# Patent

## Title
Methods to treat lymphoplasmacytic lymphoma

## Abstract

The present invention provides compounds of any one of Formulae (I) to (V) (e.g., compounds of any one of Formulae (I-1) to (I-9)), and methods for treating Waldenström's macroglobulinemia (WM) and other B cell neoplams in a subject using the compounds. The methods comprise administering to a subject in need thereof an effective amount of the compounds. Also provided are methods to treat B cell neoplasms using the compounds 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.

## Background
RELATED APPLICATIONS
The present application is a national stage filing under 35 U.S.C. § 371 of international PCT application, PCT/US2014/070167, filed Dec. 12, 2014, which claims priority under 35 U.S.C. § 119(e) to U.S. provisional patent applications, U.S. Ser. No. 62/036,917, filed Aug. 13, 2014, and U.S. Ser. No. 61/915,684, filed Dec. 13, 2013, each which is incorporated herein by reference.


GOVERNMENT SUPPORT
This invention was made with government support under grant number P50 CA100707 awarded by the National Institutes of Health. The government has certain rights in the invention.


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




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

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







and pharmaceutically acceptable salts thereof.

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




and pharmaceutically acceptable salts thereof, wherein Ring A′, Ring C′, Cy, X′, Y′, Z′, Q′, U′, RA′, RB′, RD′, RX′, k′, l′, and m′ are as defined herein.

The present invention is also based, at least in part, on the discovery that Waldenström's macroglobulinemia may be treated by administration of a compound of the invention to a subject in need thereof. The activity of these compounds was established by in vitro screening against several kinases (e.g., BTK, HCK, TAK1, HPK1) that are involved in the regulation of aberrant cell growth, as well as cell-based screening against several cell lines (e.g., BCWM.1, MWCL-1) that are disease state models of Waldenström's macroglobulinemia (Ditzel et al. Exp Hematol. 2007 September; 35(9):1366-75; Hodge et al. Blood. 2011 May 12; 117(19)).
The methods of treatment utilizing a compound of the invention also apply to B cell neoplasms of the group consisting of Hodgkin's lymphomas and most non-Hodgkin's lymphomas, such as diffuse large B cell lymphoma, Follicular lymphoma, mucosa-associated lymphatic tissue lymphoma (MALT), small cell lymphocytic lymphoma (overlaps with chronic lymphocytic leukemia), mantle cell lymphoma (MCL), Burkitt lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma (NMZL), splenic marginal zone lymphoma (SMZL), Intravascular large B-cell lymphoma, Primary effusion lymphoma, and Lymphomatoid granulomatosis.
The present invention is also based, at least in part, on pharmaceutical compositions comprising a compound of the invention and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition may be useful for modulating the activity of a kinase in vitro or in a subject in need thereof, and/or for treating and/or preventing in a subject in need thereof a condition associated with aberrant activity of a kinase (e.g., a proliferative disease). In certain embodiments, the pharmaceutical composition may be useful for treatment of Waldenström's macroglobulinemia in a subject in need thereof.
The present invention also provides kits comprising a container with a compound of the invention, or a pharmaceutical composition thereof. The kits may include a single dose or multiple doses of a compound described herein or a pharmaceutical composition thereof. The kits may be useful for modulating the activity of a kinase in a subject in need thereof. The kits may also be useful for treating and/or preventing in a subject in need thereof a condition associated with aberrant activity of a kinase. In certain embodiments, the kits further include instructions for using the kit (e.g., for administering a compound described herein, or a pharmaceutical composition thereof).
The details of particular embodiments of the invention are set forth herein. Other features, objects, and advantages of the invention will be apparent from the Detailed Description, the Examples, and the Claims.
DEFINITIONS
Chemical Definitions
Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th 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, 5h 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, 3rd Edition, Cambridge University Press, Cambridge, 1987.
Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972). The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 19F with 18F, or the replacement of a carbon by a 13C- or 14C-enriched carbon are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.
When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example “C1-6 alkyl” is intended to encompass, C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6 alkyl.
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 (“C1-10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C1-8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C1-7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C1-6 alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C1-4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C2-6 alkyl”). Examples of C1-6 alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-10 alkyl (such as unsubstituted C1-6 alkyl, e.g., —CH3 (Me), unsubstituted ethyl (Et), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted n-butyl (n-Bu), unsubstituted tert-butyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted isobutyl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1-10 alkyl (such as substituted C1-6 alkyl, e.g., —CF3, Bn).
As used herein, “haloalkyl” is a substituted alkyl group as defined herein wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. “Perhaloalkyl” is a subset of haloalkyl, and refers to an alkyl group wherein all of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In certain embodiments, the haloalkyl moiety has 1 to 8 carbon atoms (“C1-8 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 6 carbon atoms (“C1-6 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 4 carbon atoms (“C1-4 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 3 carbon atoms (“C1-3 haloalkyl”). In certain embodiments, the haloalkyl moiety has 1 to 2 carbon atoms (“C1-2 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 —CF3, —CF2CF3, —CF2CF2CF3, —CCl3, —CFCl2, —CF2Cl, and the like.
As used herein, “heteroalkyl” refers to an alkyl group as defined herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-10 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-9 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-8 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-7 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC1-6 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC1-5 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 (“heteroC1-4 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-3 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC1-2 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC1 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC1-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC1-10 alkyl.
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 (“C2-9 alkenyl”). In certain embodiments, an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”). In certain embodiments, an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”). In certain embodiments, an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkenyl”). In certain embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In certain embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In certain embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In certain embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carbon-carbon double bonds can be internal (such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), pentadienyl (C5), hexenyl (C6), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (C8), octatrienyl (C8), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C2-10 alkenyl. In certain embodiments, the alkenyl group is a substituted C2-10 alkenyl.
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 (“heteroC2-10 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8 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 (“heteroC2-7 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 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 (“heteroC2-4 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain (“heteroC2-3 alkenyl”). In certain embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 alkenyl”). Unless otherwise specified, each instance of a heteroalkenyl group is independently unsubstituted (an “unsubstituted heteroalkenyl”) or substituted (a “substituted heteroalkenyl”) with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted heteroC2-10 alkenyl. In certain embodiments, the heteroalkenyl group is a substituted heteroC2-10 alkenyl. In an alkenyl group, a C═C double bond for which the stereochemistry is not specified (e.g., —CH═CHCH3 or




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

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) (“C2-10 alkynyl”). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms (“C2-9 alkynyl”). In certain embodiments, an alkynyl group has 2 to 8 carbon atoms (“C2-8 alkynyl”). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (“C2-7 alkynyl”). In certain embodiments, an alkynyl group has 2 to 6 carbon atoms (“C2-6 alkynyl”). In certain embodiments, an alkynyl group has 2 to 5 carbon atoms (“C2-5 alkynyl”). In certain embodiments, an alkynyl group has 2 to 4 carbon atoms (“C2-4 alkynyl”). In certain embodiments, an alkynyl group has 2 to 3 carbon atoms (“C2-3 alkynyl”). In certain embodiments, an alkynyl group has 2 carbon atoms (“C2 alkynyl”). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, without limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (C6), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (C8), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents. In certain embodiments, the alkynyl group is an unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is a substituted C2-10 alkynyl.
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 (“heteroC2-10 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-9 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-8 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 (“heteroC2-7 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain (“heteroC2-6 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-5 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 4 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-4 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain (“heteroC2-3 alkynyl”). In certain embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain (“heteroC2-6 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 heteroC2-10 alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroC2-10 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 (“C3-14 carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. In certain embodiments, a carbocyclyl group has 3 to 10 ring carbon atoms (“C3-10 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C3-8 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”). In certain embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms (“C4-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms (“C5-6 carbocyclyl”). In certain embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”). Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), cyclopentyl (C5), cyclopentenyl (C5), cyclohexyl (C6), cyclohexenyl (C6), cyclohexadienyl (C6), and the like. Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), cyclooctyl (C8), cyclooctenyl (C8), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C3-10 carbocyclyl groups include, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-1H-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) or tricyclic system (“tricyclic carbocyclyl”)) and can be saturated or can contain one or more carbon-carbon double or triple bonds. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is an unsubstituted C3-14 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C3-14 carbocyclyl. In certain embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms (“C3-14 cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In certain embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In certain embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms (“C4-6 cycloalkyl”). In certain embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5-6 cycloalkyl”). In certain embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5-6 cycloalkyl groups include cyclopentyl (C5) and cyclohexyl (C5). Examples of C3-6 cycloalkyl groups include the aforementioned C5-6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C7) and cyclooctyl (C8). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is an unsubstituted C3-14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 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 aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
In certain embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In certain embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetra-hydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.
As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C6-14 aryl”). In certain embodiments, an aryl group has 6 ring carbon atoms (“C6 aryl”; e.g., phenyl). In certain embodiments, an aryl group has 10 ring carbon atoms (“C10 aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In certain embodiments, an aryl group has 14 ring carbon atoms (“C14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is independently unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is an unsubstituted C6-14 aryl. In certain embodiments, the aryl group is a substituted C6-14 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-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.
“Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl group, as defined herein, substituted by a heteroaryl group, as defined herein, wherein the point of attachment is on the alkyl moiety.
As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl moieties) as herein defined.
As used herein, the term “saturated” refers to a ring moiety that does not contain a double or triple bond, i.e., the ring contains all single bonds.
Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.
As understood from the above, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are, in certain embodiments, optionally substituted. Optionally substituted refers to a group which may be substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
Exemplary carbon atom substituents include, but are not limited to, halogen, —CN, —NO2, —N3, —SO2H, —SO3H, —OH, —ORaa, —ON(Rbb)2, —N(Rbb)2, —N(Rbb)3+X−, —N(ORcc)Rbb, —SH, —SRaa, —SSRcc, —C(═O)Raa, —CO2H, —CHO, —C(ORcc)2, —CO2Raa, —OC(═O)Raa, —OCO2Raa, —C(═O)N(Rbb)2, —OC(═O)N(Rbb)2, —NRbbC(═O)Raa, —NRbbCO2Raa, NRbbC(═O)N(Rbb)2, —C(═NRbb)Raa, —C(═NRbb)ORaa, —OC(═NRbb)Raa, —OC(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —OC(═NRbb)N(Rbb)2, —NRbbC(═NRbb)N(Rbb)2, —C(═O)NRbbSO2Raa, NRbbSO2Raa, —SO2N(Rbb)2, —SO2Raa, —SO2ORaa, —OSO2Raa, —S(═O)Raa, —OS(═O)Raa, —Si(Raa)3, —OSi(Raa)3—C(═S)N(Rbb)2, —C(═O)SRaa, —C(═S)SRaa, —SC(═S)SRaa, —SC(═O)SRaa, —OC(═O)SRaa, —SC(═O)ORaa, —SC(═O)Raa, —P(═O)2Raa, —OP(═O)2Raa, —P(═O)(Raa)2, —OP(═O)(Raa)2, —OP(═O)(ORcc)2, —P(═O)2N(Rbb)2, —OP(═O)2N(Rbb)2, —P(═O)(NRbb)2, —OP(═O)(NRbb)2, —NRbbP(═O)(ORcc)2, —NRbbP(═O)(NRbb)2, —P(Rcc)2, —P(Rcc)3, —OP(Rcc)2, —OP(Rcc)3, —B(Raa)2, —B(ORcc)2, —BRaa(ORcc), C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups;
or two geminal hydrogens on a carbon atom are replaced with the group ═O, ═S, ═NN(Rbb)2, ═NNRbbC(═O)Raa, ═NNRbbC(═O)ORaa, ═NNRbbS(═O)2Raa, ═NRbb, or ═NORcc;
each instance of Raa is, independently, selected from C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Raa 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 Rdd groups;
each instance of Rbb is, independently, selected from hydrogen, —OH, —ORaa, —N(Rcc)2, —CN, —C(═O)Raa, —C(═O)N(Rcc)2, —CO2Raa, —SO2Raa, —C(═NRcc)ORaa, —C(═NRcc)N(Rcc)2, —SO2N(Rcc)2, —SO2Rcc, —SO2ORcc, —SORaa, —C(═S)N(Rcc)2, —C(═O)SRcc, —C(═S)SRcc, —P(═O)2Raa, —P(═O)(Raa)2, —P(═O)2N(Rcc)2, —P(═O)(NRcc)2, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10alkyl, heteroC2-10alkenyl, heteroC2-10alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rbb 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 Rdd groups;
each instance of Rcc is, independently, selected from hydrogen, C1-10 alkyl, C1-10 perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, heteroC1-10 alkyl, heteroC2-10 alkenyl, heteroC2-10 alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl, or two Rcc 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 Rdd groups;
each instance of Rdd is, independently, selected from halogen, —CN, —NO2, —N3, —SO2H, —SO3H, —OH, —ORee, —ON(Rff)2, —N(Rff)2, —N(Rff)3+X−, —N(ORee)Rff, —SH, —SRee, —SSRee, —C(═O)Ree, —CO2H, —CO2Ree, —OC(═O)Ree, —OCO2Ree, —C(═O)N(Rff)2, —OC(═O)N(Rff)2, —NRffC(═O)Ree, —NRffCO2Ree, —NRffC(═O)N(Rff)2, —C(═NRff)ORee, —OC(═NRff)Ree, —OC(═NRff)ORee, —C(═NRff)N(Rff)2, —OC(═NRff)N(Rff)2, —NRffC(═NRff)N(Rff)2, —NRffSO2Ree, —SO2N(Rff)2, —SO2Ree, —SO2ORee, —OSO2Ree, —S(═O)Ree, —Si(Ree)3, —OSi(Ree)3, —C(═S)N(Rff)2, —C(═O)SRee, —C(═S)SRee, —SC(═S)SRee, —P(═O)2Ree, —P(═O)(Ree)2, —OP(═O)(Ree)2, —OP(═O)(ORee)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl, 5-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups, or two geminal Rdd substituents can be joined to form ═O or ═S;
each instance of Ree is, independently, selected from C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6 alkyl, heteroC2-6alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups;
each instance of Rff is, independently, selected from hydrogen, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C6-10 aryl and 5-10 membered heteroaryl, or two Rff 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 Rgg groups; and
each instance of Rgg is, independently, halogen, —CN, —NO2, —N3, —SO2H, —SO3H, —OH, —OC1-6 alkyl, —ON(C1-6 alkyl)2, —N(C1-6 alkyl)2, —N(C1-6 alkyl)3+X−, —NH(C1-6 alkyl)2+X−, —NH2(C1-6 alkyl)+X−, —NH3+X−, —N(OC1-6 alkyl)(C1-6 alkyl), —N(OH)(C1-6 alkyl), —NH(OH), —SH, —SC1-6 alkyl, —SS(C1-6alkyl), —C(═O)(C1-6 alkyl), —CO2H, —CO2(C1-6 alkyl), —OC(═O)(C1-6 alkyl), —OCO2(C1-6 alkyl), —C(═O)NH2, —C(═O)N(C1-6 alkyl)2, —OC(═O)NH(C1-6 alkyl), —NHC(═O)(C1-6 alkyl), —N(C1-6 alkyl)C(═O)(C1-6 alkyl), —NHCO2(C1-6 alkyl), —NHC(═O)N(C1-6 alkyl)2, —NHC(═O)NH(C1-6 alkyl), —NHC(═O)NH2, —C(═NH)O(C1-6 alkyl), —OC(═NH)(C1-6 alkyl), —OC(═NH)OC1-6 alkyl, —C(═NH)N(C1-6 alkyl)2, —C(═NH)NH(C1-6 alkyl), —C(═NH)NH2, —OC(═NH)N(C1-6 alkyl)2, —OC(NH)NH(C1-6 alkyl), —OC(NH)NH2, —NHC(NH)N(C1-6 alkyl)2, —NHC(═NH)NH2, —NHSO2(C1-6 alkyl), —SO2N(C1-6 alkyl)2, —SO2NH(C14 alkyl), —SO2NH2, —SO2C1-4 alkyl, —SO2OC1-6 alkyl, —OSO2C1-6alkyl, —SOC1-6 alkyl, —Si(C1-6 alkyl)3, —OSi(C1-6 alkyl)3-C(═S)N(C1-6 alkyl)2, C(═S)NH(C1-6 alkyl), C(═S)NH2, —C(═O)S(C1-6 alkyl), —C(═S)SC1-6 alkyl, —SC(═S)SC1-6 alkyl, —P(═O)2(C1-6 alkyl), —P(═O)(C1-6 alkyl)2, —OP(═O)(C1-6 alkyl)2, —OP(═O)(OC1-6 alkyl)2, C1-6 alkyl, C1-6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroC1-6alkyl, heteroC2-6alkenyl, heteroC2-6alkynyl, C3-10 carbocyclyl, C6-10 aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rgg 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, —ORaa, —N(Rcc)2, —C(═O)Raa, —C(═O)N(Rcc)2, —CO2Raa, —SO2Raa, —C(═NRcc)Raa, —C(═NRcc)ORaa, —C(═NRcc)N(Rcc)2, —SO2N(Rcc)2, —SO2Rcc, —SO2ORcc, —SORaa, —C(═S)N(Rcc)2, —C(═O)SRcc, —C(═S)SRcc, C1-10 alkyl (e.g., alkyl, aralkyl, heteroaralkyl), C2-10 alkenyl, C2-10 alkynyl, C1-10 heteroalkyl, C2-10 heteroalkenyl, C2-10 heteroalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, C6-14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, and wherein Raa, Rbb, Rcc and Rdd 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, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
For example, nitrogen protecting groups such as amide groups (e.g., —C(═O)Raa) include, but are not limited to, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-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)ORaa) include, but are not limited to, methyl carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc), 9-(2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), 1-(1-adamantyl)-1-methylethyl carbamate (Adpoc), 1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc), 1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2′- and 4′-pyridyl)ethyl carbamate (Pyoc), 2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl carbamate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate, 1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate, 1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate, 2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.
Nitrogen protecting groups such as sulfonamide groups (e.g., —S(═O)2Raa) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.
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, —Raa, —N(Rbb)2, —C(═O)SRaa, —C(═O)Raa, —CO2Raa, —C(═O)N(Rbb)2, —C(═NRbb)Raa, —C(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —S(═O)Raa, —SO2Raa, —Si(Raa)3, —P(Rcc)2, —P(Rcc)3, —P(═O)2Raa, —P(═O)(Raa)2, —P(═O)(ORcc)2, —P(═O)2N(Rbb)2, and —P(═O)(NRbb)2, wherein Raa, Rbb, and Rcc 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, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), methylthiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl (CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl, 4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl, p,p′-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl, α-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4′′-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4′,4′′-tris(levulinoyloxyphenyl)methyl, 4,4′,4′′-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4′,4′′-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1, 1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, o-naphthoate, nitrate, alkyl N,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).
In certain embodiments, the substituent present on an sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). Sulfur protecting groups include, but are not limited to, —Raa, —N(Rbb)2, —C(═O)SRaa, —C(═O)Raa, —CO2Raa, —C(═O)N(Rbb)2, —C(═NRbb)Raa, —C(═NRbb)ORaa, —C(═NRbb)N(Rbb)2, —S(═O)Raa, —SO2Raa, —Si(Raa)3, —P(Rcc)2, —P(Rcc)3, —P(═O)2Raa, —P(═O)(Raa)2, —P(═O)(ORcc)2, —P(═O)2N(Rbb)2, and —P(═O)(NRbb)2, wherein Raa, Rbb, and Rcc 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, 3rd 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, —NO2, trialkylammonium, and aryliodonium salts. In certain embodiments, the leaving group is a sulfonic acid ester. In certain embodiments, the sulfonic acid ester comprises the formula —OSO2RLG1 wherein RLG1 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, RLG1 is substituted or unsubstituted C1-C6 alkyl. In certain embodiments, RLG1 is methyl. In certain embodiments, RLG1 is —CF3. In certain embodiments, RLG1 is substituted or unsubstituted aryl. In certain embodiments, RLG1 is substituted or unsubstituted phenyl. In certain embodiments RLG1 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, Examples, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.
Other Definitions
The following definitions are more general terms used throughout the present application.
As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1-4 alkyl)4− salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. Compounds of the invention may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.
The term “hydrate” refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R·×H2O, wherein R is the compound and wherein x is a number greater than 0. A given compound may form more than one type of hydrates, including, e.g., monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R·0.5H2O)), and polyhydrates (x is a number greater than 1, e.g., dihydrates (R·2H2O) and hexahydrates (R·6H2O)).
The term “tautomers” refer to compounds that are interchangeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of it electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.
Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
The term “polymorphs” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.
The term “prodrugs” refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly the C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, aryl, C7-C12 substituted aryl, and C7-C12 arylalkyl esters of the compounds of the invention (e.g., the compounds of Formula (I) and compounds of any one of Formulae (II) to (V)).


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




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

wherein:

each instance of RA is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, —ORA1, —N(RA1)2, —CN, —C(═O)RA1, —C(═O)ORA1, —C(═O)N(RA1)2, —NO2, —NRA1C(═O)RA1, —NRA1C(═O)ORA1, —NRA1S(═O)2RA1, —S(═O)2RA1, or —S(═O)2N(RA1)2;
each instance of RB 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, —ORA1, —N(RA1)2, —CN, —C(═O)RA1, —C(═O)ORA1, —C(═O)N(RA1)2, —NO2, —NRA1C(═O)RA1, —NRA1C(═O)ORA1, —NRA1S(═O)2RA1, —S(═O)2RA1, or —S(═O)2N(RA1)2;
each instance of RA1 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 RA1 groups are joined to form an optionally substituted heterocyclic ring;
RX is RD or is selected from the group consisting of optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and —N(RA1)(RXa);
each instance of RXa 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)RA1, —C(═O)ORA1, —C(═O)N(RA1)2, —S(═O)RA1, —S(═O)N(RA1)2, —S(═O)2RA1, —S(═O)2ORA1, —S(═O)2N(RA1)2, and a nitrogen protecting group;
k is 0, 1, 2, 3, or 4;
l is 1, 2, 3, 4, or 5;
X and Y are taken together to be —NRA(C═O)— or —(C═O)NRA—;
Q and U are taken together to be —NRA(C═O)— or —(C═O)NRA—; and
RD 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), phosphoinositide 3-kinase (PI3K), and/or transforming growth factor b-activated kinase-1 (TAK1), and/or a Src family kinase.
Waldenstrom's macroglobulinemia (WM) is a distinct clinicopathological entity resulting from the accumulation, predominantly in the bone marrow, of clonally related lymphoplasmacytic cells which secrete a monoclonal IgM protein. This condition is considered to correspond to lymphoplasmacytic lymphoma (LPL) as defined by the World Health Organization classification system. Genetic factors play an important role in the pathogenesis of WM, with 25% of patients demonstrating a family history. IgM monoclonal gammopathy of unknown significance (MGUS) often precedes the development of WM.
As used herein, a B cell neoplasm includes both Hodgkin's lymphoma and non-Hodgkin's lymphomas. Classical Hodgkin's lymphoma (HL) includes various subtypes such as Nodular sclerosing HL, Mixed-cellularity subtype, Lymphocyte-rich or Lymphocytic predominance and Lymphocyte depleted. Examples of B cell non-Hodgkin's lymphomas include, but are not limited to, Waldenström's macroglobulinemia, diffuse large B cell lymphoma, follicular lymphoma, mucosa-associated lymphatic tissue lymphoma (MALT), small cell lymphocytic lymphoma (overlaps with chronic lymphocytic leukemia), mantle cell lymphoma (MCL), Burkitt lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma (NMZL), splenic marginal zone lymphoma (SMZL), intravascular large B-cell lymphoma, primary effusion lymphoma, and lymphomatoid granulomatosis.
In certain embodiments, the subject is administered a compound of Formula (I):




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

wherein:

each instance of RA is independently selected from the group consisting of hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, —ORA1, —N(RA1)2, —CN, —C(═O)RA1, —C(═O)ORA1, —C(═O)N(RA1)2, —NO2, —NRA1C(═O)RA1, —NRA1C(═O)ORA1, —NRA1S(═O)2RA1, —S(═O)2RA1, or —S(═O)2N(RA1)2;
each instance of RB 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, —ORA1, —N(RA1)2, —CN, —C(═O)RA1, —C(═O)ORA1, —C(═O)N(RA1)2, —NO2, —NRA1C(═O)RA1, —NRA1C(═O)ORA1, —NRA1S(═O)2RA1, —S(═O)2RA1, or —S(═O)2N(RA1)2;
each instance of RA1 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 RA1 groups are joined to form an optionally substituted heterocyclic ring;
RX is RD or is selected from the group consisting of optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and —N(RA1)(RXa);
each instance of RXa 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)RA1, —C(═O)ORA1, —C(═O)N(RA1)2, —S(═O)RA1, —S(═O)N(RA1)2, —S(═O)2RA1, —S(═O)2ORA1, —S(═O)2N(RA1)2, and a nitrogen protecting group;
k is 0, 1, 2, 3, or 4;
l is 1, 2, 3, 4, or 5;
X and Y are taken together to be —NRA(C═O)— or —(C═O)NRA—;
Q and U are taken together to be —NRA(C═O)— or —(C═O)NRA—; and
RD is an electrophilic moiety as described herein.
In certain embodiments, the subject is adminstered a compound (I-1):




or a pharmaceutically acceptable salt thereof.

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




or a pharmaceutically acceptable salt thereof.

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




or a pharmaceutically acceptable salt thereof.

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




or a pharmaceutically acceptable salt thereof.

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




or a pharmaceutically acceptable salt thereof.

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




or a pharmaceutically acceptable salt thereof.

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




or a pharmaceutically acceptable salt thereof.

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




or a pharmaceutically acceptable salt thereof.

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




or a pharmaceutically acceptable salt thereof.

Compounds of Formula (I) include a phenyl Ring A optionally substituted with one or more RA 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 (I), Ring A may be substituted with one or more RA groups. In certain embodiments, at least one RA is H. In certain embodiments, at least two RA groups are H. In certain embodiments, at least three RA groups are H. In certain embodiments, at least four RA groups are H. In certain embodiments, at least one RA is not H. In certain embodiments, at least two RA groups are not H. In certain embodiments, at least three RA groups are not H. In certain embodiments, at least one RA is halogen. In certain embodiments, at least one RA is F. In certain embodiments, at least one RA is Cl. In certain embodiments, at least one RA is Br. In certain embodiments, at least one RA is I (iodine). In certain embodiments, one RA is F. In certain embodiments, one RA is Cl. In certain embodiments, at least one RA is substituted alkyl. In certain embodiments, at least one RA is unsubstituted alkyl. In certain embodiments, at least one RA is substituted C1-6 alkyl. In certain embodiments, at least one RA is unsubstituted C1-6 alkyl. In certain embodiments, at least one RA is methyl. In certain embodiments, at least one RA is ethyl. In certain embodiments, at least one RA is propyl. In certain embodiments, at least one RA is butyl. In certain embodiments, at least one RA is substituted carbocyclyl. In certain embodiments, at least one RA is unsubstituted carbocyclyl. In certain embodiments, at least one RA is —ORA1. In certain embodiments, at least one RA is —O(C1-6 alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one RA is —OMe. In certain embodiments, at least one RA is —OH. In certain embodiments, at least one RA is —N(RA1)2. In certain embodiments, at least one RA is —NH2. In certain embodiments, at least one RA is —CN. In certain embodiments, at least one RA is —C(═O)RA1. In certain embodiments, at least one RA is acetyl. In certain embodiments, at least one RA is —C(═O)ORA1. In certain embodiments, at least one RA is —C(═O)N(RA1)2. In certain embodiments, at least one RA is —C(═O)NHRA1. In certain embodiments, at least one RA is —C(═O)NH(C1-6 alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one RA is —C(═O)NHMe. In certain embodiments, at least one RA is —C(═O)NH2. In certain embodiments, at least one RA is —NO2. In certain embodiments, at least one RA is —NRA1C(═O)RA1. In certain embodiments, at least one RA is —NRA1C(═O)ORA1. In certain embodiments, at least one RA is —NRA1S(═O)2RA1. In certain embodiments, at least one RA is —NHS(═O)2RA1. In certain embodiments, at least one RA is —NHS(═O)2(C1-6 alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one RA is —NHS(═O)2Me. In certain embodiments, at least one RA is —S(═O)2RA1. In certain embodiments, at least one RA is —S(═O)2N(RA1)2. In certain embodiments, at least one RA is —S(═O)2N(RA1)2. In certain embodiments, at least one RA is —S(═O)2N(C1-6 alkyl)2. In certain embodiments, at least one RA is —S(═O)2NH(C1-6 alkyl). In certain embodiments, at least one RA is —S(═O)2NH(t-Bu). In certain embodiments, at least one RA is —S(═O)2NH2.
In certain embodiments, RA is —ORA1; and k is 1. In certain embodiments, RA is —O(C1-6 alkyl); and k is 1. In certain embodiments, RA is —OMe; and k is 1. In certain embodiments, RA is —OH; and k is 1.
In certain embodiments, RA is substituted C1-6 alkyl; and k is 1. In certain embodiments, RA is unsubstituted C1-6 alkyl; and k is 1. In certain embodiments, RA is methyl; and k is 1. In certain embodiments, RA is —CF3; and k is 1. In certain embodiments, RA is ethyl; and k is 1. In certain embodiments, RA is propyl; and k is 1. In certain embodiments, RA is butyl; and k is 1. In certain embodiments, RA is propyl; and k is 1. In certain embodiments, RA is butyl; and k is 1.
In certain embodiments, RA is halogen; and k is 1. In certain embodiments, RA is F; and k is 1. In certain embodiments, RA is Cl; and k is 1. In certain embodiments, RA is Br; and k is 1. In certain embodiments, RA is I (iodine); and k is 1.
In certain embodiments, one instance of RA is halogen; another instance of RA is substituted C1-6 alkyl; and k is 2. In certain embodiments, one instance of RA is F; another instance of RA is substituted C1-6 alkyl; and k is 2. In certain embodiments, one instance of RA is Cl; another instance of RA is substituted C1-6 alkyl; and k is 2. In certain embodiments, one instance of RA is halogen; another instance of RA is unsubstituted C1-6 alkyl; and k is 2. In certain embodiments, one instance of RA is F; another instance of RA is unsubstituted C1-6 alkyl; and k is 2. In certain embodiments, one instance of RA is Cl; another instance of RA is unsubstituted C1-6 alkyl; and k is 2. In certain embodiments, one instance of RA is halogen; another instance of RA is methyl; and k is 2. In certain embodiments, one instance of RA is F; another instance of RA is methyl; and k is 2. In certain embodiments, one instance of RA is Cl; another instance of RA is methyl; and k is 2. In certain embodiments, one instance of RA is halogen; another instance of RA is —CF3; and k is 2. In certain embodiments, one instance of RA is F; another instance of RA is —CF3; and k is 2. In certain embodiments, one instance of RA is Cl; another instance of RA is —CF3; and k is 2.
In certain embodiments, at least one RA1 is H. In certain embodiments, at least one RA1 is substituted acyl. In certain embodiments, at least one RA1 is unsubstituted acyl. In certain embodiments, at least one RA1 is acetyl. In certain embodiments, at least one RA1 is substituted alkyl. In certain embodiments, at least one RA1 is unsubstituted alkyl. In certain embodiments, at least one RA1 is C1-6 alkyl. In certain embodiments, at least one RA1 is methyl. In certain embodiments, at least one RA1 is ethyl. In certain embodiments, at least one RA1 is propyl. In certain embodiments, at least one RA1 is butyl. In certain embodiments, at least one RA1 is substituted alkenyl. In certain embodiments, at least one RA1 is unsubstituted alkenyl. In certain embodiments, at least one RA1 is substituted alkynyl. In certain embodiments, at least one RA1 is unsubstituted alkynyl. In certain embodiments, at least one RA1 is substituted carbocyclyl. In certain embodiments, at least one RA1 is unsubstituted carbocyclyl. In certain embodiments, at least one RA1 is substituted heterocyclyl. In certain embodiments, at least one RA1 is unsubstituted heterocyclyl. In certain embodiments, at least one RA1 is substituted aryl. In certain embodiments, at least one RA1 is unsubstituted aryl. In certain embodiments, at least one RA1 is substituted phenyl. In certain embodiments, at least one RA1 is unsubstituted phenyl. In certain embodiments, at least one RA1 is substituted heteroaryl. In certain embodiments, at least one RA1 is unsubstituted heteroaryl. In certain embodiments, at least one RA1 is substituted pyridyl. In certain embodiments, at least one RA1 is unsubstituted pyridyl. In certain embodiments, at least one RA1 is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one RA1 is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, RA1 is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, RA1 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, RA1 is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, RA1 is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom.
In compounds of Formula (I), two RA1 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 RA1 groups are joined to form a substituted carbocyclic ring. In certain embodiments, two RA1 groups are joined to form an unsubstituted carbocyclic ring. In certain embodiments, two RA1 groups are joined to form a substituted heterocyclic ring. In certain embodiments, two RA1 groups are joined to form an unsubstituted heterocyclic ring. In certain embodiments, two RA1 groups are joined to form a substituted aryl ring. In certain embodiments, two RA1 groups are joined to form an unsubstituted aryl ring. In certain embodiments, two RA1 groups are joined to form a substituted phenyl ring. In certain embodiments, two RA1 groups are joined to form an unsubstituted phenyl ring. In certain embodiments, two RA1 groups are joined to form a substituted heteroaryl ring. In certain embodiments, two RA1 groups are joined to form an unsubstituted heteroaryl ring.
Compounds of Formula (I) include a phenyl Ring C optionally substituted with one or more RB 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:





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





In compounds of Formula (I), Ring C may be substituted with one or more RB groups. In certain embodiments, at least one RB is H. In certain embodiments, at least two RB groups are H. In certain embodiments, at least three RB groups are H. In certain embodiments, at least four RB groups are H. In certain embodiments, at least one RB is not H. In certain embodiments, at least two RB groups are not H. In certain embodiments, at least three RB groups are not H. In certain embodiments, at least one RB is halogen. In certain embodiments, at least one RB is F. In certain embodiments, at least one RB is Cl. In certain embodiments, at least one RB is Br. In certain embodiments, at least one RB is I (iodine). In certain embodiments, one RB is F. In certain embodiments, one RB is Cl. In certain embodiments, at least one RB is substituted alkyl. In certain embodiments, at least one RB is unsubstituted alkyl. In certain embodiments, at least one RB is substituted C1-6 alkyl. In certain embodiments, at least one RB is unsubstituted C1-6 alkyl. In certain embodiments, at least one RB is methyl. In certain embodiments, at least one RB is ethyl. In certain embodiments, at least one RB is propyl. In certain embodiments, at least one RB is




In certain embodiments, at least one RB is





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is butyl. In certain embodiments, at least one RB is substituted carbocyclyl. In certain embodiments, at least one RB is unsubstituted carbocyclyl. In certain embodiments, at least one RB is substituted heterocyclyl. In certain embodiments, at least one RB is unsubstituted heterocyclyl. In certain embodiments, at least one RB is substituted piperidine. In certain embodiments, at least one RB is unsubstituted piperidine. In certain embodiments, at least one RB substituted piperizine. In certain embodiments, at least one RB unsubstituted piperizine. In certain embodiments, at least one RB substituted pyrrolidine. In certain embodiments, at least one RB unsubstituted pyrrolidine. In certain embodiments, at least one RB is substituted morpholine. In certain embodiments, at least one RB is unsubstituted morpholine. In certain embodiments, at least one RB is substituted diazapane. In certain embodiments, at least one RB is unsubstituted diazapane. In certain embodiments, at least one RB is





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is substituted —(CH2)(heterocyclyl). In certain embodiments, at least one RB is unsubstituted —(CH2)(heterocyclyl). In certain embodiments, at least one RB is





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is substituted —(CH2)2(heterocyclyl). In certain embodiments, at least one RB is unsubstituted —(CH2)2(heterocyclyl). In certain embodiments, at least one RB is





In certain embodiments, at least one RB is substituted —(CH2)3(heterocyclyl). In certain embodiments, at least one RB is unsubstituted —(CH2)3(heterocyclyl). In certain embodiments, at least one RB is





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





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is —ORA1. In certain embodiments, at least one RB is —O(C1-6 alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one RB is —OMe. In certain embodiments, at least one RB is —OPh. In certain embodiments, at least one RB is





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is —OH. In certain embodiments, at least one RB is —N(RA1)2. In certain embodiments, at least one RB is —NEt2. In certain embodiments, at least one RB is —NMe2. In certain embodiments, at least one RB is —NHtBu. In certain embodiments, at least one RB is





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is —NH2. In certain embodiments, at least one RB is —CN. In certain embodiments, at least one RB is —C(═O)RA1. In certain embodiments, at least one RB is acetyl. In certain embodiments, at least one RB is —C(═O)ORA1. In certain embodiments, at least one RB is —C(═O)N(RA1)2. In certain embodiments, at least one RB is —C(═O)NHRA1. In certain embodiments, at least one RB is —C(═O)NH(C1-6 alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one RB is —C(═O)NHMe. In certain embodiments, at least one RB is —C(═O)NH2. In certain embodiments, at least one RB is





In certain embodiments, at least one RB is





In certain embodiments, at least one RB is —NO2. In certain embodiments, at least one RB is —NRA1C(═O)RA1. In certain embodiments, at least one RB is —NRA1C(═O)ORA1. In certain embodiments, at least one RB is —NRA1S(═O)2RA1. In certain embodiments, at least one RB is —NHS(═O)2RA1. In certain embodiments, at least one RB is —NHS(═O)2(C1-6 alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one RB is —NHS(═O)2Me. In certain embodiments, at least one RB is —S(═O)2RA1. In certain embodiments, at least one RB is —S(═O)2N(RA1)2. In certain embodiments, at least one RB is —S(═O)2N(RA1)2. In certain embodiments, at least one RB is —S(═O)2N(C1-6 alkyl)2. In certain embodiments, at least one RB is —S(═O)2NH(C1-6 alkyl). In certain embodiments, at least one RB is —S(═O)2NH(t-Bu). In certain embodiments, at least one RB is —S(═O)2NH2.

In certain embodiments, RB is substituted or unsubstituted C1-6alkyl; and l is 1. In certain embodiments, RB is substituted or unsubstituted C1-6alkyl; l is 1; and RB is meta to the point of attachment of U. In certain embodiments, RB is substituted or unsubstituted C1-6alkyl; l is 1; and RB is para to the point of attachment of U. In certain embodiments, RB is C1-6alkyl substituted with one —CN group; and l is 1. In certain embodiments, RB is C1-6alkyl substituted with one —CN group; l is 1; and RB is meta to the point of attachment of U. In certain embodiments, RB is C1-6alkyl substituted with one —CN group; l is 1; and RB is para to the point of attachment of U. In certain embodiments, RB is




and l is 1. In certain embodiments, RB is





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





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





and l is 1. In certain embodiments, RB is





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





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





and l is 1. In certain embodiments, RB is





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





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





and l is 1. In certain embodiments, RB is





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





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

In certain embodiments, at least one RB group is substituted or unsubstituted C1-6alkyl; and l is 2. In certain embodiments, at least one RB group is substituted or unsubstituted C1-6alkyl; l is 2; and at least one RB is meta to the point of attachment of U. In certain embodiments, at least one RB group is substituted or unsubstituted C1-6alkyl; l is 2; and one RB is para to the point of attachment of U. In certain embodiments, at least one RB group is C1-6alkyl substituted with one —CN group; and l is 2. In certain embodiments, at least one RB group is C1-6alkyl substituted with one —CN group; l is 2; and at least one RB is meta to the point of attachment of U. In certain embodiments, at least one RB group is C1-6alkyl substituted with one —CN group; l is 2; and one RB is para to the point of attachment of U. In certain embodiments, at least one RB group is




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





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





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





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





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





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





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





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





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





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





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





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

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




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





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





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





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




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 compounds of Formula (I), the pyridine ring may be substituted with one or more RX groups. In certain embodiments, at least one RX is substituted carbocyclyl. In certain embodiments, at least one RX is unsubstituted carbocyclyl. In certain embodiments, at least one RX is




In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is substituted heterocyclyl. In certain embodiments, at least one RX is unsubstituted heterocyclyl. In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





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





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is CN





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





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is —N(RA1)(RXa). In certain embodiments at least one RX is —NH2. In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is R





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In certain embodiments, at least one RX is





In compounds of Formula (I), RX may be substituted with one or more RXa groups. Each instance of RXa 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)RA1, —C(═O)ORA1, —C(═O)N(RA1)2, —S(═O)RA1, —S(═O)N(RA1)2, —S(═O)2RA1, —S(═O)2ORA1, —S(═O)2N(RA1)2, and a nitrogen protecting group; wherein each occurrence of RA1 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 RA1 groups are joined to form an optionally substituted heterocyclic ring.
In certain embodiments, at least one RXa is H. In certain embodiments, all RXa groups are H. In certain embodiments, at least one RXa is substituted alkyl. In certain embodiments, at least one RXa is substituted C1-6 alkyl. In certain embodiments, at least one RXa is substituted methyl. In certain embodiments, at least one RXa is unsubstituted alkyl. In certain embodiments, at least one RXa is unsubstituted C1-6 alkyl. In certain embodiments, at least one RXa is methyl. In certain embodiments, at least one RXa is ethyl. In certain embodiments, at least one RXa is propyl. In certain embodiments, at least one RXa is butyl. In certain embodiments, at least one RXa is substituted alkenyl. In certain embodiments, at least one RXa is unsubstituted alkenyl. In certain embodiments, at least one RXa is substituted alkynyl. In certain embodiments, at least one RXa is unsubstituted alkynyl. In certain embodiments, at least one RXa is substituted carbocyclyl. In certain embodiments, at least one RXa is unsubstituted carbocyclyl. In certain embodiments, at least one RXa is substituted heterocyclyl. In certain embodiments, at least one RXa is unsubstituted heterocyclyl. In certain embodiments, at least one RXa is substituted aryl. In certain embodiments, at least one RXa is unsubstituted aryl. In certain embodiments, at least one RXa is substituted phenyl. In certain embodiments, at least one RXa is unsubstituted phenyl. In certain embodiments, at least one RXa is substituted heteroaryl. In certain embodiments, at least one RXa is unsubstituted heteroaryl. In certain embodiments, at least one RXa is —C(═O)RA1. In certain embodiments, at least one RXa is —C(═O)H. In certain embodiments, at least one RXa is acetyl. In certain embodiments, at least one RXa is —C(═O)(C1-6alkyl). In certain embodiments, at least one RXa is —C(═O)ORA1. In certain embodiments, at least one RXa is —C(═O)OH. In certain embodiments, at least one RXa is —C(═O)O(C1-6alkyl). In certain embodiments, at least one RXa is —C(═O)N(RA1)2. In certain embodiments, at least one RXa is —C(═O)NHRA1. In certain embodiments, at least one RXa is —C(═O)N(C1-6 alkyl)2. In certain embodiments, at least one RXa is —C(═O)NH(C1-6 alkyl). In certain embodiments, at least one RXa is —C(═O)NH2. In certain embodiments, at least one RXa is —S(═O)RA1. In certain embodiments, at least one RXa is —S(═O)(C1-6alkyl). In certain embodiments, at least one RXa is —S(═O)N(RA1)2. In certain embodiments, at least one RXa is —S(═O)NH(RA1). In certain embodiments, at least one RXa is —S(═O)NH2. In certain embodiments, at least one RXa is —S(═O)N(C1-6alkyl)2. In certain embodiments, at least one RXa is —S(═O)NH(C1-6alkyl). In certain embodiments, at least one RXa is —S(═O)2RA1. In certain embodiments, at least one RXa is —S(═O)2(C1-6alkyl). In certain embodiments, at least one RXa is —S(═O)2ORA1. In certain embodiments, at least one RXa is —S(═O)2OH. In certain embodiments, at least one RXa is —S(═O)2N(RA1)2. In certain embodiments, at least one RXa is —S(═O)2NH(RA1). In certain embodiments, at least one RXa is —S(═O)2NH2. In certain embodiments, at least one RXa is —S(═O)2N(C1-6alkyl)2. In certain embodiments, at least one RXa is —S(═O)2NH(C1-6alkyl).
In compounds of Formula (I), RX may be substituted with one or more RXc groups. Each instance of RXc 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, —ORA1, —N(RA1)2, —SRA1, —CN, —C(═O)RA1, —C(═O)ORA1, —C(═O)N(RA1)2, —NO2, —N3, —NRA1C(═O)RA1, —NRA1C(═O)ORA1, —NRA1C(═O)N(RA1)2, —NRA1S(═O)2RA1, —NRA1S(═O)RA1, —OC(═O)RA1, —OC(═O)ORA1, —OC(═O)N(RA1)2, —S(═O)RA1, —S(═O)N(RA1)2, —S(═O)2RA1, —S(═O)2N(RA1)2; wherein each occurrence of RA1 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 RA1 groups are joined to form an optionally substituted heterocyclic ring.
In certain embodiments, at least one RXc is H. In certain embodiments, all RXc groups are H. In certain embodiments, at least one RXc is substituted alkyl. In certain embodiments, at least one RXc is substituted C1-6 alkyl. In certain embodiments, at least one RXc is substituted methyl. In certain embodiments, at least one RXc is unsubstituted alkyl. In certain embodiments, at least one RXc is unsubstituted C1-6 alkyl. In certain embodiments, at least one RXc is methyl. In certain embodiments, at least one RXc is ethyl. In certain embodiments, at least one RXc is propyl. In certain embodiments, at least one RXc is butyl. In certain embodiments, at least one RXc is substituted alkenyl. In certain embodiments, at least one RXc is unsubstituted alkenyl. In certain embodiments, at least one RXc is substituted alkynyl. In certain embodiments, at least one RXc is unsubstituted alkynyl. In certain embodiments, at least one RXc is substituted carbocyclyl. In certain embodiments, at least one RXc is unsubstituted carbocyclyl. In certain embodiments, at least one RXc is substituted heterocyclyl. In certain embodiments, at least one RXc is unsubstituted heterocyclyl. In certain embodiments, at least one RXc is substituted aryl. In certain embodiments, at least one RXc is unsubstituted aryl. In certain embodiments, at least one RXc is substituted phenyl. In certain embodiments, at least one RXc is unsubstituted phenyl. In certain embodiments, at least one RXc is substituted heteroaryl. In certain embodiments, at least one RXc is unsubstituted heteroaryl. In certain embodiments, at least one RXc is —ORA1. In certain embodiments, at least one RXc is —OH. In certain embodiments, at least one RXc is —O(C1-6alkyl). In certain embodiments, at least one RXc is —N(RA1)2. In certain embodiments, at least one RXc is —NH(RA1). In certain embodiments, at least one RXc is —N(C1-6alkyl)2. In certain embodiments, at least one RXc is —NH(C1-6alkyl). In certain embodiments, at least one RXc is —NH2. In certain embodiments, at least one RXc is —SRA1. In certain embodiments, at least one RXc is —SH. In certain embodiments, at least one RXc is —S(C1-6alkyl). In certain embodiments, at least one RXc is —CN. In certain embodiments, at least one RXc is —NO2. In certain embodiments, at least one RXc is —N3. In certain embodiments, at least one RXc is —NRA1C(═O)RA1. In certain embodiments, at least one RXc is —NHC(═O)RA1. In certain embodiments, at least one RXc is —NHC(═O)(C1-6alkyl). In certain embodiments, at least one RXc is —NRA1C(═O)ORA1. In certain embodiments, at least one RXc is —NHC(═O)ORA1. In certain embodiments, at least one RXc is —NRA1C(═O)O(C1-6alkyl). In certain embodiments, at least one RXc is —NRA1C(═O)N(RA1)2. In certain embodiments, at least one RXc is —NHC(═O)N(C1-6alkyl)2. In certain embodiments, at least one RXc is —NHC(═O)NH2. In certain embodiments, at least one RXc is —NRA1S(═O)2RA1. In certain embodiments, at least one RXc is —NHS(═O)2RA1. In certain embodiments, at least one RXc is —NHS(═O)2(C1-6alkyl). In certain embodiments, at least one RXc is —NRA1S(═O)RA1. In certain embodiments, at least one RXc is —NRA1S(═O)(C1-6alkyl). In certain embodiments, at least one RXc is —NHS(═O)(C1-6alkyl). In certain embodiments, at least one RXc is —OC(═O)RA1. In certain embodiments, at least one RXc is —OC(═O)(C1-6alkyl). In certain embodiments, at least one RXc is —OC(═O)ORA1. In certain embodiments, at least one RXc is —OC(═O)O(C1-6alkyl). In certain embodiments, at least one RXc is —OC(═O)N(RA1)2. In certain embodiments, at least one RXc is —OC(═O)NH(RA1). In certain embodiments, at least one RXc is —OC(═O)N(C1-6alkyl)2. In certain embodiments, at least one RXc is —C(═O)RA1. In certain embodiments, at least one RXc is —C(═O)H. In certain embodiments, at least one RXc is acetyl. In certain embodiments, at least one RXc is —C(═O)(C1-6alkyl). In certain embodiments, at least one RXc is —C(═O)ORA1. In certain embodiments, at least one RXc is —C(═O)OH. In certain embodiments, at least one RXc is —C(═O)O(C1-6alkyl). In certain embodiments, at least one RXc is —C(═O)N(RA1)2. In certain embodiments, at least one RXc is —C(═O)NHRA1. In certain embodiments, at least one RXc is —C(═O)N(C1-6 alkyl)2. In certain embodiments, at least one RXc is —C(═O)NH(C1-6 alkyl). In certain embodiments, at least one RXc is —C(═O)NH2. In certain embodiments, at least one RXc is —S(═O)RA1. In certain embodiments, at least one RXc is —S(═O)(C1-6alkyl). In certain embodiments, at least one RXc is —S(═O)N(RA1)2. In certain embodiments, at least one RXc is —S(═O)NH(RA1). In certain embodiments, at least one RXc is —S(═O)NH2. In certain embodiments, at least one RXc is —S(═O)N(C1-6alkyl)2. In certain embodiments, at least one RXc is —S(═O)NH(C1-6alkyl). In certain embodiments, at least one RXc is —S(═O)2RA1. In certain embodiments, at least one RXc is —S(═O)2(C1-6alkyl). In certain embodiments, at least one RXc is —S(═O)2ORA1. In certain embodiments, at least one RXc is —S(═O)2OH. In certain embodiments, at least one RXc is —S(═O)2N(RA1)2. In certain embodiments, at least one RXc is —S(═O)2NH(RA1). In certain embodiments, at least one RXc is —S(═O)2NH2. In certain embodiments, at least one RXc is —S(═O)2N(C1-6alkyl)2. In certain embodiments, at least one RXc is —S(═O)2NH(C1-6alkyl).
In compounds of Formula (I), RD is an optional electrophilic moiety that is attached to the pyridyl ring. In certain embodiments, RD is any one of Formulae (i-1)-(i-18):










RD1 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, —NO2, —ORD1a, —N(RD1a)2, —SRD1a, —CH2ORD1a, —CH2N(RD1a)2, —CH2SRD1a, —C(═O)RD1a, —C(═O)ORD1a, —C(═O)SRD1a, —C(═O)N(RD1a)2, —C(═S)RD1a, —C(═S)ORD1a, —C(═S)SRD1a, —C(═S)N(RD1a)2, —C(═NRD1a)RD1a, —C(═NRD1a)ORD1a, —C(═NRD1a)SRD1a, and —C(═NRD1a)N(RD1a)2, wherein each occurrence of RD1a 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 RD1a groups are joined to form an optionally substituted heterocyclic ring;
RD2 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, —NO2, —ORD2a, —N(RD2a)2, —SRD2a, —CH2ORD2a, —CH2N(RD2a)2, —CH2SRD2a, —C(═O)RD2a, —C(═O)ORD2a, —C(═O)SRD2a, —C(═O)N(RD2a)2, —C(═S)RD2a, —C(═S)ORD2a, —C(═S)SRD2a, —C(═S)N(RD2a)2, —C(═NRD2a)RD2a, —C(═NRD2a)ORD2a, —C(═NRD2a)SRD2a, and —C(═NRD2a)N(RD2a)2, wherein each occurrence of RD2a 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 RD2a groups are joined to form an optionally substituted heterocyclic ring;
RD3 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, —NO2, —ORD3a, —N(RD3a)2, —SRD3a, —CH2ORD3a, —CH2N(RD3a)2, —CH2SRD3a, —C(═O)RD3a, —C(═O)ORD3a, —C(═O)SRD3a, —C(═O)N(RD3a)2, —C(═S)RD3a, —C(═S)ORD3a, —C(═S)SRD3a, —C(═S)N(RD3a)2, —C(═NRD3a)RD3a, —C(═NRD3a)ORD3a, —C(═NRD3a)SRD3a, and —C(═NRD3a)N(RD3a)2, wherein each occurrence of RD3a 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 RD3a groups are joined to form an optionally substituted heterocyclic ring;
optionally RD1 and RD3, or RD2 and RD3, or RD1 and RD2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
RD4 is a leaving group;
RD5 is hydrogen, C1-6 alkyl, or a nitrogen protecting group;
YZ is —O—, —S—, or —NRD6—, wherein RD6 is hydrogen, C1-6 alkyl, or a nitrogen protecting group;
a is 1 or 2;
z is 0, 1, 2, 3, 4, 5, or 6; and
optionally RD5 and one RC are joined to form an optionally substituted heterocyclic ring.
In certain embodiments, RD 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, RD is of Formula (i-1). In certain embodiments, RD is of Formula (i-2). In certain embodiments, RD is of Formula (i-3). In certain embodiments, RD is of Formula (i-4). In certain embodiments, RD is of Formula (i-5). In certain embodiments, RD is of Formula (i-6). In certain embodiments, RD is of Formula (i-7). In certain embodiments, RD is of Formula (i-8). In certain embodiments, RD is of Formula (i-9). In certain embodiments, RD is of Formula (i-10). In certain embodiments, RD is of Formula (i-1). In certain embodiments, RD is of Formula (i-12). In certain embodiments, RD is of Formula (i-13). In certain embodiments, RD is of Formula (i-14). In certain embodiments, RD is of Formula (i-15). In certain embodiments, RD is of Formula (i-16). In certain embodiments, RD is of Formula (i-17).
In compounds of Formula (I), RD may include a substituent RD1. In certain embodiments, RD1 is H. In certain embodiments, RD1 is halogen. In certain embodiments, RD1 is F. In certain embodiments, RD1 is Cl. In certain embodiments, RD1 is Br. In certain embodiments, RD1 is I (iodine). In certain embodiments, RD1 is substituted acyl. In certain embodiments, RD1 is unsubstituted acyl. In certain embodiments, RD1 is acetyl. In certain embodiments, RD1 is substituted alkyl. In certain embodiments, RD1 is unsubstituted alkyl. In certain embodiments, RD1 is C1-6 alkyl. In certain embodiments, RD1 is methyl. In certain embodiments, RD1 is ethyl. In certain embodiments, RD1 is propyl. In certain embodiments, RD1 is butyl. In certain embodiments, RD1 is substituted alkenyl. In certain embodiments, RD1 is unsubstituted alkenyl. In certain embodiments, RD1 is substituted alkynyl. In certain embodiments, RD1 is unsubstituted alkynyl. In certain embodiments, RD1 is substituted carbocyclyl. In certain embodiments, RD1 is unsubstituted carbocyclyl. In certain embodiments, RD1 is substituted heterocyclyl. In certain embodiments, RD1 is unsubstituted heterocyclyl. In certain embodiments, RD1 is substituted aryl. In certain embodiments, RD1 is unsubstituted aryl. In certain embodiments, RD1 is substituted phenyl. In certain embodiments, RD1 is unsubstituted phenyl. In certain embodiments, RD1 is substituted heteroaryl. In certain embodiments, RD1 is unsubstituted heteroaryl. In certain embodiments, RD1 is substituted pyridyl. In certain embodiments, RD1 is unsubstituted pyridyl. In certain embodiments, RD1 is —CN. In certain embodiments, RD1 is —NO2. In certain embodiments, RD1 is —ORD1a. In certain embodiments, RD1 is —N(RD1a)2. In certain embodiments, RD1 is —SRD1. In certain embodiments, RD1 is —CH2ORD1a. In certain embodiments, RD1 is —CH2N(RD1a)2. In certain embodiments, RD1 is —CH2SRD1a.
In certain embodiments, at least one RD1a is H. In certain embodiments, at least one RD1a is substituted acyl. In certain embodiments, at least one RD1a is unsubstituted acyl. In certain embodiments, at least one RD1a is acetyl. In certain embodiments, at least one RD1a is substituted alkyl. In certain embodiments, at least one RD1a is unsubstituted alkyl. In certain embodiments, at least one RD1a is C1-6 alkyl. In certain embodiments, at least one RD1a is methyl. In certain embodiments, at least one RD1a is ethyl. In certain embodiments, at least one RD1a is propyl. In certain embodiments, at least one RD1a is butyl. In certain embodiments, at least one RD1a is substituted alkenyl. In certain embodiments, at least one RD1a is unsubstituted alkenyl. In certain embodiments, at least one RD1a is substituted alkynyl. In certain embodiments, at least one RD1a is unsubstituted alkynyl. In certain embodiments, at least one RD1a is substituted carbocyclyl. In certain embodiments, at least one RD1a is unsubstituted carbocyclyl. In certain embodiments, at least one RD1a is substituted heterocyclyl. In certain embodiments, at least one RD1a is unsubstituted heterocyclyl. In certain embodiments, at least one RD1a is substituted aryl. In certain embodiments, at least one RD1a is unsubstituted aryl. In certain embodiments, at least one RD1a is substituted phenyl. In certain embodiments, at least one RD1a is unsubstituted phenyl. In certain embodiments, at least one RD1a is substituted heteroaryl. In certain embodiments, at least one RD1a is unsubstituted heteroaryl. In certain embodiments, at least one RD1a is substituted pyridyl. In certain embodiments, at least one RD1a is unsubstituted pyridyl. In certain embodiments, at least one RD1a is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one RD1a is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, RD1a is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, RD1a 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, RD1a is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, RD1a is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two RD1a a groups are joined to form a substituted heterocyclic ring. In certain embodiments, two RD1a groups are joined to form an unsubstituted heterocyclic ring.
In compounds of Formula (I), RD may include a substituent RD2. In certain embodiments, RD2 is H. In certain embodiments, RD2 is halogen. In certain embodiments, RD2 is F. In certain embodiments, RD2 is Cl. In certain embodiments, RD2 is Br. In certain embodiments, RD2 is I (iodine). In certain embodiments, RD2 is substituted acyl. In certain embodiments, RD2 is unsubstituted acyl. In certain embodiments, RD2 is acetyl. In certain embodiments, RD2 is substituted alkyl. In certain embodiments, RD2 is unsubstituted alkyl. In certain embodiments, RD2 is C1-6 alkyl. In certain embodiments, RD2 is methyl. In certain embodiments, RD2 is ethyl. In certain embodiments, RD2 is propyl. In certain embodiments, RD2 is butyl. In certain embodiments, RD2 is substituted alkenyl. In certain embodiments, RD2 is unsubstituted alkenyl. In certain embodiments, RD2 is substituted alkynyl. In certain embodiments, RD2 is unsubstituted alkynyl. In certain embodiments, RD2 is substituted carbocyclyl. In certain embodiments, RD2 is unsubstituted carbocyclyl. In certain embodiments, RD2 is substituted heterocyclyl. In certain embodiments, RD2 is unsubstituted heterocyclyl. In certain embodiments, RD2 is substituted aryl. In certain embodiments, RD2 is unsubstituted aryl. In certain embodiments, RD2 is substituted phenyl. In certain embodiments, RD2 is unsubstituted phenyl. In certain embodiments, RD2 is substituted heteroaryl. In certain embodiments, RD2 is unsubstituted heteroaryl. In certain embodiments, RD2 is substituted pyridyl. In certain embodiments, RD2 is unsubstituted pyridyl. In certain embodiments, RD2 is —CN. In certain embodiments, RD2 is —NO2. In certain embodiments, RD2 is —ORD2a. In certain embodiments, RD2 is —N(RD2a)2. In certain embodiments, RD2 is —SRD2a. In certain embodiments, RD2 is —CH2ORD2a. In certain embodiments, RD2 is —CH2N(RD2a)2. In certain embodiments, RD2 is —CH2SRD2a.
In certain embodiments, at least one RD2a is H. In certain embodiments, at least one RD2a is substituted acyl. In certain embodiments, at least one RD2a is unsubstituted acyl. In certain embodiments, at least one RD2a is acetyl. In certain embodiments, at least one RD2a is substituted alkyl. In certain embodiments, at least one RD2a is unsubstituted alkyl. In certain embodiments, at least one RD2a is C1-6 alkyl. In certain embodiments, at least one RD2a is methyl. In certain embodiments, at least one RD2a is ethyl. In certain embodiments, at least one RD2a is propyl. In certain embodiments, at least one RD2a is butyl. In certain embodiments, at least one RD2a is substituted alkenyl. In certain embodiments, at least one RD2a is unsubstituted alkenyl. In certain embodiments, at least one RD2a is substituted alkynyl. In certain embodiments, at least one RD2a is unsubstituted alkynyl. In certain embodiments, at least one RD2a is substituted carbocyclyl. In certain embodiments, at least one RD2a is unsubstituted carbocyclyl. In certain embodiments, at least one RD2a is substituted heterocyclyl. In certain embodiments, at least one RD2a is unsubstituted heterocyclyl. In certain embodiments, at least one RD2a is substituted aryl. In certain embodiments, at least one RD2a is unsubstituted aryl. In certain embodiments, at least one RD2a is substituted phenyl. In certain embodiments, at least one RD2a is unsubstituted phenyl. In certain embodiments, at least one RD2a is substituted heteroaryl. In certain embodiments, at least one RD2a is unsubstituted heteroaryl. In certain embodiments, at least one RD2a is substituted pyridyl. In certain embodiments, at least one RD2a is unsubstituted pyridyl. In certain embodiments, at least one RD2a is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one RD2a is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, RD2a is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, RD2a 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, RD2a is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, RD2a is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two RD2a groups are joined to form a substituted heterocyclic ring. In certain embodiments, two RD2a groups are joined to form an unsubstituted heterocyclic ring.
In compounds of Formula (I), RD may include a substituent RD3. In certain embodiments, RD3 is H. In certain embodiments, RD3 is halogen. In certain embodiments, RD3 is F. In certain embodiments, RD3 is Cl. In certain embodiments, RD3 is Br. In certain embodiments, RD3 is I (iodine). In certain embodiments, RD3 is substituted acyl. In certain embodiments, RD3 is unsubstituted acyl. In certain embodiments, RD3 is acetyl. In certain embodiments, RD3 is substituted alkyl. In certain embodiments, RD3 is unsubstituted alkyl. In certain embodiments, RD3 is C1-6 alkyl. In certain embodiments, RD3 is methyl. In certain embodiments, RD3 is ethyl. In certain embodiments, RD3 is propyl. In certain embodiments, RD3 is butyl. In certain embodiments, RD3 is substituted alkenyl. In certain embodiments, RD3 is unsubstituted alkenyl. In certain embodiments, RD3 is substituted alkynyl. In certain embodiments, RD3 is unsubstituted alkynyl. In certain embodiments, RD3 is substituted carbocyclyl. In certain embodiments, RD3 is unsubstituted carbocyclyl. In certain embodiments, RD3 is substituted heterocyclyl. In certain embodiments, RD3 is unsubstituted heterocyclyl. In certain embodiments, RD3 is substituted aryl. In certain embodiments, RD3 is unsubstituted aryl. In certain embodiments, RD3 is substituted phenyl. In certain embodiments, RD3 is unsubstituted phenyl. In certain embodiments, RD3 is substituted heteroaryl. In certain embodiments, RD3 is unsubstituted heteroaryl. In certain embodiments, RD3 is substituted pyridyl. In certain embodiments, RD3 is unsubstituted pyridyl. In certain embodiments, RD3 is —CN. In certain embodiments, RD3 is —NO2. In certain embodiments, RD3 is —ORD3a. In certain embodiments, RD3 is —N(RD3a)2. In certain embodiments, RD3 is —SRD3a. In certain embodiments, RD3 is —CH2ORD3a. In certain embodiments, RD3 is —CH2N(RD3a)2. In certain embodiments, RD3 is —CH2SRD3a.
In certain embodiments, at least one RD1a is H. In certain embodiments, at least one RD3a is substituted acyl. In certain embodiments, at least one RD3a is unsubstituted acyl. In certain embodiments, at least one RD3a is acetyl. In certain embodiments, at least one RD3a is substituted alkyl. In certain embodiments, at least one RD3a is unsubstituted alkyl. In certain embodiments, at least one RD3a is C1-6 alkyl. In certain embodiments, at least one RD3a is methyl. In certain embodiments, at least one RD3a is ethyl. In certain embodiments, at least one RD3a is propyl. In certain embodiments, at least one RD3a is butyl. In certain embodiments, at least one RD3a is substituted alkenyl. In certain embodiments, at least one RD3a is unsubstituted alkenyl. In certain embodiments, at least one RD3a is substituted alkynyl. In certain embodiments, at least one RD3a is unsubstituted alkynyl. In certain embodiments, at least one RD3a is substituted carbocyclyl. In certain embodiments, at least one RD3a is unsubstituted carbocyclyl. In certain embodiments, at least one RD3a is substituted heterocyclyl. In certain embodiments, at least one RD3a is unsubstituted heterocyclyl. In certain embodiments, at least one RD3a is substituted aryl. In certain embodiments, at least one RD3a is unsubstituted aryl. In certain embodiments, at least one RD3a is substituted phenyl. In certain embodiments, at least one RD3a is unsubstituted phenyl. In certain embodiments, at least one RD3a is substituted heteroaryl. In certain embodiments, at least one RD3a is unsubstituted heteroaryl. In certain embodiments, at least one RD3a is substituted pyridyl. In certain embodiments, at least one RD3a is unsubstituted pyridyl. In certain embodiments, at least one RD3a is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one RD3a is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, RD3a is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, RD3a 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, RD3a is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, RD3a is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two RD3a groups are joined to form a substituted heterocyclic ring. In certain embodiments, two RD3a groups are joined to form an unsubstituted heterocyclic ring.
In compounds of Formula (I), RD may include a substituent RD4. In certain embodiments, RD4 is a leaving group. In certain embodiments, RD4 is halogen. In certain embodiments, RD4 is F. In certain embodiments, RD4 is Cl. In certain embodiments, RD4 is Br. In certain embodiments, RD4 is I (iodine). In certain embodiments, RD4 is —OS(═O)wRD4a. In certain embodiments, w is 1. In certain embodiments, w is 2. In certain embodiments, RD4 is —OMs. In certain embodiments, RD4 is —OTf. In certain embodiments, RD4 is —OTs. In certain embodiments, RD4 is —OBs. In certain embodiments, RD4 is 2-nitrobenzenesulfonyloxy. In certain embodiments, RD4 is —ORD4a. In certain embodiments, RD4 is —OMe. In certain embodiments, RD4 is —OCF3. In certain embodiments, RD4 is —OPh. In certain embodiments, RD4 is —OC(═O)RD4a. In certain embodiments, RD4 is —OC(═O)Me. In certain embodiments, RD4 is —OC(═O)CF3. In certain embodiments, RD4 is —OC(═O)Ph. In certain embodiments, RD4 is —OC(═O)Cl. In certain embodiments, RD4 is —OC(═O)ORD4a. In certain embodiments, RD4 is —OC(═O)OMe. In certain embodiments, RD4 is —OC(═O)O(t-Bu).
In certain embodiments, RD4a is substituted alkyl. In certain embodiments, RD4a is unsubstituted alkyl. In certain embodiments, RD4a is C1-6 alkyl. In certain embodiments, RD4a is methyl. In certain embodiments, RD4a is ethyl. In certain embodiments, RD4a is propyl. In certain embodiments, RD4a is butyl. In certain embodiments, RD4a is substituted alkenyl. In certain embodiments, RD4a is unsubstituted alkenyl. In certain embodiments, RD4a is vinyl. In certain embodiments, RD4a is substituted alkynyl. In certain embodiments, RD4a is unsubstituted alkynyl. In certain embodiments, RD4a is ethynyl. In certain embodiments, RD4a is substituted carbocyclyl. In certain embodiments, RD4a is unsubstituted carbocyclyl. In certain embodiments, RD4a is substituted heterocyclyl. In certain embodiments, RD4a is unsubstituted heterocyclyl. In certain embodiments, RD4a is substituted aryl. In certain embodiments, RD4a is unsubstituted aryl. In certain embodiments, RD4a is substituted phenyl. In certain embodiments, RD4a is unsubstituted phenyl. In certain embodiments, RD4a is substituted heteroaryl. In certain embodiments, RD4a is unsubstituted heteroaryl. In certain embodiments, RD4a is substituted pyridyl. In certain embodiments, RD4a is unsubstituted pyridyl.
In compounds of Formula (I), RD may include a substituent RD5. In certain embodiments, RD5 is H. In certain embodiments, RD5 is substituted alkyl. In certain embodiments, RD5 is unsubstituted alkyl. In certain embodiments, RD5 is C1-6 alkyl. In certain embodiments, RD5 is methyl. In certain embodiments, RD5 is ethyl. In certain embodiments, RD5 is propyl. In certain embodiments, RD5 is butyl. In certain embodiments, RD5 is a nitrogen protecting group. In certain embodiments, RD5 is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts.
In certain embodiments, RD1 and RD2 are each hydrogen. In certain embodiments, RD1 and RD3 are each hydrogen. In certain embodiments, RD2 and RD3 are each hydrogen. In certain embodiments, RD1, RD2, and RD3 are each hydrogen. In certain embodiments, RD1, RD2, and RD3, and RD5 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 —NRD6—, wherein RD6 is hydrogen, C1-6 alkyl, or a nitrogen protecting group. In certain embodiments, Y is —NH—. In certain embodiments, Y is —NCH3—. In certain embodiments, Y is —N(BOC)—. In certain embodiments, Y is —N(Fmoc)-. In certain embodiments, Y is —N(Cbz)-. In certain embodiments, Y is —N(Bn)-. In certain embodiments, Y is —C(═NRD6)—, wherein RD6 is hydrogen, C1-6 alkyl, or a nitrogen protecting group. In certain embodiments, Y is —C(═NH)—. In certain embodiments, Y is —C(═NCH3)—. In certain embodiments, Y is —C(═NTs)-. In certain embodiments, Y is —C(═NBn)-. In certain embodiments, Y is —C(═NCH(Ph)2)—.
In certain embodiments, RD is of the formula:




In certain embodiments, RD is of the formula:





In certain embodiments, RD is of the formula:





In certain embodiments, RD is of the formula:





In certain embodiments, R is of the formula:





In certain embodiments, RD is of the formula:





In certain embodiments, RD is of the formula:





In certain embodiments, RD is of the formula:





In certain embodiments, RD is of the formula:





In certain embodiments, RD is of the formula:





In certain embodiments, RD is of the formula:





In certain embodiments, RD is of the formula:





In certain embodiments, RD is of the formula:





In certain embodiments, RD is of the formula:





In certain embodiments, RD is of the formula:





In certain embodiments, RD is of the formula:





In certain embodiments, RD is of the formula:





In certain embodiments, RD is of the formula:





In certain embodiments, RD is of the formula:





In certain embodiments, RD is of the formula:





In certain embodiments, RD is of the formula:





In certain embodiments, RD is of the formula:





In certain embodiments, RD is of the formula:





In certain embodiments, RD is of the formula:





In certain embodiments, RD is of the formula:





In certain embodiments, RD is of the formula:





In certain embodiments, RD is of the formula:





In certain embodiments, RD is of the formula:





Various combinations of certain embodiments of Formula (I) are further contemplated herein.
For example, in certain embodiments, a compound of Formula (I) is a compound of Formula (I-a) or (I-b):




wherein RX, RA, RB, and l are defined herein. In certain embodiments RA is substituted or unsubstituted C1-6 alkyl. In certain embodiments, RA is methyl. In certain embodiments, l is 1. In certain embodiments, l is 1; and RB 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 RB groups are meta to the point of attachment of the amide linker. In certain embodiments, l is 2; one RB group is meta to the point of attachment of the amide linker; and the second RB group is para to the point of attachment of the amide linker. In certain embodiments, one RB group is substituted or unsubstituted C1-6alkyl. In certain embodiments, one RB group is C1-6alkyl substituted with one —CN group. In certain embodiments, one RB group is





In certain embodiments, one RB group is substituted or unsubstituted —CH2-(piperazinyl). In certain embodiments, one RB group is





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





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





In certain embodiments, one RB group is haloalkyl. In certain embodiments, one RB group is —CF3. In certain embodiments, one RB group is substituted or unsubstituted imidazoyl. In certain embodiments, one RB group is





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





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





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





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





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





In certain embodiments, one RB group is substituted or unsubstituted morpholine. In certain embodiments, two RB groups are substituted or unsubstituted morpholine. In certain embodiments, RX is substituted or unsubstituted heteroaryl. In certain embodiments, RX is substituted or unsubstituted thiophene. In certain embodiments, RX is substituted or unsubstituted isoxazole. In certain embodiments, RX is substituted or unsubstituted pyrazole.

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




wherein RXa, RXc, RA, RB, and l are defined herein. In certain embodiments RA is substituted or unsubstituted C1-6 alkyl. In certain embodiments, RA is methyl. In certain embodiments, l is 1. In certain embodiments, l is 1; and RB 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 RB groups are meta to the point of attachment of the amide linker. In certain embodiments, l is 2; one RB group is meta to the point of attachment of the amide linker; and the second RB group is para to the point of attachment of the amide linker. In certain embodiments, one RB group is substituted or unsubstituted C1-6alkyl. In certain embodiments, one RB group is C1-6alkyl substituted with one —CN group. In certain embodiments, one RB group is





In certain embodiments, one RB group is substituted or unsubstituted —CH2-(piperazinyl). In certain embodiments, one RB group is





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





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





In certain embodiments, one RB group is haloalkyl. In certain embodiments, one RB group is —CF3. In certain embodiments, one RB group is substituted or unsubstituted imidazoyl. In certain embodiments, one RB group is





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





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





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





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





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





In certain embodiments, one RB group is substituted or unsubstituted morpholine. In certain embodiments, two RB groups are substituted or unsubstituted morpholine. In certain embodiments, all instances of RXc are hydrogen. In certain embodiments, RXa is substituted or unsubstituted C1-6alkyl. In certain embodiments, RXa is methyl or ethyl.

In certain embodiments, a compound of Formula (I-b) is a compound of Formula (I-b1), (I-b2), or (I-b3):




wherein RXa, RXc, RA, RB, and l are defined herein. In certain embodiments RA is substituted or unsubstituted C1-6 alkyl. In certain embodiments, RA is methyl. In certain embodiments, l is 1. In certain embodiments, l is 1; and RB 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 RB groups are meta to the point of attachment of the amide linker. In certain embodiments, l is 2; one RB group is meta to the point of attachment of the amide linker; and the second RB group is para to the point of attachment of the amide linker. In certain embodiments, one RB group is substituted or unsubstituted C1-6alkyl. In certain embodiments, one RB group is C1-6alkyl substituted with one —CN group. In certain embodiments, one RB group is





In certain embodiments, one RB group is substituted or unsubstituted —CH2-(piperazinyl). In certain embodiments, one RB group is





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





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





In certain embodiments, one RB group is haloalkyl. In certain embodiments, one RB group is —CF3. In certain embodiments, one RB group is substituted or unsubstituted imidazoyl. In certain embodiments, one RB group is





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





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





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





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





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





In certain embodiments, one RB group is substituted or unsubstituted morpholine. In certain embodiments, two RB groups are substituted or unsubstituted morpholine. In certain embodiments, all instances of RXc are hydrogen. In certain embodiments, RXa is substituted or unsubstituted C1-6alkyl. In certain embodiments, RXa is methyl or ethyl.

In certain embodiments, a compound of Formula (I-a) is a compound of Formula (I-a4)-(I-a12):







wherein RXa, RXc, RA, and RB are defined herein. In certain embodiments RA is substituted or unsubstituted C1-6 alkyl. In certain embodiments, RA is methyl. In certain embodiments, one RB group is substituted or unsubstituted C1-6alkyl. In certain embodiments, one RB group is C1-6alkyl substituted with one —CN group. In certain embodiments, one RB group is





In certain embodiments, one RB group is substituted or unsubstituted —CH2-(piperazinyl). In certain embodiments, one RB group is





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





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





In certain embodiments, one RB group is haloalkyl. In certain embodiments, one RB group is —CF3. In certain embodiments, one RB group is substituted or unsubstituted imidazoyl. In certain embodiments, one RB group is





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





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





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





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





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





In certain embodiments, one RB group is substituted or unsubstituted morpholine. In certain embodiments, two RB groups are substituted or unsubstituted morpholine. In certain embodiments, all instances of RXc are hydrogen. In certain embodiments, RXa is substituted or unsubstituted C1-6alkyl. In certain embodiments, RXa is methyl or ethyl.

In certain embodiments, a compound of Formula (I-b) is a compound of Formula (I-b4)-(I-b12):










wherein RXa, RXc, RA, and RB are defined herein. In certain embodiments RA is substituted or unsubstituted C1-6 alkyl. In certain embodiments, RA is methyl. In certain embodiments, one RB group is substituted or unsubstituted C1-6alkyl. In certain embodiments, one RB group is C1-6alkyl substituted with one —CN group. In certain embodiments, one RB group is





In certain embodiments, one RB group is substituted or unsubstituted —CH2-(piperazinyl). In certain embodiments, one RB group is





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





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





In certain embodiments, one RB group is haloalkyl. In certain embodiments, one RB group is —CF3. In certain embodiments, one RB group is substituted or unsubstituted imidazoyl. In certain embodiments, one RB group is





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





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





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





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





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





In certain embodiments, one RB group is substituted or unsubstituted morpholine. In certain embodiments, two RB groups are substituted or unsubstituted morpholine. In certain embodiments, all instances of RXc are hydrogen. In certain embodiments, RXa is substituted or unsubstituted C1-6alkyl. In certain embodiments, RXa is methyl or ethyl.

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 RA′, RB′, and RX′ 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, —ORA1, —N(RA1′)2, —SRA1′, —CN, —C(═O)RA1′, —C(═O)ORA1′, —C(═O)SRA1′, —C(═O)N(RA1′)2, —C(═S)RA1′, —C(═S)ORA1′, —C(═S)SRA1′, —C(═S)N(RA1′)2, —C(═NRA1′)RA1′, —C(═NRA1′)ORA1′, —C(═NRA1′)SRA1′, —C(═NRA1′)N(RA1′)2, —NO2, —N3, —N(RA1′)3+X′−, wherein X′− is a counterion, —N(ORA1′)RA1′, —NRA1′C(═O)RA1′, —NRA1′C(═O)ORA1′, —NRA1′C(═O)SRA1′, —NRA1′C(═O)N(RA1′)2, —NRA1′C(═S)RA1′, —NRA1′C(═S)ORA1′, —NRA1′C(═S)SRA1′, —NRA1′C(═S)N(RA1′)2, —NRA1′C(═NRA1′)RA1′, —NRA1′C(═NRA1′)ORA1′, —NRA1′C(═NRA1′)SRA1′, —NRA1′C(═NRA1′)N(RA1′)2, —NRA1′S(═O)2RA1′, —NRA1′S(═O)2ORA1′, —NRA1′S(═O)2SRA1′, —NRA1′S(═O)2N(RA1′)2, —NRA1′S(═O)RA1′, —NRA1′S(═O)ORA1′, —NRA1′S(═O)SRA1′, —NRA1′S(═O)N(RA1′)2, —NRA1′P(═O), —NRA1′P(═O)2, —NRA1′P(═O)(RA1′)2, —NRA1′P(═O)RA1′(ORA1′), —NRA1′P(═O)(ORA1′)2, —OC(═O)RA1′, —OC(═O)ORA1′, —OC(═O)SRA1′, —OC(═O)N(RA1′)2, —OC(═NRA1′)RA1′, —OC(═NRA1′)ORA1′, —OC(═NRA1′)N(RA1′)2, —OC(═S)RA1′, —OC(═S)ORA1′, —OC(═S)SRA1′, —OC(═S)N(RA1′)2, —ON(RA1′)2, —OS(═O)RA1′, —OS(═O)ORA1′, —OS(═O)SRA1′, —OS(═O)N(RA1′)2, —OS(═O)2RA1′, —OS(═O)2ORA1′, —OS(═O)2SRA1′, —OS(═O)2N(RA1′)2, —OP(═O)2, —OP(═O)(RA1′)2, —OP(═O)RA1′(ORA1′), —OP(═O)(ORA1′)2, —OP(═O), —OP(RA1′)2, —OPRA1′(ORA1′), —OP(ORA1′)2, —OSi(RA1′)3, —OSi(RA1′)2ORA1′, —OSi(RA1′)(ORA1′)2, —OSi(ORA1′)3, —SSRA1′, —S(═O)RA1′, —S(═O)ORA1′, —S(═O)N(RA1′)2, —S(═O)2RA1′, —S(═O)2ORA1′, —S(═O)2N(RA1′)2, —SC(═O)RA1′, —SC(═O)ORA1′, —SC(═O)SRA1′, —SC(═O)N(RA1′)2, —SC(═S)RA1′, —SC(═S)ORA1′, —SC(═S)SRA1′, —SC(═S)N(RA1′)2, —P(RA1′)2, —PRA1′(ORA1′), —P(ORA1′)2, —P(═O), —P(═O)(RA1′)2, —P(═O)(ORA1′)2, —P(═O)RA1′(ORA1′), —P(═O)2, —B(RA1′)2, —B(ORA1′)2, —BRA1′(ORA1′), —Si(RA1′)3, —Si(RA1′)2ORA1′, —SiRA1′(ORA1′)2, and —Si(ORA1′)3, two RA′ or RB′ groups are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring, or RA′ or RB′ forms an optional 5 to 8 membered ring with any one of X′, Y′, Z′, Q′, U′, or Cy; wherein each occurrence of RA1′ 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 RA1′ 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 —CH2, —CHRA′, —CH, —C(RA′)2, —C, —N, —NRA′, —O, —S or —C═O, or bond and may optionally form a 5 to 8 membered ring with RA′ or RB′;
Q′ and U′ are each independently —NRA′, —O, —C═O, —NRA′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 RA′ 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′, RA′, RB′, RX′, k′, and l′ are as defined herein.

Compounds of Formula (V) include an aryl group for Ring A′ optionally substituted with one or more RA′ 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′, RA′, RB′, RX′, k′, and l′ are as defined herein.

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




wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, RA′, RB′, RX′, k′, and l′ are as defined herein.

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




wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, RA′, RB′, RX′, k′, and l′ are as defined herein.

Compounds of Formula (V) include an heteroaryl group for Ring A′ optionally substituted with one or more RA′ 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′, RA′, RB′, RX′, k′, and l′ are as defined herein.

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




wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, RA′, RB′, RX′, k′, and l′ are as defined herein.

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




wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, RA′, RB′, RX′, k′, and l′ are as defined herein.

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




wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, RA′, RB′, RX′, k′, and l′ are as defined herein.

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




wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, RA′, RB′, RX′, k′, and l′ are as defined herein.

Compounds of Formula (V) include an heteroaryl group for Ring A′ optionally substituted with one or more RA′ groups. In certain embodiments, when Ring A′ is phenyl, and at least one RA′ 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′, RA′, RB′, RX′, k′, and l′ are as defined herein.

Compounds of Formula (V) include an heteroaryl group for Ring A′ optionally substituted with one or more RA′ groups. In certain embodiments, when Ring A′ is phenyl, and at least one RA′ 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′, RA′, RB′, RX′, k′, and l′ are as defined herein.

In some embodiments, the subject is administered a compound of Formula (III):




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

wherein:

each instance of each instance of RA′, RB′, and RX′ 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, —ORA1′, —N(RA1′)2, —SRA1′, —CN, —C(═O)RA1′, —C(═O)ORA1′, —C(═O)SRA1′, —C(═O)N(RA1′)2, —C(═S)RA1′, —C(═S)ORA1′, —C(═S)SRA1′, —C(═S)N(RA1′)2, —C(═NRA1′)RA1′, —C(═NRA1′)ORA1′, —C(═NRA1′)SRA1′, —C(═NRA1′)N(RA1′)2, —NO2, —N3, —N(RA1′)3+X′−, wherein X′− is a counterion, —N(ORA1′)RA1′, —NRA1′C(═O)RA1′, —NRA1′C(═O)ORA1′, —NRA1′C(═O)SRA1′, —NRA1′C(═O)N(RA1′)2, —NRA1′C(═S)RA1′, —NRA1′C(═S)ORA1′, —NRA1′C(═S)SRA1′, —NRA1′C(═S)N(RA1′)2, —NRA1′C(═NRA1′)RA1′, —NRA1′C(═NRA1′)ORA1′, —NRA1′C(═NRA1′)SRA1′, —NRA1′C(═NRA1′)N(RA1′)2, —NRA1′S(═O)2RA1′, —NRA1′S(═O)2ORA1′, —NRA1′S(═O)2SRA1′, —NRA1′S(═O)2N(RA1′)2, —NRA1′S(═O)RA1′, —NRA1′S(═O)ORA1′, —NRA1′S(═O)SRA1′, —NRA1′S(═O)N(RA1′)2, —NRA1′P(═O), —NRA1′P(═O)2, —NRA1′P(═O)(RA1′)2, —NRA1′P(═O)RA1′(ORA1′), —NRA1′P(═O)(ORA1′)2, —OC(═O)RA1, —OC(═O)ORA1′, —OC(═O)SRA1′, —OC(═O)N(RA1′)2, —OC(═NRA1′)RA1′, —OC(═NRA1′)ORA1′, —OC(═NRA1′)N(RA1′)2, —OC(═S)RA1′, —OC(═S)ORA1′, —OC(═S)SRA1′, —OC(═S)N(RA1′)2, —ON(RA1′)2, —OS(═O)RA1′, —OS(═O)ORA1′, —OS(═O)SRA1′, —OS(═O)N(RA1′)2, —OS(═O)2RA1′, —OS(═O)2ORA1′, —OS(═O)2SRA1′, —OS(═O)2N(RA1′)2, —OP(═O)2, —OP(═O)(RA1′)2, —OP(═O)RA1′(ORA1′), —OP(═O)(ORA1′)2, —OP(═O), —OP(RA1′)2, —OPRA1′(ORA1′), —OP(ORA1′)2, —OSi(RA1′)3, —OSi(RA1′)2ORA1′, —OSi(RA1′)(ORA1′)2, —OSi(ORA1′)3, —SSRA1′, —S(═O)RA1′, —S(═O)ORA1′, —S(═O)N(RA1′)2, —S(═O)2RA1′, —S(═O)2ORA1′, —S(═O)2N(RA1′)2, —SC(═O)RA1′, —SC(═O)ORA1′, —SC(═O)SRA1′, —SC(═O)N(RA1′)2, —SC(═S)RA1′, —SC(═S)ORA1′, —SC(═S)SRA1′, —SC(═S)N(RA1′)2, —P(RA1′)2, —PRA1′(ORA1′), —P(ORA1′)2, —P(═O), —P(═O)(RA1′)2, —P(═O)(ORA1′)2, —P(═O)RA1′(ORA1′), —P(═O)2, —B(RA1′)2, —B(ORA1′)2, —BRA1′(ORA1′), —Si(RA1′)3, —Si(RA1′)2ORA1′, —SiRA1′(ORA1′)2, and —Si(ORA1′)3, two RA′ or RB′ groups are joined to form an optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl ring, or RA′ or RB′ forms an optional 5 to 8 membered ring with any one of X′, Y′, Z′, Q′, U′, or Cy; wherein each occurrence of RA1′ 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 RA1′ 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 —CH2, —CHRA′, —CH, —C(RA′)2, —C, —N, —NRA′, —O, —S or —C═O, or bond and may optionally form a 5 to 8 membered ring with RA′ or RB′;
Q′ and U′ are each independently —NRA′, —O, —C═O, —NRA′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.
In another aspect, provided herein are compound of Formula (II):




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

each instance of RD′ 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′, RA′, RB′, RX′, k′, and l′ are as defined herein.
In certain embodiments, RD′ is an optional electrophilic moiety that can be attached to Cy, Ring A′, or Ring C′; and m′ is 0 or 1. In compounds of Formula (II), RD′ is an optional electrophilic moiety that can be attached to Cy, Ring A′, or Ring C′. In certain embodiments, RD′ is any one of Formulae (i-1)-(i-17):










RD1′ 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, —NO2, —ORD1a′, —N(RD1a′)2, —SRD1a′, —CH2ORD1a′, —CH2N(RD1a′)2, —CH2SRD1a′, —C(═O)RD1a′, —C(═O)ORD1a′, —C(═O)SRD1a′, —C(═O)N(RD1a′)2, —C(═S)RD1a′, —C(═S)ORD1a′, —C(═S)SRD1a′, —C(═S)N(RD1a′)2, —C(═NRD1a′)RD1a′, —C(═NRD1a′)ORD1a′, —C(═NRD1a′)SRD1a′, and —C(═NRD1a′)N(RD1a′)2, wherein each occurrence of RD1a′ 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 RD1a′ groups are joined to form an optionally substituted heterocyclic ring;
RD2′ 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, —NO2, —ORD2a′, —N(RD2a′)2, —SRD2a, —CH2ORD2a′, —CH2N(RD2a′)2, —CH2SRD2a′, —C(═O)RD2a′, —C(═O)ORD2a′, —C(═O)SRD2a′, —C(═O)N(RD2a′)2, —C(═S)RD2a′, —C(═S)ORD2a′, —C(═S)SRD2a′, —C(═S)N(RD2a′)2, —C(═NRD2a′)RD2a′, —C(═NRD2a′)ORD2a′, —C(═NRD2a′)SRD2a′, and —C(═NRD2a′)N(RD2a′)2, wherein each occurrence of RD2a′ 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 RD2a′ groups are joined to form an optionally substituted heterocyclic ring;
RD3′ 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, —NO2, —ORD3a′, —N(RD3a′)2, —SRD3a, —CH2ORD3a′, —CH2N(RD3a′)2, —CH2SRD3a′, —C(═O)RD3a′, —C(═O)ORD3a′, —C(═O)SRD3a, —C(═O)N(RD3a′)2, —C(═S)RD3a′, —C(═S)ORD3a′, —C(═S)SRD3a′, —C(═S)N(RD3a′)2, —C(═NRD3a′)RD3a′, —C(═NRD3a′)ORD3a′, —C(═NRD3a′)SRD3a′, and —C(═NRD3a′)N(RD3a′)2, wherein each occurrence of RD3a′ 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 RD3a′ groups are joined to form an optionally substituted heterocyclic ring;
optionally RD1′ and RD3′, or RD2′ and RD3′, or RD1′ and RD2′ are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
RD4′ is a leaving group;
RD5′ is hydrogen, C1-6 alkyl, or a nitrogen protecting group;
YZ′ is —O, —S, or —NRD6′, wherein RD6′ is hydrogen, C1-6 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 RA′ 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′, RA′, RB′, RD′, RX′, k′, l′, and m′ are as defined herein.

Compounds of Formula (II) include an aryl group for Ring A′ optionally substituted with one or more RA′ 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′, RA′, RB′, RD′, RX′, k′, l′, and m′ are as defined herein.

Compounds of Formula (II) include an aryl group for Ring A′ optionally substituted with one or more RA′ 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′, RA′, RB′, RD′, RX′, k′, l′, and m′ are as defined herein.

Compounds of Formula (II) include an aryl group for Ring A′ optionally substituted with one or more RA′ 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′, RA′, RB′, RD′, RX′, k′, l′, and m′ are as defined herein.

Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more RA′ 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′, RA′, RB′, RD′, RX′, k′, l′, and m′ are as defined herein.

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




wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, RA′, RB′, RD′, RX′, k′, l′, and m′ are as defined herein.

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




wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, RA′, RB′, RD′, RX′, k′, l′, and m′ are as defined herein.

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




wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, RA′, RB′, RX′, k′, and l′ are as defined herein.

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




wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, RA′, RB′, RX′, k′, and l′ are as defined herein.

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




wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, RA′, RB′, RD′, RX′, k′, l′, and m′ are as defined herein.

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




wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, RA′, RB′, RD′, RX′, k′, l′, and m′ are as defined herein.

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




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

each instance of RD′ 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′, RA′, RB′, RX′, k′, and l′ are as defined herein.
In certain embodiments, RD′ is an optional electrophilic moiety that can be attached to Cy, Ring A′, or Ring C′; and m′ is 0 or 1. In compounds of Formula (IV), RD′ is an optional electrophilic moiety that can be attached to Cy, Ring A′, or Ring C′. In certain embodiments, RD′ is any one of Formulae (i-1)-(i-17):










RD1′ 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, —NO2, —ORD1a′, —N(RD1a′)2, —SRD1a′, —CH2ORD1a′, —CH2N(RD1a′)2, —CH2SRD1a′, —C(═O)RD1a′, —C(═O)ORD1a′, —C(═O)SRD1a′, —C(═O)N(RD1a′)2, —C(═S)RD1a′, —C(═S)ORD1a′, —C(═S)SRD1a′, —C(═S)N(RD1a′)2, —C(═NRD1a′)RD1a′, —C(═NRD1a′)ORD1a′, —C(═NRD1a′)SRD1a′, and —C(═NRD1a′)N(RD1a′)2, wherein each occurrence of RD1a′ 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 RD1a′ groups are joined to form an optionally substituted heterocyclic ring;
RD2′ 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, —NO2, —ORD2a′, —N(RD2a′)2, —SRD2a′, —CH2ORD2a′, —CH2N(RD2a′)2, —CH2SRD2a′, —C(═O)RD2a′, —C(═O)ORD2a′, —C(═O)SRD2a′, —C(═O)N(RD2a′)2, —C(═S)RD2a′, —C(═S)ORD2a′, —C(═S)SRD2a′, —C(═S)N(RD2a′)2, —C(═NRD2a′)RD2a′, —C(═NRD2a′)ORD2a′, —C(═NRD2a′)SRD2a′, and —C(═NRD2a′)N(RD2a′)2, wherein each occurrence of RD2a′ 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 RD2a′ groups are joined to form an optionally substituted heterocyclic ring;
RD3′ 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, —NO2, —ORD3a′, —N(RD3a′)2, —SRD3a′, —CH2ORD3a′, —CH2N(RD3a′)2, —CH2SRD3a′, —C(═O)RD3a′, —C(═O)ORD3a′, —C(═O)SRD3a′, —C(═O)N(RD3a′)2, —C(═S)RD3a′, —C(═S)ORD3a′, —C(═S)SRD3a′, —C(═S)N(RD3a′)2, —C(═NRD3a′)RD3a′, —C(═NRD3a′)ORD3a′, —C(═NRD3a′)SRD3a′, and —C(═NRD3a′)N(RD3a′)2, wherein each occurrence of RD3a′ 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 RD3a′ groups are joined to form an optionally substituted heterocyclic ring;
optionally RD1′ and RD3′, or RD2′ and RD3′, or RD1′ and RD2′ are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
RD4′ is a leaving group;
RD5′ is hydrogen, C1-6 alkyl, or a nitrogen protecting group;
YZ′ is —O, —S, or —NRD6′, wherein RD6′ is hydrogen, C1-6 alkyl, or a nitrogen protecting group;
a′ is 1 or 2; and
z′ is 0, 1, 2, 3, 4, 5, or 6.
In compounds of Formula (II) and (IV), RD′ is a substituent on Ring A′, Ring C′, or Cy. In certain embodiments, RD′ 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, RD′ is of Formula (i-1). In certain embodiments, RD′ is of Formula (i-2). In certain embodiments, RD′ is of Formula (i-3). In certain embodiments, RD′ is of Formula (i-4). In certain embodiments, RD′ is of Formula (i-5). In certain embodiments, RD′ is of Formula (i-6). In certain embodiments, RD′ is of Formula (i-7). In certain embodiments, RD′ is of Formula (i-8). In certain embodiments, RD′ is of Formula (i-9). In certain embodiments, RD′ is of Formula (i-10). In certain embodiments, RD′ is of Formula (i-11). In certain embodiments, RD′ is of Formula (i-12). In certain embodiments, RD′ is of Formula (i-13). In certain embodiments, RD′ is of Formula (i-14). In certain embodiments, RD′ is of Formula (i-15). In certain embodiments, RD′ is of Formula (i-16). In certain embodiments, RD′ is of Formula (i-17).
In compounds of Formula (II) and (IV), RD′ may include a substituent RD′. In certain embodiments, RD1′ is H. In certain embodiments, RD1′ is halogen. In certain embodiments, RD1′ is F. In certain embodiments, RD1′ is Cl. In certain embodiments, RD1′ is Br. In certain embodiments, RD1′ is I (iodine). In certain embodiments, RD1′ is substituted acyl. In certain embodiments, RD1′ is unsubstituted acyl. In certain embodiments, RD1′ is acetyl. In certain embodiments, RD1′ is substituted alkyl. In certain embodiments, RD1′ is unsubstituted alkyl. In certain embodiments, RD1′ is C1-6 alkyl. In certain embodiments, RD1′ is methyl. In certain embodiments, RD1′ is ethyl. In certain embodiments, RD1′ is propyl. In certain embodiments, RD1′ is butyl. In certain embodiments, RD1′ is substituted alkenyl. In certain embodiments, RD1′ is unsubstituted alkenyl. In certain embodiments, RD1′ is substituted alkynyl. In certain embodiments, RD1′ is unsubstituted alkynyl. In certain embodiments, RD1′ is substituted carbocyclyl. In certain embodiments, RD1′ is unsubstituted carbocyclyl. In certain embodiments, RD1′ is substituted heterocyclyl. In certain embodiments, RD1′ is unsubstituted heterocyclyl. In certain embodiments, RD1′ is substituted aryl. In certain embodiments, RD1′ is unsubstituted aryl. In certain embodiments, RD1′ is substituted phenyl. In certain embodiments, RD1′ is unsubstituted phenyl. In certain embodiments, RD1′ is substituted heteroaryl. In certain embodiments, RD1′ is unsubstituted heteroaryl. In certain embodiments, RD1′ is substituted pyridyl. In certain embodiments, RD1′ is unsubstituted pyridyl. In certain embodiments, RD1′ is —CN. In certain embodiments, RD1′ is —NO2. In certain embodiments, RD1′ is —ORD1a′. In certain embodiments, RD1′ is —N(RD1a′)2. In certain embodiments, RD1′ is —SRD1a′. In certain embodiments, RD1′ is —CH2ORD1a′. In certain embodiments, RD1′ is —CH2N(RD1a′)2. In certain embodiments, RD1′ is —CH2SRD1a′.
In certain embodiments, at least one RD1a′ is H. In certain embodiments, at least one RD1a′ is substituted acyl. In certain embodiments, at least one RD1a′ is unsubstituted acyl. In certain embodiments, at least one RD1a′ is acetyl. In certain embodiments, at least one RD1a′ is substituted alkyl. In certain embodiments, at least one RD1a′ is unsubstituted alkyl. In certain embodiments, at least one RD1a′ is C1-6 alkyl. In certain embodiments, at least one RD1a′ is methyl. In certain embodiments, at least one RD1a′ is ethyl. In certain embodiments, at least one RD1a′ is propyl. In certain embodiments, at least one RD1a′, is butyl. In certain embodiments, at least one RD1a′ is substituted alkenyl. In certain embodiments, at least one RD1a′ is unsubstituted alkenyl. In certain embodiments, at least one RD1a′ is substituted alkynyl. In certain embodiments, at least one RD1a′ is unsubstituted alkynyl. In certain embodiments, at least one RD1a′ is substituted carbocyclyl. In certain embodiments, at least one RD1a′ is unsubstituted carbocyclyl. In certain embodiments, at least one RD1a′ is substituted heterocyclyl. In certain embodiments, at least one RD1a′ is unsubstituted heterocyclyl. In certain embodiments, at least one RD1a′ is substituted aryl. In certain embodiments, at least one RD1a′ is unsubstituted aryl. In certain embodiments, at least one RD1a′ is substituted phenyl. In certain embodiments, at least one RD1a′ is unsubstituted phenyl. In certain embodiments, at least one RD1a′ is substituted heteroaryl. In certain embodiments, at least one RD1a′ is unsubstituted heteroaryl. In certain embodiments, at least one RD1a′ is substituted pyridyl. In certain embodiments, at least one RD1a′ is unsubstituted pyridyl. In certain embodiments, at least one RD1a′ is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one RD1a′, is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, RD1a′ is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, RD1a′ 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, RD1a′ is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, RD1a′ is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two RD1a′ groups are joined to form a substituted heterocyclic ring. In certain embodiments, two RD1a′ groups are joined to form an unsubstituted heterocyclic ring.
In compounds of Formula (II) and (IV), RD′ may include a substituent RD2′. In certain embodiments, RD2′ is H. In certain embodiments, RD2′ is halogen. In certain embodiments, RD2′ is F. In certain embodiments, RD2′ is Cl. In certain embodiments, RD2′ is Br. In certain embodiments, RD2′ is I (iodine). In certain embodiments, RD2′ is substituted acyl. In certain embodiments, RD2′ is unsubstituted acyl. In certain embodiments, RD2′ is acetyl. In certain embodiments, RD2′ is substituted alkyl. In certain embodiments, RD2′ is unsubstituted alkyl. In certain embodiments, RD2′ is C1-6 alkyl. In certain embodiments, RD2′ is methyl. In certain embodiments, RD2′ is ethyl. In certain embodiments, RD2′ is propyl. In certain embodiments, RD2′ is butyl. In certain embodiments, RD2′ is substituted alkenyl. In certain embodiments, RD2′ is unsubstituted alkenyl. In certain embodiments, RD2′ is substituted alkynyl. In certain embodiments, RD2′ is unsubstituted alkynyl. In certain embodiments, RD2′ is substituted carbocyclyl. In certain embodiments, RD2′ is unsubstituted carbocyclyl. In certain embodiments, RD2′ is substituted heterocyclyl. In certain embodiments, RD2′ is unsubstituted heterocyclyl. In certain embodiments, RD2′ is substituted aryl. In certain embodiments, RD2′ is unsubstituted aryl. In certain embodiments, RD2′ is substituted phenyl. In certain embodiments, RD2′ is unsubstituted phenyl. In certain embodiments, RD2′ is substituted heteroaryl. In certain embodiments, RD2′ is unsubstituted heteroaryl. In certain embodiments, RD2′ is substituted pyridyl. In certain embodiments, RD2′ is unsubstituted pyridyl. In certain embodiments, RD2′ is —CN. In certain embodiments, RD2′ is —NO2. In certain embodiments, RD2′ is —ORD2a′. In certain embodiments, RD2′ is —N(RD2a′)2. In certain embodiments, RD2′ is —SRD2a′. In certain embodiments, RD2′ is —CH2ORD2a′. In certain embodiments, RD2′ is —CH2N(RD2a′)2. In certain embodiments, RD2′ is —CH2SRD2a′.
In certain embodiments, at least one RD2a′ is H. In certain embodiments, at least one RD2a′ is substituted acyl. In certain embodiments, at least one RD2a′ is unsubstituted acyl. In certain embodiments, at least one RD2a′ is acetyl. In certain embodiments, at least one RD2a′ is substituted alkyl. In certain embodiments, at least one RD2a′ is unsubstituted alkyl. In certain embodiments, at least one RD2a′ is C1-6 alkyl. In certain embodiments, at least one RD2a′ is methyl. In certain embodiments, at least one RD2a′ is ethyl. In certain embodiments, at least one RD2a′ is propyl. In certain embodiments, at least one RD2a′ is butyl. In certain embodiments, at least one RD2a′ is substituted alkenyl. In certain embodiments, at least one RD2a′ is unsubstituted alkenyl. In certain embodiments, at least one RD2a′ is substituted alkynyl. In certain embodiments, at least one RD2a′ is unsubstituted alkynyl. In certain embodiments, at least one RD2a′ is substituted carbocyclyl. In certain embodiments, at least one RD2a′ is unsubstituted carbocyclyl. In certain embodiments, at least one RD2a′ is substituted heterocyclyl. In certain embodiments, at least one RD2a′ is unsubstituted heterocyclyl. In certain embodiments, at least one RD2a′ is substituted aryl. In certain embodiments, at least one RD2a′ is unsubstituted aryl. In certain embodiments, at least one RD2a′ is substituted phenyl. In certain embodiments, at least one RD2a′ is unsubstituted phenyl. In certain embodiments, at least one RD2a′ is substituted heteroaryl. In certain embodiments, at least one RD2a′ is unsubstituted heteroaryl. In certain embodiments, at least one RD2a′ is substituted pyridyl. In certain embodiments, at least one RD2a′ is unsubstituted pyridyl. In certain embodiments, at least one RD2a′ is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one RD2a′ is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, RD2a′ is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, RD2a′ 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, RD2a′ is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, RD2a′ is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two RD2a′ groups are joined to form a substituted heterocyclic ring. In certain embodiments, two RD2a′ groups are joined to form an unsubstituted heterocyclic ring.
In compounds of Formula (II) and (IV), RD′ may include a substituent RD3′. In certain embodiments, RD3′ is H. In certain embodiments, RD3′ is halogen. In certain embodiments, RD3′ is F. In certain embodiments, RD3′ is Cl. In certain embodiments, RD3′ is Br. In certain embodiments, RD3′ is I (iodine). In certain embodiments, RD3′ is substituted acyl. In certain embodiments, RD3′ is unsubstituted acyl. In certain embodiments, RD3′ is acetyl. In certain embodiments, RD3′ is substituted alkyl. In certain embodiments, RD3′ is unsubstituted alkyl. In certain embodiments, RD3′ is C1-6 alkyl. In certain embodiments, RD3′ is methyl. In certain embodiments, RD3′ is ethyl. In certain embodiments, RD3′ is propyl. In certain embodiments, RD3′ is butyl. In certain embodiments, RD3′ is substituted alkenyl. In certain embodiments, RD3′ is unsubstituted alkenyl. In certain embodiments, RD3′ is substituted alkynyl. In certain embodiments, RD3′ is unsubstituted alkynyl. In certain embodiments, RD3′ is substituted carbocyclyl. In certain embodiments, RD3′ is unsubstituted carbocyclyl. In certain embodiments, RD3′ is substituted heterocyclyl. In certain embodiments, RD3′ is unsubstituted heterocyclyl. In certain embodiments, RD3′ is substituted aryl. In certain embodiments, RD3′ is unsubstituted aryl. In certain embodiments, RD3′ is substituted phenyl. In certain embodiments, RD3′ is unsubstituted phenyl. In certain embodiments, RD3′ is substituted heteroaryl. In certain embodiments, RD3′ is unsubstituted heteroaryl. In certain embodiments, RD3′ is substituted pyridyl. In certain embodiments, RD3′ is unsubstituted pyridyl. In certain embodiments, RD3′ is —CN. In certain embodiments, RD3′ is —NO2. In certain embodiments, RD3′ is —ORD3a′. In certain embodiments, RD3′ is —N(RD3a′)2. In certain embodiments, RD3′ is —SRD3a′. In certain embodiments, RD3′ is —CH2ORD3a′. In certain embodiments, RD3′ is —CH2N(RD3a′)2. In certain embodiments, RD3′ is —CH2SRD3a′.
In certain embodiments, at least one RD3a′ is H. In certain embodiments, at least one RD3a′ is substituted acyl. In certain embodiments, at least one RD3a′ is unsubstituted acyl. In certain embodiments, at least one RD3a′ is acetyl. In certain embodiments, at least one RD3a′ is substituted alkyl. In certain embodiments, at least one RD3a′ is unsubstituted alkyl. In certain embodiments, at least one RD3a′ is C1-6 alkyl. In certain embodiments, at least one RD3a′ is methyl. In certain embodiments, at least one RD3a′ is ethyl. In certain embodiments, at least one RD3a′ is propyl. In certain embodiments, at least one RD3a′ is butyl. In certain embodiments, at least one RD3a′ is substituted alkenyl. In certain embodiments, at least one RD3a′ is unsubstituted alkenyl. In certain embodiments, at least one RD3a′ is substituted alkynyl. In certain embodiments, at least one RD3a′ is unsubstituted alkynyl. In certain embodiments, at least one RD3a′ is substituted carbocyclyl. In certain embodiments, at least one RD3a′ is unsubstituted carbocyclyl. In certain embodiments, at least one RD3a′ is substituted heterocyclyl. In certain embodiments, at least one RD3a′ is unsubstituted heterocyclyl. In certain embodiments, at least one RD3a′ is substituted aryl. In certain embodiments, at least one RD3a′ is unsubstituted aryl. In certain embodiments, at least one RD3a′ is substituted phenyl. In certain embodiments, at least one RD3a′ is unsubstituted phenyl. In certain embodiments, at least one RD3a′ is substituted heteroaryl. In certain embodiments, at least one RD3a′ is unsubstituted heteroaryl. In certain embodiments, at least one RD3a′ is substituted pyridyl. In certain embodiments, at least one RD3a′ is unsubstituted pyridyl. In certain embodiments, at least one RD3a′ is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one RD3a′ is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, RD3a′ is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, RD3a′ 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, RD3a′ is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, RD3a′ is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom. In certain embodiments, two RD3a′ groups are joined to form a substituted heterocyclic ring. In certain embodiments, two RD3a′ groups are joined to form an unsubstituted heterocyclic ring.
In compounds of Formula (II) and (IV), RD′ may include a substituent RD4′. In certain embodiments, RD4′ is a leaving group. In certain embodiments, RD4′ is halogen. In certain embodiments, RD4′ is F. In certain embodiments, RD4′ is Cl. In certain embodiments, RD4′ is Br. In certain embodiments, RD4′ is I (iodine). In certain embodiments, RD4′ is —OS(═O)w′RD4a′. In certain embodiments, w′ is 1. In certain embodiments, w′ is 2. In certain embodiments, RD4′ is —OMs. In certain embodiments, RD4′ is —OTf. In certain embodiments, RD4′ is —OTs. In certain embodiments, RD4′ is —OBs. In certain embodiments, RD4′ is 2-nitrobenzenesulfonyloxy. In certain embodiments, RD4′ is —ORD4a′. In certain embodiments, RD4′ is —OMe. In certain embodiments, RD4′ is —OCF3. In certain embodiments, RD4′ is —OPh. In certain embodiments, RD4′ is —OC(═O)RD4a′. In certain embodiments, RD4′ is —OC(═O)Me. In certain embodiments, RD4′ is —OC(═O)CF3. In certain embodiments, RD4′ is —OC(═O)Ph. In certain embodiments, RD4′ is —OC(═O)Cl. In certain embodiments, RD4′ is —OC(═O)ORD4a′. In certain embodiments, RD4′ is —OC(═O)OMe. In certain embodiments, RD4′ is —OC(═O)O(t-Bu).
In certain embodiments, RD4a′ is substituted alkyl. In certain embodiments, RD4a′ is unsubstituted alkyl. In certain embodiments, RD4a′ is C1-6 alkyl. In certain embodiments, RD4a′ is methyl. In certain embodiments, RD4a′ is ethyl. In certain embodiments, RD4a′ is propyl. In certain embodiments, RD4a′ is butyl. In certain embodiments, RD4a′ is substituted alkenyl. In certain embodiments, RD4a′ is unsubstituted alkenyl. In certain embodiments, RD4a′ is vinyl. In certain embodiments, RD4a′ is substituted alkynyl. In certain embodiments, RD4a′ is unsubstituted alkynyl. In certain embodiments, RD4a′ is ethynyl. In certain embodiments, RD4a′ is substituted carbocyclyl. In certain embodiments, RD4a′ is unsubstituted carbocyclyl. In certain embodiments, RD4a′ is substituted heterocyclyl. In certain embodiments, RD4a′ is unsubstituted heterocyclyl. In certain embodiments, RD4a′ is substituted aryl. In certain embodiments, RD4a′ is unsubstituted aryl. In certain embodiments, RD4a′ is substituted phenyl. In certain embodiments, RD4a′ is unsubstituted phenyl. In certain embodiments, RD4a′ is substituted heteroaryl. In certain embodiments, RD4a′ is unsubstituted heteroaryl. In certain embodiments, RD4a′ is substituted pyridyl. In certain embodiments, RD4a′ is unsubstituted pyridyl.
In compounds of Formula (II) and (IV), RD′ may include a substituent RD5′. In certain embodiments, RD5′ is H. In certain embodiments, RD5′ is substituted alkyl. In certain embodiments, RD5′ is unsubstituted alkyl. In certain embodiments, RD5′ is C1-6 alkyl. In certain embodiments, RD5′ is methyl. In certain embodiments, RD5′ is ethyl. In certain embodiments, RD5′ is propyl. In certain embodiments, RD5′ is butyl. In certain embodiments, RD5′ is a nitrogen protecting group. In certain embodiments, RD5′ is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts.
In certain embodiments, RD1′ and RD2′ are each hydrogen. In certain embodiments, RD1′ and RD3′ are each hydrogen. In certain embodiments, RD2′ and RD3′ are each hydrogen. In certain embodiments, RD1′, RD2′, and RD3′ are each hydrogen. In certain embodiments, RD1′, RD2′, and RD3′, and RD5′ 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, YZ′ is —O—. In certain embodiments, YZ′ is ═O. In certain embodiments, YZ′ is —S—. In certain embodiments, YZ′ is ═S. In certain embodiments, YZ′ is —NRD6′—, wherein RD6′ is hydrogen, C1-6 alkyl, or a nitrogen protecting group. In certain embodiments, YZ′ is —NH—. In certain embodiments, YZ′ is —NCH3—. In certain embodiments, YZ′ is —N(BOC)—. In certain embodiments, YZ′ is —N(Fmoc)-. In certain embodiments, YZ′ is —N(Cbz)-. In certain embodiments, YZ′ is —N(Bn)-. In certain embodiments, YZ′ is ═NRD6′, wherein RD6′ is hydrogen, C1-6 alkyl, or a nitrogen protecting group. In certain embodiments, YZ′ is ═NH. In certain embodiments, YZ′ is ═NCH3. In certain embodiments, YZ′ is =NTs. In certain embodiments, YZ′ is ═NBn. In certain embodiments, YZ′ is ═NCH(Ph)2.
In certain embodiments, RD′ is of the formula:




In certain embodiments, RD′ is of the formula:





In certain embodiments, RD′ is of the formula:





In certain embodiments, RD′ is of the formula:





In certain embodiments, RD′ is of the formula:





In certain embodiments, RD′ is of the formula:





In certain embodiments, RD′ is of the formula:





In certain embodiments, RD′ is of the formula:





In certain embodiments, RD′ is of the formula:





In certain embodiments, RD′ is of the formula:





In certain embodiments, RD′ is of the formula:





In certain embodiments, RD′ is of the formula:





In certain embodiments, RD′ is of the formula:





In certain embodiments, RD′ is of the formula:





In certain embodiments, RD′ is of the formula:





In certain embodiments, RD′ is of the formula:





In certain embodiments, RD′ is of the formula:





In certain embodiments, RD′ is of the formula:





In certain embodiments, RD′ is of the formula:





In certain embodiments, RD′ is of the formula:





In certain embodiments, RD′ is of the formula:





In certain embodiments, RD′ is of the formula:





In certain embodiments, RD′ is of the formula:





In certain embodiments, RD′ is of the formula:





In certain embodiments, RD, is of the formula:





In certain embodiments, RD′ is of the formula:





Compounds of any one of Formulae (II) to (V) include an aryl Ring A′ optionally substituted with one or more RA′ 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 any one of Formulae (II) to (V) include an aryl Ring A′ optionally substituted with one or more RA′ 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 any one of Formulae (II) to (V), Ring A′ may be substituted with one or more RA′ groups. In certain embodiments, at least one RA′ is H. In certain embodiments, at least two RA′ groups are H. In certain embodiments, at least three RA′ groups are H. In certain embodiments, at least four RA′ groups are H. In certain embodiments, at least one RA′ is halogen. In certain embodiments, at least one RA′ is F. In certain embodiments, at least one RA′ is Cl. In certain embodiments, at least one RA′ is Br. In certain embodiments, at least one RA′ is I (iodine). In certain embodiments, at least one RA′ is substituted acyl. In certain embodiments, at least one RA′ is —C(═O)N(RA′)2. In certain embodiments, at least one RA′ is —C(═O)NHRA1′. In certain embodiments, at least one RA′ is —C(═O)NH(C1-6 alkyl). In certain embodiments, at least one RA′ is —C(═O)NHMe. In certain embodiments, at least one RA′ is —C(═O)NH2. In certain embodiments, at least one RA′ is unsubstituted acyl. In certain embodiments, at least one RA′ is acetyl. In certain embodiments, at least one RA′ is substituted alkyl. In certain embodiments, at least one RA′ is substituted methyl. In certain embodiments, at least one RA′ is unsubstituted alkyl. In certain embodiments, at least one RA′ is C1-6 alkyl. In certain embodiments, at least one RA′ is methyl. In certain embodiments, at least one RA′ is ethyl. In certain embodiments, at least one RA′ is propyl. In certain embodiments, at least one RA′ is butyl. In certain embodiments, at least one RA′ is substituted alkenyl. In certain embodiments, at least one RA′ is unsubstituted alkenyl. In certain embodiments, at least one RA′ is substituted alkynyl. In certain embodiments, at least one RA′ is unsubstituted alkynyl. In certain embodiments, at least one RA′ is substituted carbocyclyl. In certain embodiments, at least one RA′ is unsubstituted carbocyclyl. In certain embodiments, at least one RA′ is substituted heterocyclyl. In certain embodiments, at least one RA′ is unsubstituted heterocyclyl. In certain embodiments, at least one RA′ is




In certain embodiments, at least one RA′ is substituted aryl. In certain embodiments, at least one RA′ is unsubstituted aryl. In certain embodiments, at least one RA′ is substituted phenyl. In certain embodiments, at least one RA′ is unsubstituted phenyl. In certain embodiments, at least one RA′ is substituted heteroaryl. In certain embodiments, at least one RA′ is unsubstituted heteroaryl. In certain embodiments, at least one RA′ is substituted pyridyl. In certain embodiments, at least one RA′ is unsubstituted pyridyl. In certain embodiments, at least one RA′ is —ORA1′. In certain embodiments, at least one RA′ is —O(C1-6 alkyl). In certain embodiments, at least one RA′ is —OMe. In certain embodiments, at least one RA′ is —OH. In certain embodiments, at least one RA′ is —N(RA1′)2. In certain embodiments, at least one RA′ is —NH2. In certain embodiments, at least one RA′ is —SRA1′. In certain embodiments, at least one RA′ is —SH. In certain embodiments, at least one RA′ is —NRA1′C(═O)N(RA′)2. In certain embodiments, at least one RA′ is —NHC(═O)N(RA′)2. In certain embodiments, at least one RA′ is —NHC(═O)NHRA1′. In certain embodiments, at least one RA′ is —NHC(═O)NH(C1-6 alkyl). In certain embodiments, at least one RA′ is —NHC(═O)NHMe. In certain embodiments, at least one RA′ is —NHC(═O)NH2. In certain embodiments, at least one RA′ is —NRA1′C(═O)NHRA1′. In certain embodiments, at least one RA′ is —NRA1′C(═O)NH2. In certain embodiments, at least one RA′ is —NRA1′S(═O)2RA1′. In certain embodiments, at least one RA′ is —NHS(═O)2RA1′. In certain embodiments, at least one RA′ is —NHS(═O)2(C1-6 alkyl). In certain embodiments, at least one RA′ is —NHS(═O)2Me. In certain embodiments, at least one RA′ is —S(═O)2N(RA1′)2. In certain embodiments, at least one RA′ is —S(═O)2N(RA1′)2. In certain embodiments, at least one RA′ is —S(═O)2N(C1-6 alkyl)2. In certain embodiments, at least one RA′ is —S(═O)2NH(C1-6 alkyl). In certain embodiments, at least one RA′ is —S(═O)2NH(t-Bu). In certain embodiments, at least one RA′ is —S(═O)2NH2.

In compounds of any one of Formulae (II) to (V), Ring C′ may be substituted with one or more RB′ groups. In certain embodiments, at least one RB′ is H. In certain embodiments, at least two RB′ groups are H. In certain embodiments, at least three RB′ groups are H. In certain embodiments, at least four RB′ groups are H. In certain embodiments, at least one RB′ is halogen. In certain embodiments, at least one RB′ is F. In certain embodiments, at least one RB′ is Cl. In certain embodiments, at least one RB′ is Br. In certain embodiments, at least one RB′ is I (iodine). In certain embodiments, at least one RB′ is substituted acyl. In certain embodiments, at least one RB′ is —C(═O)N(RA1)2. In certain embodiments, at least one RB′ is —C(═O)NHRA1′. In certain embodiments, at least one RB′ is —C(═O)NH(C1-6 alkyl). In certain embodiments, at least one RB′ is —C(═O)NHMe. In certain embodiments, at least one RB′ is —C(═O)NH2. In certain embodiments, at least one RB′ is unsubstituted acyl. In certain embodiments, at least one RB′ is acetyl. In certain embodiments, at least one RB′ is substituted alkyl. In certain embodiments, at least one RB′ is substituted methyl. In certain embodiments, at least one RB′ is unsubstituted alkyl. In certain embodiments, at least one RB′ is C1-6 alkyl. In certain embodiments, at least one RB′ is methyl. In certain embodiments, at least one RB′ is ethyl. In certain embodiments, at least one RB′ is propyl. In certain embodiments, at least one RB′ is butyl. In certain embodiments, at least one RB′ is —CF3. In certain embodiments, at least one RB′ is substituted alkenyl. In certain embodiments, at least one RB′ is unsubstituted alkenyl. In certain embodiments, at least one RB′ is substituted alkynyl. In certain embodiments, at least one RB′ is unsubstituted alkynyl. In certain embodiments, at least one RB′ is substituted carbocyclyl. In certain embodiments, at least one RB′ is unsubstituted carbocyclyl. In certain embodiments, at least one RB′ is substituted heterocyclyl. In certain embodiments, at least one RB′ is unsubstituted heterocyclyl. In certain embodiments, at least one RB′ is substituted aryl. In certain embodiments, at least one RB′ is unsubstituted aryl. In certain embodiments, at least one RB′ is substituted phenyl. In certain embodiments, at least one RB′ is unsubstituted phenyl. In certain embodiments, at least one RB′ is substituted heteroaryl. In certain embodiments, at least one RB′ is unsubstituted heteroaryl. In certain embodiments, at least one RB′ is substituted pyridyl. In certain embodiments, at least one RB′ is unsubstituted pyridyl. In certain embodiments, at least one RB′ is —OA1. In certain embodiments, at least one RB′ is —O(C1-6 alkyl). In certain embodiments, at least one RB′ is —OMe. In certain embodiments, at least one RB′ is —OH. In certain embodiments, at least one RB′ is —N(RA1′)2. In certain embodiments, at least one RB′ is —NH2. In certain embodiments, at least one RB′ is —SRA1′. In certain embodiments, at least one RB′ is —SH. In certain embodiments, at least one RB′ is —NRA1′C(═O)N(RA1)2. In certain embodiments, at least one RB′ is —NHC(═O)N(RA1′)2. In certain embodiments, at least one RB′ is —NHC(═O)NHRA′. In certain embodiments, at least one RB′ is —NHC(═O)NH(C1-6 alkyl). In certain embodiments, at least one RB′ is —NHC(═O)NHMe. In certain embodiments, at least one RB′ is —NHC(═O)NH2. In certain embodiments, at least one RB′ is —NRA1′C(═O)NHRA′. In certain embodiments, at least one RB′ is —NRA1′C(═O)NH2. In certain embodiments, at least one RB′ is —NRA1′S(═O)2RA1. In certain embodiments, at least one RB′ is —NHS(═O)2RA1′. In certain embodiments, at least one RB′ is —NHS(═O)2(C1-6 alkyl). In certain embodiments, at least one RB′ is —NHS(═O)2Me. In certain embodiments, at least one RB′ is —S(═O)2N(RA1′)2. In certain embodiments, at least one RB′ is —S(═O)2N(RA1′)2. In certain embodiments, at least one RB′ is —S(═O)2N(C1-6 alkyl)2. In certain embodiments, at least one RB′ is —S(═O)2NH(C1-6 alkyl). In certain embodiments, at least one RB′ is —S(═O)2NH(t-Bu). In certain embodiments, at least one RB′ is —S(═O)2NH2. In certain embodiments, at least one RB′ is substituted imidazole. In certain embodiments, at least one RB′ is substituted piperidine. In certain embodiments, at least one RB′ substituted piperizine. In certain embodiments, at least one RB′ substituted pyrrolidine. In certain embodiments, at least one RB′ is substituted morpholine. In certain embodiments, at least one RB′ is substituted diazapane. In certain embodiments, at least one RB′ is




In certain embodiments, at least one RB is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, at least one RB′ is





In certain embodiments, two RB′ groups are are joined to form a 1,3 dioxolane. In certain embodiments, two RB′ groups are 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 RB′ groups are joined to form a 1,2,3-thiadiazole. In certain embodiments, two RB′ 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 RA1′ is H. In certain embodiments, at least one RA1′ is substituted acyl. In certain embodiments, at least one RA1′ is unsubstituted acyl. In certain embodiments, at least one RA1′ is acetyl. In certain embodiments, at least one RA1′ is substituted alkyl. In certain embodiments, at least one RA1′ is unsubstituted alkyl. In certain embodiments, at least one RA1′ is C1-6 alkyl. In certain embodiments, at least one RA1′ is methyl. In certain embodiments, at least one RA1′ is ethyl. In certain embodiments, at least one RA1′ is propyl. In certain embodiments, at least one RA1′ is butyl. In certain embodiments, at least one RA1′ is substituted alkenyl. In certain embodiments, at least one RA1′ is unsubstituted alkenyl. In certain embodiments, at least one RA1′ is substituted alkynyl. In certain embodiments, at least one RA1′ is unsubstituted alkynyl. In certain embodiments, at least one RA1′ is substituted carbocyclyl. In certain embodiments, at least one RA1′ is unsubstituted carbocyclyl. In certain embodiments, at least one RA1′ is substituted heterocyclyl. In certain embodiments, at least one RA1′ is unsubstituted heterocyclyl. In certain embodiments, at least one RA1′ is substituted aryl. In certain embodiments, at least one RA1′ is unsubstituted aryl. In certain embodiments, at least one RA1′ is substituted phenyl. In certain embodiments, at least one RA1′ is unsubstituted phenyl. In certain embodiments, at least one RA1′ is substituted heteroaryl. In certain embodiments, at least one RA1′ is unsubstituted heteroaryl. In certain embodiments, at least one RA1′ is substituted pyridyl. In certain embodiments, at least one RA1′ is unsubstituted pyridyl. In certain embodiments, at least one RA1′ is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one RA1′ is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, RA1′ is an oxygen protecting group when attached to an oxygen atom. In certain embodiments, RA1′ 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, RA1′ is a sulfur protecting group when attached to a sulfur atom. In certain embodiments, RA1′ is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom.
In compounds of any one of Formulae (II) to (V), two RA1′ 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 RA1′ groups are joined to form a substituted carbocyclic ring. In certain embodiments, two RA1′ groups are joined to form an unsubstituted carbocyclic ring. In certain embodiments, two RA1′ groups are joined to form a substituted heterocyclic ring. In certain embodiments, two RA1′ groups are joined to form an unsubstituted heterocyclic ring. In certain embodiments, two RA1′ groups are joined to form a substituted aryl ring. In certain embodiments, two RA1′ groups are joined to form an unsubstituted aryl ring. In certain embodiments, two RA1′ groups are joined to form a substituted phenyl ring. In certain embodiments, two RA1′ groups are joined to form an unsubstituted phenyl ring. In certain embodiments, two RA1′ groups are joined to form a substituted heteroaryl ring. In certain embodiments, two RA1′ groups are joined to form an unsubstituted heteroaryl ring.
In certain embodiments, RA′ is —ORA1′ and k′ is 1. In certain embodiments, RA′ is —O(C1-6 alkyl) and k′ is 1. In certain embodiments, RA′ is —OMe and k′ is 1. In certain embodiments, RA′ is —OH and k′ is 1.
In certain embodiments, RA′ is substituted C1-6 alkyl; and k′ is 1. In certain embodiments, RA′ is unsubstituted C1-6 alkyl; and k′ is 1. In certain embodiments, RA′ is methyl; and k′ is 1. In certain embodiments, RA′ is —CF3; and k′ is 1. In certain embodiments, RA′ is ethyl; and k′ is 1. In certain embodiments, RA′ is propyl; and k′ is 1. In certain embodiments, RA′ is butyl; and k′ is 1. In certain embodiments, RA′ is propyl; and k′ is 1. In certain embodiments, RA′ is butyl; and k′ is 1.
In certain embodiments, RA′ is halogen; and k′ is 1. In certain embodiments, RA′ is F; and k′ is 1. In certain embodiments, RA′ is Cl; and k′ is 1. In certain embodiments, RA′ is Br; and k′ is 1. In certain embodiments, RA′ is I (iodine); and k′ is 1.
In certain embodiments, one instance of RA′ is halogen, another instance of RA′ is substituted C1-6 alkyl; and k′ is 2. In certain embodiments, one instance of RA′ is F, another instance of RA′ is substituted C1-6 alkyl; and k′ is 2. In certain embodiments, one instance of RA′ is Cl, another instance of RA′ is substituted C1-6 alkyl; and k′ is 2. In certain embodiments, one instance of RA′ is halogen, another instance of RA′ is unsubstituted C1-6 alkyl; and k′ is 2. In certain embodiments, one instance of RA′ is F, another instance of RA′ is unsubstituted C1-6 alkyl; and k′ is 2. In certain embodiments, one instance of RA′ is Cl, another instance of RA′ is unsubstituted C1-6 alkyl; and k′ is 2. In certain embodiments, one instance of RA′ is halogen, another instance of RA′ is methyl; and k′ is 2. In certain embodiments, one instance of RA′ is F, another instance of RA′ is methyl; and k′ is 2. In certain embodiments, one instance of RA′ is Cl, another instance of RA′ is methyl; and k′ is 2. In certain embodiments, one instance of RA′ is halogen, another instance of RA′ is —CF3; and k′ is 2. In certain embodiments, one instance of RA′ is F, another instance of RA′ is —CF3; and k′ is 2. In certain embodiments, one instance of RA′ is Cl, another instance of RA′ is —CF3; and k′ is 2.
In compounds of any one of Formulae (II) to (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 —CH2. In certain embodiments, X′ is —CHRA′. In certain embodiments, X′ is —CH. In certain embodiments, X′ is —C(RA′)2. In certain embodiments, X′ is —C. In certain embodiments, X′ is —N. In certain embodiments, X′ is —NRA′. 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 RA′ or RB′. In certain embodiments, Y′ is a bond. In certain embodiments, Y′ is a single bond. In certain embodiments, Y′ is —CH2. In certain embodiments, Y′ is —CHRA′. In certain embodiments, Y′ is —CH. In certain embodiments, Y′ is —C(RA′)2. In certain embodiments, Y′ is —C. In certain embodiments, Y′ is —N. In certain embodiments, Y′ is —NRA′. 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 RA′ or RB′. In certain embodiments, Z′ is a bond. In certain embodiments, Z′ is a single bond. In certain embodiments, Z′ is —CH2. In certain embodiments, Z′ is —CHRA′. In certain embodiments, Z′ is —CH. In certain embodiments, Z′ is —C(RA′)2. In certain embodiments, Z′ is —C. In certain embodiments, Z′ is —N. In certain embodiments, Z′ is —NRA′. 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 RA′ or RB′.
In compounds of any one of Formulae (II) to (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 any one of Formulae (II) to (V), linker Q′ and U′ are divalent linker moieties. In certain embodiments, Q′ is —NRA′. In certain embodiments, Q′ is —NH. In certain embodiments, Q′ is —C═O. In certain embodiments, Q′ is —NRA′CO. In certain embodiments, Q′ is a bond. In certain embodiments, X′ may optionally form a 5 to 8 membered ring with RA′ or RB′. In certain embodiments, U′ is —NRA′. In certain embodiments, U′ is —NH. In certain embodiments, U′ is —C═O. In certain embodiments, U′ is —NRA′CO. In certain embodiments, U′ is a bond. In certain embodiments, U′ may optionally form a 5 to 8 membered ring with RA′ or RB′.
In compounds of any one of Formulae (II) to (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 O





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 any one of Formulae (II) to (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 any one of Formulae (II) to (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 thiazolyl. 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 any one of Formulae (II) to (V), Cy may be substituted with one or more RX′ groups. In certain embodiments, at least one RX′ is H. In certain embodiments, at least two RX′ groups are H. In certain embodiments, at least three RX′ groups are H. In certain embodiments, at least four RX′ groups are H. In certain embodiments, at least one RX′ is halogen. In certain embodiments, at least one RX′ is F. In certain embodiments, at least one RX′ is Cl. In certain embodiments, at least one RX′ is Br. In certain embodiments, at least one RX′ is I (iodine). In certain embodiments, at least one RX′ is substituted acyl. In certain embodiments, at least one RX′ is —C(═O)N(RA1′)2. In certain embodiments, at least one RX′ is —C(═O)NHRA1′. In certain embodiments, at least one RX′ is —C(═O)NH(C1-6 alkyl). In certain embodiments, at least one RX′ is —C(═O)NHMe. In certain embodiments, at least one RX′ is —C(═O)NH2. In certain embodiments, at least one RX′ is unsubstituted acyl. In certain embodiments, at least one RX′ is acetyl. In certain embodiments, at least one RX′ is substituted alkyl. In certain embodiments, at least one RX′ is substituted methyl. In certain embodiments, at least one RX′ is unsubstituted alkyl. In certain embodiments, at least one RX′ is C1-6 alkyl. In certain embodiments, at least one RX′ is methyl. In certain embodiments, at least one RX′ is ethyl. In certain embodiments, at least one RX′ is propyl. In certain embodiments, at least one RX′ is butyl. In certain embodiments, at least one RX′ is substituted alkenyl. In certain embodiments, at least one RX′ is unsubstituted alkenyl. In certain embodiments, at least one RX′ is substituted alkynyl. In certain embodiments, at least one RX′ is unsubstituted alkynyl. In certain embodiments, at least one RX′ is substituted carbocyclyl. In certain embodiments, at least one RX′ is unsubstituted carbocyclyl. In certain embodiments, at least one RX′ is substituted heterocyclyl. In certain embodiments, at least one RX′ is unsubstituted heterocyclyl. In certain embodiments, at least one RX′ is substituted aryl. In certain embodiments, at least one RX′ is unsubstituted aryl. In certain embodiments, at least one RX′ is substituted phenyl. In certain embodiments, at least one RX′ is unsubstituted phenyl. In certain embodiments, at least one RX′ is substituted heteroaryl. In certain embodiments, at least one RX′ is unsubstituted heteroaryl. In certain embodiments, at least one RX′ is substituted pyridyl. In certain embodiments, at least one RX′ is unsubstituted pyridyl. In certain embodiments, at least one RX′ is —ORA1′. In certain embodiments, at least one RX′ is —O(C1-6 alkyl). In certain embodiments, at least one RX′ is —OMe. In certain embodiments, at least one RX′ is —OH. In certain embodiments, at least one RX′ is —N(RA1′)2. In certain embodiments, at least one RX′ is —NH2. In certain embodiments, at least one RX′ is —SRA1′. In certain embodiments, at least one RX′ is —SH. In certain embodiments, at least one RX′ is —NRA1′C(═O)N(RA1)2. In certain embodiments, at least one RX′ is —NHC(═O)N(RA1′)2. In certain embodiments, at least one RX′ is —NHC(═O)NHRA1′. In certain embodiments, at least one RX′ is —NHC(═O)NH(C1-6 alkyl). In certain embodiments, at least one RX′ is —NHC(═O)NHMe. In certain embodiments, at least one RX′ is —NHC(═O)NH2. In certain embodiments, at least one RX′ is —NRA1′C(═O)NHRA1′. In certain embodiments, at least one RX′ is —NRA1′C(═O)NH2. In certain embodiments, at least one RX′ is —NRA1′S(═O)2RA1′. In certain embodiments, at least one RX′ is —NHS(═O)2RA1′. In certain embodiments, at least one RX′ is —NHS(═O)2(C1-6 alkyl). In certain embodiments, at least one RX′ is —NHS(═O)2Me. In certain embodiments, at least one RX′ is —S(═O)2N(RA1′)2. In certain embodiments, at least one RX′ is —S(═O)2N(RA1′)2. In certain embodiments, at least one RX′ is —S(═O)2N(C1-6 alkyl)2. In certain embodiments, at least one RX′ is —S(═O)2NH(C1-6 alkyl). In certain embodiments, at least one RX′ is —S(═O)2NH(t-Bu). In certain embodiments, at least one RX′ is —S(═O)2NH2. In certain embodiments, at least one RX′ is




In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiments, at least one RX′ is





In certain embodiment, a compound of the invention is a compound of Formula (I), 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), 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 (III), 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 (III), or a pharmaceutically acceptable salt thereof. In certain embodiment, a compound of the invention is a compound of Formula (IV), 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 (IV), 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) 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 knock-down 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 Aug. 16; 91(17): 8152-8155). 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, phagocytosis, 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 (I) (e.g., compounds of Formula (I-1)-(I-9)) and compounds of any one of Formulae (II) to (V), 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 IC50 value. In some embodiments, a the IC50 value for a selective inhibitor is <100 μM for TAK1, HCK, or HPK1, but >100 μM for other kinases.
The IC50 value is defined as the concentration of inhibitor required to inhibit 50% of the kinase activity. In certain embodiments, the compounds of of the invention may exhibit IC50 values <100 μM. In certain other embodiments, the compounds exhibit IC50 values <50 μM. In certain other embodiments, the compounds exhibit IC50 values <40 μM. In certain other embodiments, the compounds exhibit IC50 values <30 μM. In certain other embodiments, the compounds exhibit IC50 values <20 μM. In certain other embodiments, the compounds exhibit IC50 values <10 μM. In certain other embodiments, the compounds exhibit IC50 values <7.5 μM. In certain embodiments, the compounds exhibit IC50 values <5 μM. In certain other embodiments, the compounds exhibit IC50 values <2.5 μM. In certain embodiments, the compounds exhibit IC50 values <1 μM. In certain embodiments, the compounds exhibit IC50 values <0.75 μM. In certain embodiments, the compounds exhibit IC50 values <0.5 μM. In certain embodiments, the compounds exhibit IC50 values <0.25 μM. In certain embodiments, the compounds exhibit IC50 values <0.1 μM. In certain other embodiments, the compounds exhibit IC50 values <75 nM. In certain other embodiments, the compounds exhibit IC50 values <50 nM. In certain other embodiments, the compounds exhibit IC50 values <25 nM. In certain other embodiments, the compounds exhibit IC50 values <10 nM. In other embodiments, the compounds exhibit IC50 values <7.5 nM. In other embodiments, the compounds exhibit IC50 values <5 nM.
Icertain embodiments, the compounds of the invention (e.g., the compounds of Formula (I) and compounds of any one of Formulae (II) to (V)) inhibit HCK selectively. A non-limiting example of a selective HCK inhibitor is:




In some embodiments, this selective HCK inhibitor has an IC50 value <50 nM.

In certain embodiments, the compounds of the invention (e.g., the compounds of Formula (I) and compounds of any one of Formulae (II) to (V)) inhibit both TAK1 and HCK. In certain embodiments, the compounds of the invention (e.g., the compounds of Formula (I) and compounds of any one of Formulae (II) to (V)) inhibit HPK1 selectively.
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 (PI3K6). 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 autophosphorylation 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 IRAK4 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




or its analogs.

“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 PublicationsWO 2013/088404, WO 2012/068096, and WO 2013/052699, which are incorporated herein by reference.
In certain embodiments, the PI3K inhibitor is of formula:




or an analog thereof.

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 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 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 (PI3K6) 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 (ie., 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 herein 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 effective 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 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 antibiotics, 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 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 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 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, 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 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, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
An effective amount may be included in a single dose (e.g., single oral dose) or multiple doses (e.g., multiple oral doses). In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, any two doses of the multiple doses include different or substantially the same amounts of a compound described herein. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses a day, two doses a day, one dose a day, one dose every other day, one dose every third day, one dose every week, one dose every two weeks, one dose every three weeks, or one dose every four weeks. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is one dose per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is two doses per day. In certain embodiments, the frequency of administering the multiple doses to the subject or applying the multiple doses to the tissue or cell is three doses per day. In certain embodiments, when multiple doses are administered to a subject or applied to a tissue or cell, the duration between the first dose and last dose of the multiple doses is one day, two days, four days, one week, two weeks, three weeks, one month, two months, three months, four months, six months, nine months, one year, two years, three years, four years, five years, seven years, ten years, fifteen years, twenty years, or the lifetime of the subject, tissue, or cell. In certain embodiments, the duration between the first dose and last dose of the multiple doses is three months, six months, or one year. In certain embodiments, the duration between the first dose and last dose of the multiple doses is the lifetime of the subject, tissue, or cell. In certain embodiments, a dose (e.g., a single dose, or any dose of multiple doses) described herein includes independently between 0.1 μg and 1 μg, between 0.001 mg and 0.01 mg, between 0.01 mg and 0.1 mg, between 0.1 mg and 1 mg, between 1 mg and 3 mg, between 3 mg and 10 mg, between 10 mg and 30 mg, between 30 mg and 100 mg, between 100 mg and 300 mg, between 300 mg and 1,000 mg, or between 1 g and 10 g, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 1 mg and 3 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 3 mg and 10 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 10 mg and 30 mg, inclusive, of a compound described herein. In certain embodiments, a dose described herein includes independently between 30 mg and 100 mg, inclusive, of a compound described herein.
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 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-1




N-(5-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamido)-2-methylphenyl)-5-(thiophen-2-yl)nicotinamide (I-1)
To a solution of 5-(thiophen-2-yl)nicotinic acid (205 mg, 1.0 mmol), DMAP (147 mg, 1.2 mmol), HATU (456 mg, 1.2 mmol) and iPr2NEt (440 uL, 2.5 mmol) in CH2Cl2 (5 mL) was added N-(3-amino-4-methylphenyl)-4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)benzamide (420 mg, 1.0 mmol) and the resulting mixture was stirred at room temperature for 24 hours. The solution was filtered to remove solids, concentrated and purified by reverse phase HPLC to afford 485 mg (80%) of title compound as a white solid.
Preparation of I-3




N-(2-methyl-5-((3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)carbamoyl)phenyl)-5-(thiophen-2-yl)nicotinamide (I-3)
To a solution of 5-(thiophen-2-yl)nicotinic acid (205 mg, 1.0 mmol), DMAP (147 mg, 1.2 mmol), HATU (456 mg, 1.2 mmol) and iPr2NEt (440 uL, 2.5 mmol) in CH2Cl2 (5 mL) was added 3-amino-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (375 mg, 1.0 mmol) and the resulting mixture was stirred at room temperature for 24 hours. The solution was filtered to remove solids, concentrated and purified by reverse phase HPLC to afford 425 mg (76%) of title compound as a white solid.
Compounds I-2, I-4, I-5, I-6 and I-7 were prepared similarly to I-3.
Characterization data for all final compounds is in the table below.













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







I-1




N-(5-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl) benzamido)-2- methylphenyl)-5- (thiophen-2- yl)nicotinamide
1H NMR (600 MHz, TFA salt, DMSO) δ 10.57 (s, 1H), 10.33 (s, 1H), 9.50 (br, 1H), 9.17 (s, 1H), 9.10 (s, 1H), 8.59 (s, 1H), 8.37 (s, 1H), 8.32 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 8.4 Hz, 1H), 7.94 (s, 1H), 7.84 (d, J = 3.6 Hz, 1H), 7.79 (d, J = 4.8, 1H), 7.68 (d, J = 3.6 Hz, 1H), 7.36 (d, J = 8.4 Hz, 1H), 7.31 (dd, J = 5.4, 3.6 Hz, 1H), 3.80 (s, 2H), 3.38 (m, 2H), 3.14 (q, J = 7.2 Hz, 1H), 3.01 (m, 2H), 2.94 (m, 2H), 2.45 (m, 2H), 2.25 (s, 3H), 1.22 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 608 (M + H)+.


 


I-2




N-(2-chloro-5- ((4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl) phenyl) carbamoyl) phenyl)-5- (thiophen-2- yl)nicotinamide
1H NMR (600 MHz, TFA salt, DMSO) δ 10.65 (s, 1H), 10.64 (s, 1H), 9.54 (br, 1H), 9.13 (s, 1H), 9.04 (s, 1H), 8.54 (s, 1H), 8.22 (s, 1H), 8. 21 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 3.6 Hz, 1H), 7.73 (d, J = 4.8, 1H), 7.72 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 4.8, 3.6 Hz, 1H), 3.68 (s, 2H), 3.44 (m, 2H), 3.12 (m, 2H), 2.98 (m, 2H), 2.92 (m, 2H), 2.41 (m, 2H), 1.20 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 628 (M + H)+.


 


I-3




N-(2-methyl-5- ((3-(4- methyl-1H- imidazol-1- yl)-5- (trifluoromethyl) phenyl) carbamoyl) phenyl)-5- (thiophen-2- yl)nicotinamide
1H NMR (600 MHz, TFA salt, DMSO) δ 10.82 (s, 1H), 10.38 (s, 1H), 9.45 (br, 1H), 9.12 (s, 1H), 9.05 (s, 1H), 8.55 (s, 1H), 8.52 (s, 1H), 8.23 (s, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.88 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 3.6 Hz, 1H), 7.72 (d, J = 4.8 Hz, 1H), 7.52 (d, J = 8.4, 1H), 7.24 (dd, J = 4.8, 3.6 Hz, 1H), 2.36 (s, 3H), 2.33 (s, 3H). MS (ESI) m/z 562 (M + H)+.


 


I-4




N-(2-methyl-5- ((3-(4- methylpiperazin- 1-yl)-5- (trifluoromethyl) phenyl) carbamoyl) phenyl)-5- (thiophen-2- yl)nicotinamide
1H NMR (600 MHz, TFA salt, DMSO) δ 10.38 (s, 1H), 10.37 (s, 1H), 9.87 (br, 1H), 9.11 (s, 1H), 9.04 (s, 1H), 8.53 (s, 1H), 8.02 (s, 1H), 7.84 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 3.6 Hz, 1H), 7.70-7.75 (m, 3H), 7.48 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 4.8, 3.6 Hz, 1H), 7.06 (s, 1H), 3.91 (m, 2H), 3.54 (m, 2H), 3.16 (m, 2H), 3.05 (m, 2H), 2.86 (s, 3H), 2.35 (s, 3H). MS (ESI) m/z 580 (M + H)+.


 


I-5




N-(5-((4-(4- ethylpiperazin- 1-yl)-3- (trifluoromethyl) phenyl) carbamoyl)-2- methylphenyl)- 5-(thiophen-2- yl)nicotinamide
1H NMR (600 MHz, TFA salt, DMSO) δ 10.43 (s, 1H), 10.32 (s, 1H), 9.43 (br, 1H), 9.06 (s, 1H), 8.99 (s, 1H), 8.47 (s, 1H), 8.13 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.97 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 4.8 Hz, 1H), 7.67 (d, J = 4.8 Hz, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.18 (dd, J = 4.8, 4.8 Hz, 1H), 3.51 (m, 4H), 3.18 (m, 2H), 3.00 (m, 4H), 2.29 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H). MS (ESI) ni/z 594 (M + H)+.


 


I-6




N-(5-((3-(2- cyanopropan-2- yl)phenyl) carbamoyl)-2- methylphenyl)- 5-(thiophen-2- yl)nicotinamide
1H NMR (600 MHz, TFA salt, DMSO) δ 10.32 (s, 1H), 10.28 (s, 1H), 9.06 (s, 1H), 9.00 (s, 1H), 8.49 (s, 1H), 7.96 (s, 1H), 7.89 (s, 1H), 7.81 (s, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.72 (d, J = 3.6 Hz, 1H), 7.67 (d, J = 4.8 Hz, 1H), 7.42 (d, J = 8.4, 1H), 7.18 (m, 2H), 2.29 (s, 3H), 1.63 (s, 6H), MS (ESI) m/z 481 (M + H)+.


 


I-7




N-(5-((3,5- dimorpholino- phenyl) carbamoyl)-2- methylphenyl)- 5-(thiophen-2- yl)nicotinamide
1H NMR (600 MHz, TFA salt, DMSO) δ 10.30 (s, 1H), 9.89 (s, 1H), 9.06 (s, 1H), 8.99 (s, 1H), 8.48 (s, 1H), 7.93 (s, 1H), 7.75 (d, J = 7.8 Hz, 1H), 7.72 (d, J = 3.6 Hz, 1H), 7.64 (d, J = 4.8 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.18 (dd, J = 4.8, 3.6 Hz, 1H), 6.96 (s, 2H), 6.26 (s, 1H), 3.67 (m, 8H), 3.04 (m, 8H), 2.28 (s, 3H). MS (ESI) m/z 584 (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 (Promega) 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 BDTM FACSCanto II flow cytometer and analyzed with BD FACS DIVA Software.
Results
A number of compounds described herein show inhibitory activity against TAK1, HCK, BTK and other kinases. Shown in Table 1 and 1a are exemplary in vitro IC50 data of these compounds. Table 2 and 2a shows the in vitro EC50 values of these compounds.












TABLE 1






Com-
BTK

TAK1
GCK



pound
IC50
HCK IC50
IC50
IC50


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











(I-1)
 22.9
 7.4
   8210
—


 






(I-2)
—
—
—
—


 






(I-3)
 196  
 62.2
—
—


 






(I-4)
 459  
 22.8
—
—


 






(I-5)
3910  
117  
>10000
—


 






(I-6)
1150  
 29.9
 >3330
—


 






(I-7)
3420  
 56.5
—
—




















TABLE 1a





Structure
Compound ID
BTK IC50 (nM)
HCK IC50 (nM) Inv
TAK1 IC50 (nM)











(I-8)
69.7
5.33
—


 






(I-9)
25.3
2.43
—























TABLE 2





Compound
BCWM.1
MWCL-1
RPCIWM-1
OCI-Ly3
Ramos
OCI-Ly19
Mec1 EC50


ID
EC50 (nM)
EC50 (nM)
EC50 (nM)
EC50 (nM)
EC50 (nM)
EC50 (nM)
(nM)






















(I-1)
38
459
—
2900
4150
552
—


(I-2)
12
16
110
161
60
52
—


(I-3)
141
355
725
411
555
508
—


(I-4)
—
—
—
—
—
—
—


(I-5)
365
1090
0.02
2160
989
1560
—


(I-6)
—
—
—
—
—
—
—


(I-7)
180
1760
4800
3540
2380
2970
—























TABLE 2a





Compound
BCWM.1
MWCL-1
TMD8
OCI-Ly7 EC50
OCI-Ly3
Ramos
OCI-Ly19 EC50


ID
EC50 (nM)
EC50 (nM)
EC50 (nM)
(nM)
EC50 (nM)
EC50 (nM)
(nM)






















(I-8)
2.7
15
—
—
76
329
56



<1
<1


356


(I-9)
542
294
—
—
5300
7470
2650



305
281


356









Kinative

The kinase selectivity of I-6 was 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 3 shows that compound I-6 inhibits a number of kinases at 1 μM, including Abl (>90%), FYN (55.7%), LYN (87.6%), and ZAK (>95%).













TABLE 3









SEQ
Labeling
Compund I-6


Kinase
Reference
Description
Sequence
ID NO:
Site
(1 μM)





















ABL,
UniRef100_P00519
Proto-oncogene tyrosine-
LMTGDTYT
1
Activation
>90


ARG

protein kinase ABL1 
AHAGAKFP

Loop





[Homo sapiens (Human)]
IK





 


ACK
UniRef100_Q07912
Activated CDC42 kinase 1
TVSVAVKC
2
Lys1
-1.2




[Homo sapiens (Human)]
LKPDVLSQ








PEAMDDFI








R





 


AMPKa1,
UniRef100_Q13131
5′-AMP-activated protein
VAVKILNR
3
Lys1
15.3


AMPKa2

kinase catalytic 








subunit alpha-1








[Homo sapiens (Human)]






 


ATR
UniRef100_Q13535
Serine/threonine-
FYIMMCKP
4
ATP
26.2




protein kinase ATR
K







[Homo sapiens (Human)]






 


AurA
UniRef100_O14965
Serine/threonine-
DIKPENLL
5
Lys2
-21.6




protein kinase 6
LGSAGELK







[Homo sapiens (Human)]






 


AurB
UniRef100_Q96GD4
Serine/threonine-
SHFIVALK
6
Lys1
-94




protein kinase 12
VLFK







[Homo sapiens (Human)]






 


BARK1
UniRef100_P25098
Beta-adrenergic
DLKPANIL
7
Lys2
-1.2




receptor kinase 1 n = 1 
LDEHGHVR







Tax = Homo sapiens








RepID = ARBK1_HUMAN






 


BLK
UniRef100_P51451
Tyrosine-protein kinase BLK
IIDSEYTA
8
Activation
68.8




n = 2 TAX = Homo sapiens
QEGAKFPI

Loop





RepID = BLK_HUMAN
K





 


BRAF
UniRef100_P15056
B-Raf proto-oncogene
DLKSNNIF
9
Lys2
-20.3




serine/threonine-
LHEDLTVK







protein kinase








[Homo sapiens (Human)]






 


BTK
UniRef100_Q06187
Tyrosine-protein kinase BTK
GQYDVAIK
10
Lys1
7.8




[Homo sapiens]
MIK





 


BTK
UniRef100_Q06187
Tyrosine-protein kinase BTK
YVLDDEYT
11
Activation
-12.5




[Homo sapiens]
SSVGSKFP

Loop






VR





 


CaMK1d
UniRef100_Q8IU85
Calcium/calmodulin-dependent
LFAVKCIP
12
Lys1
-17.8




protein kinase type 1D
K







[Homo sapiens (Human)]






 


CaMK2a,
UniRef100_Q9UQM7
Calcium/calmodulin-dependent
DLKPENLL
13
Lys2
0.7


CaMK2b,

protein kinase type II
LASK





CaMK2d,

alpha chain






CaMK2g

[Homo sapiens (Human)]






 


CaMK2d
UniRef100_Q13557
Calcium/calmodulin-dependent
IPTGQEYA
14
Lys1
-1.1




protein kinase type II
AKIINTKK







delta chain n = 2








Tax = Euarchontoglires








RepID = KCC2D_HUMAN






 


CaMK4
UniRef100_Q16566
Calcium/calmodulin-dependent
DLKPENLL
15
Lys2
20.7




protein kinase type IV
YATPAPDA







[Homo sapiens (Human)]
PLK





 


CDC2
UniRef100_P06493
Cell division control
DLKPQNLL
16
Lys2
-7.9




protein 2 homolog
IDDKGTIK







[Homo sapiens (Human)]






 


CDK11,
UniRef100_P49336
Cell division protein
DLKPANIL
17
Lys2
20.7


CDK8

kinase 8
VMGEGPER







[Homo sapiens (Human)]






 


CDK2
UniRef100_P24941
Cell division protein
DLKPQNLL
18
Lys2
8.6




kinase 2
INTEGAIK







[Homo sapiens (Human)]






 


CDK5
UniRef100_Q00535
Cell division protein
DLKPQNLL
19
Lys2
9.3




kinase 5
INR







[Homo sapiens (Human)]






 


CDK7
UniRef100_P50613
Cell division protein
DLKPNNLL
20
Lys2
-6.8




kinase 7
LDENGVLK







[Homo sapiens (Human)]






 


CHK2
UniRef100_O96017
Serine/threonine-protein
VAIKIISK
21
Lys1
4.7




kinase Chk2








[Homo sapiens (Human)]






 


CK1a
UniRef100_P48729
Casein kinase I
DIKPDNFL
22
Lys2
25.1




isoform alpha
MGIGR







[Homo sapiens (Human)]






 


CK1g1
UniRef100_Q9HCP0
Casein kinase I
DVKPENFL
23
Lys2
14.4




isoform gamma-1
IGR







[Homo sapiens (Human)]






 


CK1g2
UniRef100_P78368
Casein kinase I
DVKPENFL
24
Lys2
10.8




isoform gamma-2
VGRPGTK







[Homo sapiens (Human)]






 


CSK
UniRef100_P41240
Tyrosine-protein kinase CSK
VSDFGLTK
25
Activation
23.3




[Homo sapiens (Human)]
EASSTQDT

Loop






GKLPVK





 


DNAPK
UniRef100_P78527
DNA-dependent protein
EHPFLVKG
26
ATP
4.6




kinase catalytic subunit
GEDLR







[Homo sapiens (Human)]






 


eEF2K
UniRef100_O00418
Elongation factor 2 kinase
YIKYNSNS
27
ATP
12




[Homo sapiens (Human)]
GFVR





 


Erk1
UniRef100_P27361
Mitogen-activated
DLKPSNLL
28
Lys2
-3




protein kinase 3
INTTCDLK







[Homo sapiens (Human)]






 


Erk2
UniRef100_P28482
Mitogen-activated
DLKPSNLL
29
Lys2
-11




protein kinase 1
LNTTCDLK







[Homo sapiens]






 


FER
UniRef100_P16591
Proto-oncogene tyrosine-
TSVAVKTC
30
Lys1
-9.6




protein kinase FER n = 2
KEDLPQEL







Tax = Homo sapiens
K







RepID = FER_HUMAN






 


FGR
UniRef100_P09769
Proto-oncogene tyrosine-
LIKDDEYN
31
Activation
3.5




protein kinase FGR
PCQGSKFP

Loop





[Homo sapiens (Human)]
IK





 


FRAP
UniRef100_P42345
FKBP12-rapamycin complex-
IQSIAPSL
32
ATP
-8.8




associated protein
QVITSKQR







[Homo sapiens (Human)]
PR





 


FYN,
UniRef100_P06241
Proto-oncogene tyrosine-
QGAKFPIK
33
Activation
55.7


SRC,

protein kinase Fyn n = 2
WTAPEAAL

Loop



YES

Tax = Homo sapiens
YGR







RepID = FYN_HUMAN






 


GCK
UniRef100_Q12851
Mitogen-activated protein
DIKGANLL
34
Lys2
21.9




kinase kinase kinase kinase 2
LTLQGDVK







n = 1 Tax = Homo sapiens








RepID = M4K2_HUMAN






 


GSK3A
UniRef100_P49840
Glycogen synthase
DIKPQNLL
35
Lys2
17.3




kinase-3 alpha
VDPDTAVL







[Homo sapiens (Human)]
K





 


GSK3B
UniRef100_P49841
Glycogen synthase
DIKPQNLL
36
Lys2
15.9




kinase-3 beta n = 2
LDPDTAVL







Tax = Homo sapiens
K







RepID = GSK3B_HUMAN






 


HPK1
UniRef100_Q92918
Mitogen-activated protein
DKVSGDLV
37
Lys1
7.5




kinase kinase kinase kinase 1
ALKMVK







[Homo sapiens (Human)]






 


IKKe
UniRef100_Q14164
Inhibitor of nuclear
SGELVAVK
38
Lys1
3.8




factor kappa-B kinase
VFNTTSYL







epsilon subunit
RPR







[Homo sapiens (Human)]






 


IKKe,
UniRef100_Q14164
Inhibitor of nuclear
DIKPGNIM
39
Lys2
24.8


TBK1

factor kappa-B kinase
R







epsilon subunit








[Homo sapiens (Human)]






 


ILK
UniRef100_Q13418
Integrin-linked protein
ISMADVKF
40
Protein
17.2




kinase 1
SFQCPGR

Kinase





[Homo sapiens (Human)]


Domain



 


IRAK4
UniRef100_Q9NWZ3
Interleukin-1 receptor-
DIKSANIL
41
Lys2
-1.4




associated kinase 4
LDEAFTAK







[Homo sapiens (Human)]






 


JAK1
UniRef100_P23458
Tyrosine-protein
QLASALSY
42
Protein
16.6




kinase JAK1 n = 1
LEDKDLVH

Kinase





Tax = Homo sapiens
GNVCTKNL

Domain





RepID = JAK1_HUMAN
LLAR





 


JAK1
UniRef100_P23458
Tyrosine-protein
YDPEGDNT
43
Lys1
3.3


domain2

kinase JAK1 n = 1
GEQVAVKS







Tax = Homo sapiens
LKPESGGN







RepID = JAK1_HUMAN
HIADLKK





 


JNK1,
UniRef100_P45983
Mitogen-activated
DLKPSNIV
44
Lys2
11.7


JNK2,

protein kinase 8
VK





JNK3

[Homo sapiens (Human)]






 


KHS1
UniRef100_Q9Y4K4
Mitogen-activated
NVHTGELA
45
Lys1
-21.8




protein kinase kinase
AVKIIK







kinase kinase 5








[Homo sapiens (Human)]






 


LCK
UniRef100_P06239
Proto-oncogene tyrosine-
EGAKFPIK
46
Activation
82.1




protein kinase LCK n = 2
WTAPEAIN

Loop





Tax = Homo sapiens
YGTFTIK







RepID = LCK_HUMAN






 


LKB1
UniRef100_Q15831
Serine/threonine-
DIKPGNLL
47
Lys2
4.9




protein kinase 11
LTTGGTLK







[Homo sapiens (Human)]






 


LOK
UniRef100_O94804
Serine/threonine-
DLKAGNVL
48
Lys2
23.9




protein kinase 10
MTLEGDIR







[Homo sapiens (Human)]






 


LYN
UniRef100_P07948
Tyrosine-protein
VAVKTLKP
49
Lys1
87.6




kinase Lyn n= 1
GTMSVQAF







Tax = Homo sapiens
LEEANLMK







RepID = LYN_HUMAN






 


LYN
UniRef100_P07948
Tyrosine-protein
EGAKFPIK
50
Activation
68.5




kinase Lyn n = 1
WTAPEAIN

Loop





Tax = Homo sapeins
FGCFTIK







RepID = LYN_HUMAN






 


MAP2K1
UniRef100_Q02750
Dual specificity mitogen-
IMHRDVKP
51
Lys2
10.8




activated protein kinase
SNILVNSR







kinase 1 n = 4








Tax = Eutheria








RepID = MP2K1_HUMAN






 


MAP2K1,
UniRef100_Q02750
Dual specificity mitogen-
DVKPSNIL
52
Lys2
4.1


MAP2K2

activated protein kinase
VNSR







kinase 1 n = 4








Tax = Eutheria








RepID = MP2K1_HUMAN






 


MAP2K3
UniRef100_P46734
Dual specificity mitogen-
DVKPSNVL
53
Lys2
4.9




activated protein kinase
INK







kinase 3








[Homo sapiens (Human)]






 


MAP2K4
UniRef100_P45985
Dual specificity mitogen-
DIKPSNIL
54
Lys2
-14.6




activated protein kinase
LDR







kinase 4








[Homo sapiens (Human)]






 


MAP2K5
UniRef100_Q13163
Dual specificity mitogen-
DVKPSNML
55
Lys2
28.7




activated protein kinase
VNTR







kinase 5 n = 1








Tax = Homo sapiens








RepID = MP2K5_HUMAN






 


MAP2K6
UniRef100_P52564
Dual specificity mitogen-
DVKPSNVL
56
Lys2
9.4




activated protein kinase
INALGQVK







kinase 6








[Homo sapiens (Human)]






 


MAP2K7
UniRef100_O14733
Dual specificity mitogen-
DVKPSNIL
57
Lys2
-3




activated protein kinase
LDER







kinase 7








[Homo sapiens (Human)]






 


MAP3K1
UniRef100_Q13233
Mitogen-activated protein
DVKGANLL
58
Lys2
9.8




kinase kinase kinase 1 n = 1
IDSTGQR







Tax = Homo sapiens








RepID = M3K1_HUMAN






 


MAP3K2,
UniRef100_Q9Y2U5
Mitogen-activated protein
DIKGANIL
59
Lys2
-15.3


MAP3K3

kinase kinase kinase 2 n = 3
R







Tax = Homo sapiens








RepID = M3K2_HUMAN






 


MAP3K4
UniRef100_Q9Y6R4
Mitogen-activated protein
DIKGANIF
60
Lys2
6.5




kinase kinase kinase 4
LTSSGLIK







[Homo sapiens (Human)]






 


MAP3K5
UniRef100_Q99683
Mitogen-activated protein
DIKGDNVL
61
Lys2
16.2




kinase kinase kinase 5
INTYSGVL







[Homo sapiens (Human)]
K





 


MARK1,
UniRef100_Q7KZI7
Serine/threonine-
EVAVKIID
62
Lys1
-4.9


MARK2

protein kinase MARK2
K







[Homo sapiens (Human)]






 


MARK2,
UniRef100_P27448
MAP/microtubule affinity-
DLKAENLL
63
Lys2
17.2


MARK3

regulating kinase 3
LDADMNIK







[Homo sapiens (Human)]






 


MARK3
UniRef100_P27448
MAP/microtubule affinity-
EVAIKIID
64
Lys1
-2.2




regulating kinase 3
KTQLNPTS







[Homo sapiens (Human)]
LQK





 


MAST3
UniRef100_O60307
Microtubule-associated serine/
DLKPDNLL
65
Lys2
18.9




threonine-protein kinase 3
ITSLGHIK







[Homo sapiens (Human)]






 


MASTL
UniRef100_Q96GX5
Microtubule-associated serine/
LYAVKVVK
66
Lys1
-3.7




threonine-protein kinase-like








[Homo sapiens (Human)]






 


MST1
UniRef100_Q13043
Serine/threonine-
ETGQIVAI
67
Lys1
-26.3




protein kinase 4
KQVPVESD







[Homo sapiens (Human)]
LQEIIK





 


MST2
UniRef100_Q13188
Serine/threonine-
ESGQVVAI
68
Lys1
-6.1




protein kinase 3
KQVPVESD







[Homo sapiens (Human)]
LQEIIK





 


MST3
UniRef100_Q9Y6E0
Serine/threonine-
DIKAANVL
69
Lys2
-0.4




protein kinase 24
LSEHGEVK







[Homo sapiens (Human)]






 


MST4,
UniRef100_O00506
Serine/threonine-
DIKAANVL
70
Lys2
22


YSK1

protein kinase 25
LSEQGDVK







[Homo sapiens (Human)]






 


NDR1
UniRef100_Q15208
Serine/threonine-
DTGHVYAM
71
Lys1
-10.5




protein kinase 38
KILR







[Homo sapiens (Human)]






 


NDR2
UniRef100_Q9Y2H1
Serine/threonine-
DIKPDNLL
72
Lys2
-12.5




protein kinase 38-like
LDAK







[Homo sapiens (Human)]






 


NEK3
UniRef100_P51956
Serine/threonine-
SKNIFLTQ
73
Activation
10




protein kinase Nek3
NGK

Loop





[Homo sapiens (Human)]






 


NEK6,
UniRef100_Q9HC98
Serine/threonine-
DIKPANVF
74
Lys2
-3.7


NEK7

protein kinase Nek6
ITATGVVK







[Homo sapiens (Human)]






 


NEK7
UniRef100_Q8TDX7
Serine/threonine-
AACLLDGV
75
Lys1
10.7




protein kinase Nek7
PVALKK







[Homo sapiens (Human)]






 


NEK9
UniRef100_Q8TD19
Serine/threonine-protein
DIKTLNIF
76
Lys2
-0.3




kinase Nek9 n = 1
LTK







Tax = Homo sapiens








RepID = NEK9_HUMAN






 


p38a
UniRef100_Q16539
Mitogen-activated
QELNKTIW
77
Protein
85.1




protein kinase 14 n = 3
EVPER

Kinase





Tax = Eutheria


Domain





RepID = MK14_HUMAN






 


p38d,
UniRef100_P53778
Mitogen-activated
DLKPGNLA
78
Lys2
17.8


p38g

protein kinase 12
VNEDCELK







[Homo sapiens (Human)]






 


p70S6K
UniRef100_P23443
Ribosomal protein S6 kinase 1
DLKPENIM
79
Lys2
7.4




(EC 2.7.1.37)(S6K)(S6K1)
LNHQGHVK







(70 kDa ribosomal protein S6








kinase 1)(p70 S6 kinase alpha)








(p70(S6K)-alpha)








[Homo sapiens (Human)]






 


PFTAIRE1
UniRef100_O94921
Serine/threonine-protein
LVALKVIR
80
Lys1
-31.3




kinase PFTAIRE-1 n = 1








Tax = Homo sapiens








RepID = PFTK1_HUMAN






 


PI4KB
UniRef100_Q9UBF8
Phosphatidylinositol
VPHTQAVV
81
ATP
-15.1




4-kinase beta n = 2
LNSKDK







Tax = Homo sapiens








RepID = PI4KB_HUMAN






 


PIK3C3
UniRef100_Q8NEB9
Phosphatidylinositol
TEDGGKYP
82
ATP
-23.1




3-kinase catalytic
VIFKHGDD







subunit type 3
LR







[Homo sapiens (Human)]






 


PIK3CB
UniRef100_P42338
Phosphatidylinositol-4,5-
VFGEDSVG
83
ATP
2.8




bisphosphate 3-kinase
VIFKNGDD







catalytic subunit
LR







beta isoform








[Homo sapiens (Human)]






 


PIK3CD
UniRef100_O00329
Phosphatidylinositol-4,5-
VNWLAHNV
84
ATP
-6.8




bisphosphate 3-kinase
SKDNRQ







catalytic subunit








delta isoform








[Homo sapiens (Human)]






 


PIP4K2A
UniRef100_P48426
Phosphatidylinositol-4-
AKELPTLK
85
ATP
12.8




phosphate 5-kinase type II
DNDFINEG







alpha (EC 2.7.1.68)
QK







(1-Phosphatidylinositol-4-








phosphate 5-kinase 2-alpha)








(PtdIns(4)P-5-kinase isoform








2-alpha (PIP5KII-alpha)








(Diphosphoinositide kinase








2-alpha)(PtdIns(4)P-5-kinase








B isoform)(PIP5KI






 


PIP4K2C
UniRef100_Q8TBX8
Phosphatidylinositol-5-
TLVIKEVS
86
ATP
12.3




phosphate 4-kinase
SEDIADMH







type-2 gamma n = 1
SNLSNYHQ







Tax = Homo sapiens
YIVK







RepID = PI42C_HUMAN






 


PIP5K3
UniRef100_Q9Y2I7
FYVE finger-containing
GGKSGAAF
87
ATP
17.8




phosphoinositide kinase
YATEDDRF







(EC 2.7.1.68) (1-
ILK







phosphatidylinositol-4-








phosphate 5-kinase)








(Phosphatidylinositol-3-








phosphate 5-kinase type 








III)(PIP5K)(PtdIns(4)








P-5-kinase)








[Homo sapiens (Human)]






 


PITSLRE
UniRef100_P21127
PITSLRE serine/threonine-
DLKTSNLL
88
Lys2
1.9




protein kinase CDC2L1
LSHAGILK







[Homo sapiens (Human)]






 


PKCi
UniRef100_P41743
Protein kinase C iota type
DLKLDNVL
89
Lys2
-17.5




[Homo sapiens (Human)]
LDSEGHIK





 


PKD1,
UniRef100_Q15139
Serine/threonine-protein
NIVHCDLK
90
Lys2
-2.5


PKD2

kinase D1 n = 1
PENVLLAS







Tax = Homo sapiens
ADPFPQVK







RepID = KPCD1_HUMAN






 


PKD2
UniRef100_Q9BZL6
Protein kinase D2
DVAVKVID
91
Lys1
-17.8




[Homo sapiens (Human)]
K





 


PKD3
UniRef100_O94806
Protein kinase D3
NIVHCDLK
92
Lys2
-4.5




[Homo sapiens (Human)]
PENVLLAS








AEPFPQVK





 


PKN1
UniRef100_Q16512
Protein kinase N1
VLLSEFRP
93
Lys1
-35.2




[Homo sapiens (Human)]
SGELFAIK








ALK





 


PKR
UniRef100_P19525
Interferon-induced, double-
DLKPSNIF
94
Lys2
3.2




stranded RNA-activated
LVDTK







protein kinase








[Homo sapiens (Human)]






 


PLK1
UniRef100_P53350
Serine/threonine-
CFEISDAD
95
Lys1
-5.4




protein kinase PLK1
TKEVFAGK







[Homo sapiens (Human)]
IVPK





 


PYK2
UniRef100_Q14289
Protein tyrosine
YIEDEDYY
96
Activation
5.4




kinase 2 beta
KASVTR

Loop





[Homo sapiens (Human)]






 


ROCK1,
UniRef100_O75116
Rho-associated
DVKPDNML
97
Lys2
12.7


ROCK2

protein kinase 2
LDK







[Homo sapiens (Human)]






 


RSK1
UniRef100_Q15418
Ribosomal protein S6
DLKPENIL
98
Lys2
33.3


domain1

kinase alpha 1
LDEEGHIK







[Homo sapiens (Human)]
LTDFGLSK








EAIDHEK





 


RSK1
UniRef100_Q15418
Ribosomal protein S6
DLKPSNIL
99
Lys2
-22.9


domain2

kinase alpha 1
YVDESGNP







[Homo sapiens (Human)]
ECLR





 


RSK2
UniRef100_P51812
Ribosomal protein S6
DLKPENIL
100
Lys2
5


domain1

kinase alpha 3
LDEEGHIK







[Homo sapiens (Human)]
LTDFGLSK








ESIDHEK





 


RSK2
UniRef100_P51812
Ribosomal protein S6
DLKPSNIL
101
Lys2
-15.8


domain2

kinase alpha 3
YVDESGNP







[Homo sapiens (Human)]
ESIR





 


SGK3
UniRef100_Q96BR1
Serine/threonine-
FYAVKVLQ
102
Lys1
-7.2




protein kinase Sgk3
K







[Homo sapiens (Human)]






 


SLK
UniRef100_Q9H2G2
CTCL tumor antigen se20-9
DLKAGNIL
103
Lys2
-19.5




[Homo sapiens (Human)]
FTLDGDIK





 


STLK5
UniRef100_Q7RTN6
STE20-related
YSVKVLPW
104
Activation
-17.8




adaptor protein
LSPEVLQQ

Loop





[Homo sapiens (Human)]
NLQGYDAK





 


STLK6
UniRef100_Q9C0K7
Serine/threonine-
SIKASHIL
105
Lys2
44.8




protein kinase
ISGDGLVT







ALS2CR2
LSGLSHLH







[Homo sapiens (Human)]
SLVK





 


SYK
UniRef100_P43405
Tyrosine-protein
ISDFGLSK
106
Activation
-7.9




kinase SYK
ALR

Loop





[Homo sapiens (Human)]






 


SYK
UniRef100_P43405
Tyrosine-protein
TVAVKILK
107
Lys1
-38.5




kinase SYK








[Homo sapiens (Human)]






 


TAO1,
UniRef100_Q9H2K8
Serine/threonine-
DIKAGNIL
108
Lys2
11.9


TAO3

protein kinase TAO3
LTEPGQVK







[Homo sapiens (Human)]






 


TAO2
UniRef100_Q9UL54
Serine/threonine-protein
DVKAGNIL
109
Lys2
33.4




kinase TAO2 n = 2
LSEPGLVK







Tax = Homo sapiens








RepID = TAOK2_HUMAN






 


TEC
UniRef100_P42680
Tyrosine-protein
YVLDDQYT
110
Activation
-28.9




kinase Tec n = 2
SSSGAKFP

Loop





Tax = Homo sapiens
VK







RepID = TEC_HUMAN






 


TLK1
UniRef100_Q9UKI8
Serine/threonine-
YLNEIKPP
111
Lys2
3.9




protein kinase
IIHYDLKP







tousled-like 1
GNILLVDG







[Homo sapiens (Human)]
TACGEIK





 


TLK2
UniRef100_Q86UE8
Serine/threonine-
YLNEIKPP
112
Lys2
-18.8




protein kinase
IIHYDLKP







tousled-like 2
GNILLVNG







[Homo sapiens (Human)]
TACGEIK





 


ULK3
UniRef100_Q6PHR2
Unc-51-like kinase 3
EVVAIKCV
113
Lys1
-21.5




[Homo sapiens (Human)]
AK





 


ZAK
UniRef100_Q9NYL2
Mitogen-activated protein
WISQDKEV
114
Lys1
>95




kinase kinase kinase MLT
AVKK







[Homo sapiens (Human)]






 


ZAP70
UniRef100_P43403
Tyrosine-protein
ISDFGLSK
115
Activation
7.5




kinase ZAP-70
ALGADDSY

Loop





[Homo sapiens (Human)]
YTAR





 


ZC1/HGK,
UniRef100_O95819
Mitogen-activated protein
DIKGQNVL
116
Lys2
27


ZC2/TNIK,

kinase kinase kinase kinase 4
LTENAEVK





ZC3/MINK

[Homo sapiens (Human)]









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. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.
Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.

## Claims

1. A compound of Formula (I-a):



or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof;
wherein:
RA is hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, —ORA1, —N(RA1)2, —CN, —C(═O)RA1, —C(═O)ORA1, —C(═O)N(RA1)2, —NO2, —NRA1C(═O)RA1, —NRA1C(═O)ORA1, —NRA1S(═O)2RA1, —S(═O)2RA1, or —S(═O)2N(RA1)2;
each instance of RB is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —ORA1, —N(RA1)2, —CN, —C(═O)RA1, —C(═O)ORA1, —C(═O)N(RA1)2, —NO2, —NRA1C(═O)RA1, —NRA1C(═O)ORA1, —NRA1S(═O)2RA1, —S(═O)2RA1, or —S(═O)2N(RA1)2;
each instance of RA1 is independently 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, or a sulfur protecting group when attached to a sulfur atom, or two RA1 groups are joined to form an optionally substituted heterocyclic ring;
RX is optionally substituted heteroaryl;
and
l is 1, 2, 3, 4, or 5.

2. The compound of claim 1, wherein the compound is of Formula (I-a1), (I-a2), or (I-a3):



or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof,
wherein:
RXa is hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C(═O)RA1, —C(═O)N(RA1)2, —S(═O)RA1, —S(═O)N(RA1)2, —S(═O)2RA1, —S(═O)2N(RA1)2, or a nitrogen protecting group; and
each instance of RXc is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —ORA1, —N(RA1)2, —SRA1, —CN, —C(═O)RA1, —C(═O)ORA1, —C(═O)N(RA1)2, —NO2, —N3, —NRA1C(═O)RA1, —NRA1C(═O)ORA1, —NRA1C(═O)N(RA1)2, —NRA1S(═O)2RA1, —NRA1S(═O)RA1, —OC(═O)RA1, —OC(═O)ORA1, —OC(═O)N(RA1)2, —S(═O)RA1, —S(═O)N(RA1)2, —S(═O)2RA1, or —S(═O)2N(RA1)2.

3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein RA is substituted or unsubstituted, C1-6 alkyl.

4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein l is 1 or 2.

5. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein at least one instance of RB is substituted or unsubstituted, C1-6 alkyl.

6. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein one instance of RB is substituted or unsubstituted —CH2-(piperazinyl).

7. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein one instance of RB is haloalkyl.

8. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein at least one instance of RB is substituted or unsubstituted imidazolyl.

9. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein at least one instance of RB is substituted or unsubstituted piperazinyl.

10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein at least one instance of RB is substituted or unsubstituted morpholinyl.

11. The compound of claim 1, wherein the compound is of the formula:



or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof.

12. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient.

13. A method of treating a non-Hodgkin's lymphoma in a subject comprising administering an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, to the subject.

14. A kit comprising a container, a compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, and instructions for use in a subject.

15. The compound of claim 1, or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein RX is optionally substituted, 5- or 6-membered, monocyclic heteroaryl.

17. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein RX is optionally substituted, 5-membered, monocyclic heteroaryl.

18. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein RA is halogen.

19. The compound of claim 1, wherein the compound is of the formula:



or a pharmaceutically acceptable salt thereof.

20. The method of claim 13, wherein the non-Hodgkin's lymphoma is Waldenström's macroglobulinemia.

21. The pharmaceutical composition of claim 12 comprising a compound of Formula (I-1):



or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient.

22. The pharmaceutical composition of claim 12 comprising a compound of Formula (I-1):



or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient.

23. The method of claim 13 comprising administering to the subject an effective amount of a compound of Formula (I-1):



or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof.

24. The compound of claim 2, wherein the compound is of Formula (I-a1):



or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof.

25. The compound of claim 2, wherein the compound is of any one of Formulae (I-a4) to (I-a12):






or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein each instance of RB is independently halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —ORA1, —N(RA1)2, —CN, —C(═O)RA1, —C(═O)ORA1, —C(═O)N(RA1)2, —NO2, —NRA1C(═O)RA1, —NRA1C(═O)ORA1, —NRA1S(═O)2RA1, —S(═O)2RA1, or —S(═O)2N(RA1)2.

26. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isotopically labeled derivative, or prodrug thereof, wherein



wherein each instance of RB is independently halogen, optionally substituted alkyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —ORA1, —N(RA1)2, —CN, —C(═O)RA1, —C(═O)ORA1, —C(═O)N(RA1)2, —NO2, —NRA1C(═O)RA1, —NRA1C(═O)ORA1, —NRA1S(═O)2RA1, —S(═O)2RA1, or —S(═O)2N(RA1)2.