180.60% 23.25 137.70%

A-14 46.86 277.40% 39.24 232.30%

Patient 6 N 8.66 117.50%

DMSO 7.37 100%

A-5 17.82 241.80%

A-14 20.88 283.30%

Patient 7 DMSO 6.46 100.00%

A-5 18.2 281.70% 17.23 266.70%

A-14 31.51 487.80% 22.62 350.20%

Patient 8 DMSO 5.38 100.00%

A-5 17.31 321.75% 11.04 205.20%

A-14 31.58 586.99% 12.9 239.78%

Patient 9 DMSO 7.6 100.00%

A-14 43.7 575.00% 24.8 326.32%

Patient N 17.6 113.50%

10 DMSO 15.5 100%

A-5 28.7 185.20% 21.5 138.70%

A-14 52 335.50% 27.9 180.00%

Patient N 26.2 112.70%

11 DMSO 25.5 100%

A-5 47 184.30% 30.2 118.40%

A-14 71.8 281.60% 53.1 208.20%

EQUIVALENTS AND SCOPE

In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in. employed in, or otherwise relevant to a given product or process.

Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. lf there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.