The present invention provides compounds of any one of Formulae (A), (I-11), (II), and (V) (e.g., compounds of formula (A-1)-(A-18)), and methods for treating Waldenström's macroglobulinemia (WM) and other B cell neoplasm 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.
##STR00001##
|
##STR00709##
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof;
wherein:
each instance of RA is independently hydrogen, halogen, optionally substituted alkyl, optionally substituted carbocyclyl, —ORA1, —N(RA1)2, —CN, —C(═O)RA1, —(═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, —(═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, provided that at least one instance of RB is optionally substituted heterocyclyl, optionally substituted —(CH2)(heterocyclyl), optionally substituted —(CH2)2(heterocyclyl), or optionally substituted —(CH2)3(heterocyclyl);
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;
ring B is of the formula:
##STR00710##
RY is hydrogen, halogen, or substituted or unsubstituted C1-6 alkyl;
RX is RD, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, or —N(RA1)(RXa) —NH2, —NH(optionally substituted acyl), —N(RA1)N(RA1)2,
##STR00711##
##STR00712##
each instance of RxXa 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)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, —N(RA1)2, or a nitrogen protecting group;
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;
k is 0, 1, 2, 3, or 4;
l is 1, 2, 3, 4, or 5; and
—U—Q— is —NRA(C═O)— or —(C═O)NRA—; and
RD is an electrophilic moiety of any one of Formulae (i-1) to (i-18):
##STR00713##
##STR00714##
##STR00715##
RD1 is 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, or —C(═NRD1a)N(RD1a)2, wherein each occurrence of RD1a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl, or two RD1a groups are joined to form an optionally substituted heterocyclic ring;
RD2 is 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, or —C(═NRD2a)N(RD2a)2, wherein each occurrene 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, or optionally substituted heteroaryl, or two RD2a groups are joined to form an optionally substituted heterocyclic ring;
RD3 is 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, or —C(═NRD3a)N(RD3a)2, wherein each occurrence of RD3a is independently hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or 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;
wherein, unless otherwise provided:
each instance of the alkyl is independently C1-6 alkyl;
each instance of the alkenyl is independently C2-6 alkenyl;
each instance of the alkynyl is independently C2-6 alkynyl;
each instance of the carbocyclyl and carbocyclic ring is independently 3- to 10-membered, monocyclic or bicyclic carbocyclyl;
each instance of the heterocyclyl and heterocyclic ring is independently 5- to 10-membered, monocyclic or bicyclic heterocyclyl;
each instance of the aryl is independently 6- or 10-membered, monocyclic or bicyclic aryl; and
each instance of the heteroaryl is independently 5- to 10-membered, monocyclic or bicyclic heteroaryl.
2. The compound of
##STR00716##
##STR00717##
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof.
##STR00718##
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof,
wherein:
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)(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.
0. 5. The compound of
##STR00719##
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotropically labeled derivative thereof.
0. 6. The compound of
##STR00720##
7. The compound of
8. The compound of
9. The compound of
10. The compound of
11. The compound of
##STR00721##
##STR00722##
##STR00723##
##STR00724##
##STR00725##
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof.
13. A pharmaceutical composition comprising a compound of
14. The compound of
##STR00726##
15. The compound of
0. 16. The compound of
0. 17. The compound of
0. 18. The compound of
0. 19. The compound of
20. The compound of
##STR00727##
is of the formula:
##STR00728##
21. The compound of
22. The compound of
##STR00729##
is of the formula:
##STR00730##
##STR00731##
or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, stereoisomer, or isotopically labeled derivative thereof.
0. 24. The compound of
0. 25. The compound of
0. 26. The compound of
0. 27. The compound of
0. 28. The compound of
##STR00732##
0. 29. The compound of
0. 30. The compound of
0. 31. The compound of
0. 32. A pharmaceutical composition comprising a compound of
0. 33. A pharmaceutical composition comprising a compound of
|
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This invention was made with govemment support under grant numbers 5R01CA130876-05, 5P50CA090578-10, 5R01CA136851-04, 2R01CA136851-05, and IR01CA172592-01A1, awarded by the National Institutes of Health. The government has certain rights in the invention.
The present application is a reissue application of U.S. Pat. No. 9,856,223 B2, issued Jan. 2, 2018 from U.S. patent application Ser. No. 15/104,132, filed Jun. 13, 2016, which is a national stage filing under 35 U.S.C. § 371 of international PCT application, PCT/US2014/070162, filed Dec. 12, 2014, which claims priority under 35 U.S.C. § 119(e) to U.S. provisional patent applications, U.S. Ser. No. 62/036,934, filed Aug. 13, 2014, and U.S. Ser. No. 61/915,684, filed Dec. 13, 2013, the entire contents of each of which are incorporated herein by reference.
Waldenström's macroglobulinemia (WM) is a distinct clinicopathological entity resulting from the accumulation, predominantly in the bone marrow, of clonally related lymphoplasmacytic cells which secrete a monoclonal IgM protein. This condition is considered to correspond to lymphoplasmacytic lymphoma (LPL) as defined by the World Health Organization classification system. WM is a rare disorder, with fewer than 1,500 cases occurring in the United States annually. There is a 2- to 3-fold risk increase of developing WM in people with a personal history of auto-immune diseases with autoantibodies and particularly elevated risks associated with hepatitis, human immunodeficiency virus, and rickettsiosis (Arch. Intern. Med., 2008, 168(17), 1903-9). There is no single accepted treatment for WM, and there can be a marked variation in clinical out-come. Objective response rates are high (>80%) but complete response rates are low (0-15%) (Clin. Adv. Hematol. Oncol., 2009, 7(10), 677-81, 687-90). Thus, there is a need for effective treatment of WM.
The present invention is based, at least in part, on the discovery of compounds of the Formula (A):
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein Q, U, RA, RB, RK, k and l are defined herein, for the treatment of Waldenström's macroglobulinemia. The activity of these compounds was established by in vitro screening against several kinases (e.g., BTK, HCK, TAK1, HPK1).
In certain embodiments, compounds of Formula (A) are of formula:
##STR00003##
##STR00004##
##STR00005##
##STR00006##
##STR00007##
and pharmaceutically acceptable salts thereof.
Another aspect of the invention relates to the compound of Formula (1-11):
##STR00008##
and pharmaceutically acceptable salts thereof.
The present invention also provides compounds of Formula (II) or (V):
##STR00009##
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., BCWM1, MWCL1) that are disease state models of Waldenström's macroglobulinemia (Ditzel et al. Exp Hematol. 2007 September; 35(9):1366-75; Hodge et al. Blood. 2011 May 12; ll7(19)).
The methods of treatment utilizing a compound of the invention also apply to B cell neoplasms of the group consisting of Hodgkin's lymphomas and most non-Hodgkin's lymphomas, such as diffuse large B cell lymphoma, Follicular lymphoma, mucosa-associated lymphatic tissue lymphoma (MALT), small cell lymphocytic lymphoma (overlaps with chronic lymphocytic leukemia), mantle cell lymphoma (MCL), Burkitt lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma (NMZL), splenic marginal zone lymphoma (SMZL), Intra-vascular large B-cell lymphoma, Primary effusion lymphoma, and Lymphomatoid granulomatosis.
The present invention is also based, at least in part, on pharmaceutical compositions comprising a compound of the invention (e.g., a compound of Formula (A), (I-11), (II), or (V) (e.g., compounds of Formula (A-1)-(A-18))) and a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition may be useful for modulating the activity of a kinase in vitro or in a subject in need thereof, and/or for treating and/or preventing in a subject in need thereof a condition associated with aberrant activity of a kinase (e.g., a proliferative disease). In certain embodiments, the pharmaceutical composition may be useful for treatment of Waldenström's macroglobulinemia in a subject in need thereof.
The present invention also provides kits comprising a container with a compound of the invention (e.g., a compound of Formula (A), (I-11), (II), or (V) (e.g., compounds of Formula (A-1)-(A-18))), or a pharmaceutical composition thereof. The kits may include a single dose or multiple doses of a compound described herein or a pharmaceutical composition thereof. The kits may be useful for modulating the activity of a kinase in a subject in need thereof. The kits may also be useful for treating and/or preventing in a subject in need thereof a condition associated with aberrant activity of a kinase. In certain embodiments, the kits further include instructions for using the kit (e.g., for administering a compound described herein, or a pharmaceutical composition thereof).
The details of particular embodiments of the invention are set forth herein. Other features, objects, and advantages of the invention will be apparent from the Detailed Description, the FIGURES, the Examples, and the Claims.
Definitions 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, 5th 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, N Y, 1962); and Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972). The invention additionally encompasses compounds as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.
Unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, replacement of 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 “C1-6alkyl” 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 C5-6alkyl.
The term “aliphatic,” as used herein, refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term “heteroaliphatic” as used herein, refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
The term “alkyl” refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms (“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. In an alkenyl group, a C═C double bond for which the stereochemistry is not specified (e.g., —CH═CHCH3 or
##STR00010##
may be an (E)- or (Z)-double bond
As used herein, “heteroalkenyl” refers to an alkenyl group as defined herein which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, nitrogen, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain (“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.
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 ary1 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 (“C3-4 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 (“C5-10 cycloalkyl”). In certain embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”). Examples of C5 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 C3-4 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 ary1 or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
In certain embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-10 membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In certain embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”). In certain embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In certain embodiments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
Exemplary 3-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azirdinyl, oxiranyl, and thiiranyl. Exemplary 4-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary 5-membered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, triazinanyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-1,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, 1H-benzo[e][1,4]diazepinyl, 1,4,5,7-tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H-furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, 2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl, 4,5,6,7-tetra-hydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4-tetrahydro-1,6-naphthyridinyl, and the like.
As used herein, “aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 it electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“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-bicyelic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl and phenazinyl.
“Heteroaralkyl” is a subset of “alkyl” and refers to an alkyl group, as defined herein, substituted by a heteroaryl group, as defined herein, wherein the point of attachment is on the alkyl moiety.
As used herein, the term “partially unsaturated” refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aromatic groups (e.g., aryl or heteroaryl moieties) as herein defined.
As used herein, the term “saturated” refers to a ring moiety that does not contain a double or triple bond, i.e., the ring contains all single bonds.
Affixing the suffix “-ene” to a group indicates the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the divalent moiety of alkynyl, heteroalkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the divalent moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the divalent moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.
As understood from the above, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are, in certain embodiments, optionally substituted. Optionally substituted refers to a group which may be substituted or unsubstituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” heteroalkyl, “substituted” or “unsubstituted” heteroalkenyl, “substituted” or “unsubstituted” heteroalkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted” means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or didderent at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, and includes any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety.
Exemplary carbon atom substituents include, but are not limited to, halogen, —CN, —NO2, —N3, —SO2H, —SO3H, —OH, —ORaa, —ON(Rbb)2, —N(Rbb)2, —N(Rbb), +X−, —N(ORaa)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, heteroC1-10 alkyl, 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, heteroC1-10 alkyl, heteroC2-10alkenyl, hetero2-10 alkynyl, 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 heterocycly1 or 5-l4 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 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, —ORaa, —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(═RRff)N(Rff)2, —NRffC(═NRff)N(Rff)2, —NRffSO2Ree, —SO2N(Rff)2, —SO2Ree, —SO2ORee, —OSO2Ree, —S(═O)Ree, —Si(Ree)3, —Osi(Ree)2, —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, C3-10carbocyclyl, 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, heteroC1-6alkyl, 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-l0 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(C1-6 alkyl), —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(C1-6alkyl)2, —OC(═O)NH(C1-6 alkyl), —NHC(═O)(C1 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(C1-6 alkyl), —SO2NH2, —SO2C1-6 alkyl, —SO2OC1-6 alkyl, —OSO2C1-6 alkyl, —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, C3-20 carboxyxlyl, 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, —OR, —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, —SO2RRee, —SO2ORcc, —SORaa, —C(═S)N(Rcc)2, —C(═O)SRcc, —C(═S)SRcc, C1-10 alkyl (e.g., alkyl, aralkyl, heteroalkyl), 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, isobornyl carbamate, isobutyl carbamate, isonicotinyl carbamate, p-(p′-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1 -cyclopropylmethyl carbamate, 1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate, 1-methyl-1-(p-phenylazophenyl)ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium) benzyl carbamate, and 2,4,6-trimethylbenzyl carbamate.
Nitrogen protecting groups such as sulfonamide groups (e.g., —S(═O)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-trimethybenzenesulfonamide (Mts), 2,6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pme), methanesulfonamide (Ms), β-trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4-(4′,8′-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.
Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(10)-acyl derivative, N′-p-toluenesulfonylaminoacyl derivative, N′-phenylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted 3,5-dinitro-4-pyridone, N-methylamine, N-allylamine, N-[2-(trimethylsilyl)ethoxy]methylamine (SEM), N-3-acetoxypropylamine, N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine, N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr), N-9-phenylfluorenylamine (PhF), N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N′-oxide, N-1,1-dimethylthiomethyleneamine, N-benzylideneamine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine, N—(N′,N′-dimethylaminomethylene) amine, N,N′-isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylideneamine, N-5-chlorosalicylideneamine, N-(5-chloro-2-hydroxyphenyl) phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine, N-borane derivative, N-diphenylborinic acid derivative, N-[phenyl (pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, benzenesulfenamide, o-nitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide, and 3-nitropyridinesulfenamide (Npys).
In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to herein as an “hydroxyl protecting group”). Oxygen protecting groups include, but are not limited to, —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, a-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4′-bromophenacyloxyphenyl)diphenylmethyl, 4,4′,4″-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4′,4″-tris(levulinoyloxyphenyl)methyl, 4,4′,4″-tris(benzoyloxyphenyl)methyl, 3-(imidazol-1-yl)bis(4′,4″-dimethoxyphenyl)methyl, 1,1-bis(4-methoxyphenyl)-1′-pyrenylmethyl, 9-anthryl, 9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl, 1,3-benzodithiolan-2-yl, benzisothiazolyl S,S-dioxido, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS), t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl (DPMS), t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2,4,6-trimethylbenzoate (mesitoate), methyl carbonate, 9-fluoronylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl carbonate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4-dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl carbonate, S-benzyl thiocarbonate, 4-ethoxy-1-naphthyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate, 2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate, 2,6-dichloro-4-methylphenoxyacetate, 2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate, 2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate, o-(methoxyacyl)benzoate, α-naphthoate, nitrate, alkyl N,N,N′,N′-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts).
In certain embodiments, the substituent present on an sulfur atom is a sulfur protecting group (also referred to as a “thiol protecting group”). Sulfur protecting groups include, but are not limited to, —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:
##STR00011##
In some cases, the leaving group is toluenesulfonate (tosylate, Ts), methanesulfonate (mesylate, Ms), p-bromobenzenesulfonyl (brosylate, Bs), or trifluoromethanesulfonate (triflate, Tf). In some cases, the leaving group is a brosylate (p-bromobenzenesulfonyl). In some cases, the leaving group is a nosylate (2-nitrobenzenesulfonyl). In certain embodiments, the leaving group is a sulfonate-containing group. In certain embodiments, the leaving group is a tosylate group. The leaving group may also be a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate.
These and other exemplary substituents are described in more detail in the Detailed Description, FIGURES, Examples, and Claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.
The following definitions are more general terms used throughout the present application.
As used herein, the term “pharmaceutically acceptable salt” refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Phannaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N+(C1 alkyl)4− salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
The term “solvate” refers to forms of the compound, or a salt thereof, that are associated with a solvent, usually by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, and the like. Compounds of the invention may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. “Solvate” encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates, and methanolates.
The term “hydrate” refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be represented, for example, by the general formula R.x 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 inter-changeable forms of a particular compound structure, and that vary in the displacement of hydrogen atoms and electrons. Thus, two structures may be in equilibrium through the movement of π electrons and an atom (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Another example of tautomerism is the aci- and nitro-forms of phenylnitromethane, that are likewise formed by treatment with acid or base. Tautomeric forms may be relevant to the attainment of the optimal chemical reactivity and biological activity of a compound of interest.
It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers.” Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”.
Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are non-superimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four diiferent groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (−)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.
The term “polymorphs” refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.
The term “prodrugs” refers to compounds that have cleavabie groups and become by solvolysis or under physiological conditions the compounds of the invention, which are pharmaceutically active in vivo. Such examples include, but are not limited to, choline ester derivatives and the like, N-alkylmorpholine esters and the like, Other derivatives of the compounds of this invention have activity in both their acid and acid derivative forms, but in the acid sensitive form often offers advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, Bundgard, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a substituted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides and anhydrides derived from acidic groups pendant on the compounds of this invention are particular prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Particularly the 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 (A), (I-11), (II), or (V)).
In an effort to identify novel treatments for Waldenström's macroglobulinemia, in vitro screens were carried out against several kinases (e.g., BTK, HCK, TAK1, HPK1). These kinases are involved in the regulation of aberrant cell growth associated with this condition. Cell-based screening was also carried out in several disease state model lines of Waldenström's macroglobulinemia (eg, BCWM.1, MWCL-1). Based on these screening etforts and subsequent lead optimization, compounds of any one of Formulae (A), (I-11), (II), and (V) (e.g., compounds of Formula (A-1)-(A18)) were identified.
In one aspect, the present invention provides compounds of Formula (A):
##STR00012##
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:
one instance of A that is included in Ring B is CRY;
the other instance of A that is included in Ring B is CRY or N;
each instance of RY is independently H, halogen, or substituted or unsubstituted C1-6alkyl;
each instance of RX is independently selected from the group consisting of RD, 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)2RA1, —S(═O)2N(RA1)2, —N(RA1)2, and a nitrogen protecting group;
k is 0, 1, 2, 3, or 4;
l is 1, 2, 3, 4, or 5;
Q and U are taken together to be —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:
##STR00013##
##STR00014##
##STR00015##
##STR00016##
##STR00017##
and pharmaceutically acceptable salts thereof.
In another aspect, the present invention provides methods for treating Waldenström's macroglobulinemia (WM) in a subject using compounds of the invention. The methods comprise administering to a subject in need thereof an effective amount of a compound of the invention. Also provided are methods to treat other B cell neoplasms using compounds of the invention in combination with inhibitors of Bruton's tyrosine kinase (BTK), interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), bone marrow on X chromosome kinase (BMX), phosphoinositide 3-kinase (PI3K), transforming growth factor b-activated kinase-1 (TAK1), and/or a Src family kinase. In certain embodiments, one or more compounds of the invention are used in combination with an inhibitor of the phosphoinositide 3-kinase delta isoform (PI3Kδ). In certain embodiments, combinations of 2, 3, 4, 5, 6, 7, 8, 9, 10, or more of the agents described herein are used for treating WM. In certain embodiments, the agents described herein are used in combination with kinase inhibitors such as inhibitors of Bruton's tyrosine kinase (BTK), interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), bone marrow on X chromosome kinase (BMX), and/or phosphoinositide 3-kinase (PI3K), transforming growth factor b-activated kinase-1 (TAK1), and/or a Src family kinase.
Waldenström's macroglobulinemia (WM) is a distinct clinicopathological entity resulting from the accumulation, predominantly in the bone marrow, of clonally related lymphoplasmacytic cells which secrete a monoclonal IgM protein. This condition is considered to correspond to lymphoplasmacytic lymphoma (LPL) as defined by the World Health Organization classification system. Genetic factors play an important role in the pathogenesis of WM, with 25% of patients demonstrating a family history. IgM monoclonal gammopathy of unknown significance (MGUS) often precedes the development of WM.
As used herein, a B cell neoplasm includes both Hodgkin's lymphoma and non-Hodgkin's lymphomas. Classical Hodgkin's lymphoma (HL) includes various subtypes such as Nodular sclerosing HL, Mixed-cellularity subtype, Lymphocyte-rich or Lymphocytic predominance and Lymphocyte depleted. Examples of B cell non-Hodgkin's lymphomas include, but are not limited to, Waldenström's macroglobulinemia, diffuse large B cell lymphoma, follicular lymphoma, mucosa-associated lymphatic tissue lymphoma (MALT), small cell lymphocytic lymphoma (overlaps with chronic lymphocytic leukemia), mantle cell lymphoma (MCL), Burkitt lymphoma, mediastinal large B cell lymphoma, nodal marginal zone B cell lymphoma (NMZL), splenic marginal zone lymphoma (SMZL), intra-vascular large B-cell lymphoma, primary effusion lymphoma, and lymphomatoid granulomatosis.
In certain embodiments, the subject is administered a compound of Formula (A):
##STR00018##
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 heterocycl, 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;
each instance of RX is independently selected from the group consisting of RD, 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, —S(═O)2N(RA1)2, —N(RA1)2, and a nitrogen protecting group;
k is 0, 1, 2, 3, or 4;
l is 1, 2, 3, 4, or 5;
Q and U are taken together to be —NRA(C═O)— or —(C═O)NRA—; and
RD is an electrophilic moiety as described herein.
In certain embodiments, the subject is adminstered compound (A-1):
##STR00019##
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the subject is adminstered compound (A-2):
##STR00020##
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the subject is adminstered compound (A-3):
##STR00021##
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the subject is adminstered compound (A-4):
##STR00022##
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the subject is adminstered compound (A-5):
##STR00023##
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the subject is adminstered compound (A-6):
##STR00024##
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the subject is adminstered compound (A-7):
##STR00025##
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the subject is adminstered compound (A-8):
##STR00026##
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the subject is adminstered compound (A-9):
##STR00027##
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the subject is adminstered compound (A-10):
##STR00028##
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the subject is adminstered compound (A-11):
##STR00029##
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the subject is adminstered compound (A-12):
##STR00030##
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the subject is adminstered compound (A-13):
##STR00031##
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the subject is adminstered compound (A-14):
##STR00032##
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the subject is adminstered compound (A-15):
##STR00033##
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the subject is adminstered compound (A-16):
##STR00034##
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the subject is adminstered compound (A-17):
##STR00035##
or a pharmaceutically acceptable salt thereof.
In certain embodiments, the subject is adminstered compound (A-18):
##STR00036##
or a pharmaceutically acceptable salt thereof.
Compounds of Formula (A) 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:
##STR00037##
In certain embodiments, Ring A is of the formula:
##STR00038##
In certain embodiments, Ring A is of the formula:
##STR00039##
In certain embodiments, Ring A is of the formula:
##STR00040##
In certain embodiments, Ring A is of the formula:
##STR00041##
In certain embodiments, k is 2. In certain embodiments, Ring A is of the formula:
##STR00042##
In certain embodiments, Ring A is of the formula:
##STR00043##
In certain embodiments, Ring A is of the formula:
##STR00044##
In certain embodiments, Ring A is of the formula:
##STR00045##
In certain embodiments, Ring A is of the formula:
##STR00046##
In certain embodiments, Ring A is of the formula:
##STR00047##
In certain embodiments, k is 3. In certain embodiments, Ring A is of the formula:
##STR00048##
In certain embodiments, Ring A is of the formula:
##STR00049##
In certain embodiments, Ring A is of the formula:
##STR00050##
In certain embodiments, k is 4. In certain embodiments, Ring A is of the formula:
##STR00051##
In compounds of Formula (A), 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 embodments, 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 subtituted carbocyclyl. In certain embodiments, at least one RA is unubstituted carbocyclyl. In certain embodiments, at least one RA is —ORA1. In certain embodiments, at least one RA —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 aubstituted 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 embodiment 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 (A), 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 (A) 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:
##STR00052##
In certain embodiments, Ring C is of the formula:
##STR00053##
In certain embodiments, Ring C is of the formula:
##STR00054##
certain embodiments, l is 2. In certain embodiments, Ring C is of the formula:
##STR00055##
In certain embodiments, l is 2. In certain embodiments, Ring C is of the formula:
##STR00056##
In certain embodiments, Ring C is of the formula:
##STR00057##
In certain embodiments, Ring C is of the formula:
##STR00058##
In certain embodiments, Ring C is of the formula:
##STR00059##
In certain embodiments, Ring C is of the formula:
##STR00060##
In certain embodiments, l is 3. In certain embodiments, Ring C is of the formula:
##STR00061##
In certain embodiments, Ring C is of the formula:
##STR00062##
In certain embodiments, Ring C is of the formula:
##STR00063##
In certain embodiments, Ring C is of the formula:
##STR00064##
In certain embodients, l is 4. In certain embodiments, Ring C is of the formula:
##STR00065##
In certain embodiments, Ring C is of the formula:
##STR00066##
In certain embodiments, Ring C is of the formula:
##STR00067##
In certain embodiments, l is 5. In certain embodiments, Ring C is of the formula:
##STR00068##
In compounds of Formula (A), 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
##STR00069##
In certain embodiments, at least one RB is
##STR00070##
In certain embodiments, at least one RB is
##STR00071##
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 diazepane. In certain embodiments, at least one RB is unsubstituted diazepane. In certain embodiments, at least one RB is
##STR00072##
In certain embodiments, at least one RB is
##STR00073##
In certain embodiments, at least one RB is
##STR00074##
In certain embodiments, at least one RB is
##STR00075##
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
##STR00076##
In certain embodiments, at least one RB is
##STR00077##
In certain embodiments, at least one RB is
##STR00078##
In certain embodiments, at least one RB is
##STR00079##
In certain embodiments, at least one RB is
##STR00080##
In certain embodiments, at least one RB is
##STR00081##
In certain embodiments, at least one RB is
##STR00082##
In certain embodiments, at least one RB is
##STR00083##
In certain embodiments, at least one RB is
##STR00084##
In certain embodiments, at least one RB is
##STR00085##
In certain embodiments, at least one RB is
##STR00086##
In certain embodiments, at least one RB is
##STR00087##
In certain embodiments, at least one RB is
##STR00088##
In certain embodiments, at least one RB is
##STR00089##
In certain embodiments, at least one RB is
##STR00090##
In certain embodiments, at least one RB is
##STR00091##
In certain embodiments, at least one RB is
##STR00092##
In certain embodiments, at least one RB is
##STR00093##
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
##STR00094##
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
##STR00095##
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
##STR00096##
In certain embodiments, at least one RB is
##STR00097##
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
##STR00098##
In certain embodiments, at least one RB is
##STR00099##
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
##STR00100##
In certain embodiments, at least one RB is
##STR00101##
In certain embodiments, at least one RB is —NH2. In certain embodiments, at least one RB certain embodiments, at least one RB is —NH2. In certain embodiments, at least one R 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 embodnnents, at least one RB is
##STR00102##
In certain embodiments, at least one RB is
##STR00103##
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 is —S(═O)2N(A1)2. In certain embodiments, at least one RB is —S(═O)2N(C1-6alkyl)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 C1-6 alkyl; 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; RB is para to the point of attachment of U. In certain embodiments, RB is C1-6 alkyl 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
##STR00104##
and l is 1. In certain embodiments, RB is
##STR00105##
l is 1; and RB is meta to the point of attachment of U. In certain embodiments, RB is
##STR00106##
l is 1; and RB is para to the point of attachment of U. In certain embodiments, RB is substituted or unsubstituted —CH2-(piperazinyl); and l is 1. In cwrtain embodiments, RB is substitued to 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
##STR00107##
and l is 1. In certain embodiments, RB is
##STR00108##
l is 1; and RB is meta to the point of attachment of U. In certain embodiments, RB is
##STR00109##
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; l 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
##STR00110##
and l is 1. In certain embodiments, RB is
##STR00111##
is 1; and RB is meta to the point of attachment of U. In certain embodiments, RB is
##STR00112##
l is 1; and RB is meta to the point of attachment of U. In certain embodiments, RB 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
##STR00113##
and l is 1. In certain embodiments, RB is
##STR00114##
l is 1; and RB is meta to the point of attachment of U. In certain embodiments, RB is
##STR00115##
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
##STR00116##
and l is 2. In certain embodiments, at least one RB group is
##STR00117##
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
##STR00118##
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
##STR00119##
and l is 2. In certain embodiments, at least one RB group is
##STR00120##
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
##STR00121##
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
##STR00122##
and l is 2. In certain embodiments, at least one RB group is
##STR00123##
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
##STR00124##
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
##STR00125##
l is 2. In certain embodiments, at least one RB group is
##STR00126##
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
##STR00127##
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 (A), Q and U are taken together to represent a divalent linker moiety. In certain embodiments, Q and U are taken together to represent
##STR00128##
In certain embodiments, Q and U are taken together to represent
##STR00129##
In certain embodiments, Q and U are taken together to represent
##STR00130##
In certain embodiments, Q and U are taken together to represent
##STR00131##
Formula (A) includes a pyridine or pyrimidine ring as Ring B. In certain embodiments, each instance of A included in Ring B is carbon. In certain embodiments, one instance of A included in Ring B is carbon, and the other instance of A included in Ring B is nitrogen. In certain embodiments, Ring B is of the formula:
##STR00132##
In certain embodiments, Ring B is of the formula:
##STR00133##
In certain embodiments, Ring B is of the formula:
##STR00134##
In certain embodiments, Ring B is of the formula:
##STR00135##
In certain embodiments, Ring B is of the formula:
##STR00136##
Formula (A) may include one or more RY groups. When Formula (A) includes two instances of RY, the two instances of RY may be the same or different from each other. In certain embodiments, at least one instance of RY is H. In certain embodiments, each instance of RY is H. In certain embodiments, at least one instance of RY is halogen (e.g., F, Cl, Br, or I). In certain embodiments, at least one instance of RY is substituted or unsubstituted C1-6 alkyl. In certain embodiments, at least one instance of RY is Me. In certain embodiments, at least one instance of RY is substituted methyl (e. g., —CF3 or Bn). In certain embodiments, at least one instance of RY is Et, substituted ethyl (e.g., perfluoroethyl), Pr, substituted propyl (e.g., perfluoropropyl), Bu, or substituted butyl (e.g., perfluorobutyl).
In compounds of Formula (A), the pyridine or pyrimidine ring may be substituted with one or more RX groups. When Formula (A) includes two instances of RX, the two instances of RX may be the same or different from each other. 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
##STR00137##
In certain embodiments, at least one RX is
##STR00138##
In certain embodiments, at least one RX is
##STR00139##
In certain embodiments, at least one RX is substituted heterocyclyl. In certain embodiments, at least one RX is unbustituted hererocyclyl. In certain embodiments, at least one RX is
##STR00140##
In certain embodiments, at least one RX is
##STR00141##
In certain embodiments, at least one RX is
##STR00142##
In certain embodiments, at least one RX is
##STR00143##
In certain embodiments, at least one RX is
##STR00144##
In certain embodiments, at least one RX is
##STR00145##
In certain embodiments, at least one RX is
##STR00146##
In certain embodiments, at least one RX is
##STR00147##
In certain embodiments, at least one RX is
##STR00148##
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
##STR00149##
In certain embodiments, at least one RX is
##STR00150##
In certain embodiments, at least one RX is
##STR00151##
In certain embodiments, at least one RX is
##STR00152##
In certain embodiments, at least one RX is
##STR00153##
In certain embodiments, at least one RX is
##STR00154##
In certain embodiments, at least one RX is
##STR00155##
In certain embodiments, at least one RX is
##STR00156##
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
##STR00157##
In certain embodiments, at least one RX is
##STR00158##
In certain embodiments, at least one RX is
##STR00159##
In certain embodiments, at least one RX is
##STR00160##
In certain embodiments, at least one RX is
##STR00161##
In certain embodiments, at least one RX is
##STR00162##
In certain embodiments, at least one RX is
##STR00163##
In certain embodiments, at least one RX is
##STR00164##
In certain embodiments, at least one RX is
##STR00165##
In certain embodiments, at least one RX is
##STR00166##
In certain embodiments, at least one RX is
##STR00167##
In certain embodiments, at least one RX is
##STR00168##
In certain embodiments, at least one RX is
##STR00169##
In certain embodiments, at least one RX is
##STR00170##
In certain embodiments, at least one RX is
##STR00171##
In certain embodiments, at least one RX is
##STR00172##
In certain embodiments, at least one RX is
##STR00173##
In certain embodiments, at least one RX is
##STR00174##
In certain embodiments, at least one RX is
##STR00175##
In certain embodiments, at least one RX is
##STR00176##
In certain embodiments, at least one RX is
##STR00177##
In certain embodiments, at least one RX is
##STR00178##
In certain embodiments, at least one RX is
##STR00179##
In certain embodiments, at least one RX is
##STR00180##
In certain embodiments, at least one RX is
##STR00181##
In certain embodiments, at least one RX is
##STR00182##
In certain embodiments, at least one RX is
##STR00183##
In certain embodiments, at least one RX is
##STR00184##
In certain embodiments, at least one RX is
##STR00185##
In certain embodiments, at least one RX is
##STR00186##
In certain embodiments, at least one RX is
##STR00187##
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 —NH (3-6 membered cycloalkyl) where the cycloalkyl is substituted or unsubstituted. In certain embodiments, at least one RX is
##STR00188##
In certain embodiments, at least one RX is —NH(C1-6alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one RX is —N(C1-6alkyl)2 where the alkyl is substituted or unsubstituted. In certain embodiments, at least one RX is
##STR00189##
In certain embodiments, at least one RX is —NH(acyl). In certain embodiments, at least one RX is
##STR00190##
In certain embodiments, at least one RX is
##STR00191##
In certain embodiments, at least one RX is
##STR00192##
In certain embodiments, at least one RX is
##STR00193##
In certain embodiments, at least one RX is —NHC(═O)(3-6 membered cycloalkyl) where the cycloalkyl is ubtituted or unsubstituted. In certain embodiments, at least one RX is
##STR00194##
In certain embodiments, at least one RX is —NHC(═O)(C1-6alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one RX is
##STR00195##
In certain embodiments, at least one RX is
##STR00196##
In certain embodiments, at least one RX is
##STR00197##
In certain embodiments, at least one RX is
##STR00198##
In certain embodiments, at least one RX is
##STR00199##
In certain embodiments, at least one RX is
##STR00200##
In certain embodiments, at least one RX is
##STR00201##
In certain embodiments, at least one RX is
##STR00202##
In certain embodiments, at least one RX is
##STR00203##
In certain embodiments, at least one RX is
##STR00204##
In certain embodiments, at least one RX is
##STR00205##
In certain embodiments, at least one RX is
##STR00206##
In certain embodiments, at least one RX is
##STR00207##
In certain embodiments, at least one RX is
##STR00208##
In certain embodiments, at least one RX is
##STR00209##
In certain embodiments, at least one RX is
##STR00210##
In certain embodiments, at least one RX is
##STR00211##
In certain embodiments, at least one RX is
##STR00212##
In certain embodiments, at least one RX is
##STR00213##
In certain embodiments, at least one RX is
##STR00214##
In certain embodiments, at least one RX is
##STR00215##
In certain embodiments, at least one RX is
##STR00216##
In certain embodiments, at least one RX is
##STR00217##
In certain embodiments, at least one RX is
##STR00218##
In certain embodiments, at least one RX is
##STR00219##
In certain embodiments, at least one RX is
##STR00220##
In certain embodiments, at least one RX is
##STR00221##
In certain embodiments, at least one RX is
##STR00222##
In certain embodiments, at least one RX is
##STR00223##
In certain embodiments, at least one RX is
##STR00224##
In certain embodiments, at least one RX is
##STR00225##
In certain embodiments, at least one RX is
##STR00226##
In certain embodiments, at least one RX is
##STR00227##
In certain embodiments, at least one RX is
##STR00228##
In certain embodiments, at least one RX is
##STR00229##
In certain embodiments, at least one RX is
##STR00230##
In certain embodiments, at least one RX is
##STR00231##
In certain embodiments, at least one RX is
##STR00232##
In certain embodiments, at least one RX is
##STR00233##
In certain embodiments, at least one RX is
##STR00234##
In certain embodiments, at least one RX is
##STR00235##
In certain embodiments, at least one RX is
##STR00236##
In certain embodiments, at least one RX is
##STR00237##
In certain embodiments, at least one RX is
##STR00238##
In certain embodiments, at least one RX is
##STR00239##
In certain embodiments, at least one RX is
##STR00240##
In certain embodiments, at least one RX is
##STR00241##
In certain embodiments, at least one RX is
##STR00242##
In certain embodiments, at least one RX is
##STR00243##
In certain embodiments, at least one RX is
##STR00244##
In certain embodiments, at least one RX is
##STR00245##
In certain embodiments, at least one RX is
##STR00246##
In certain embodiments, at least one RX is
##STR00247##
In certain embodiments, at least one RX is —N(RA1)N(RA1)2. In certain embodiments, at least one RX is —NHN(RA1)2. In certain embodiments, at least one RX is —NHNH(acyl). In certain embodiments, at least one RX is —NHNHC(═O)Me. In certain embodiments, at least one RX is —NHN(C1-6alkyl)2 where the alkyl is substituted or unsubstituted. In certain embodiments, at least one RX is —NHNMe2.
In compounds of Formula (A), 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)2RA1S(═O)2ORA, —S(═O)2RA1, —S(═O)2N(RA1)2, —N(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 —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 —(═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 certain embodiments, at least one RXa is —N(RA1)2. In certain embodiments, at least one RXa is —NH(RA1). In certain embodiments, at least one RXa is —NH(acyl). In certain embodiments, at least one RXa is —NHC(—O)Me. In certain embodiments, at least one RXa is —N(C1-6alkyl)2 where the alkyl is substituted or unsubstituted. In certain embodiments, at least one RXa is —NMe2.
In compounds of Formula (A), 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) . 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 RXa 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 RXcis —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(═)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 RXcis —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(C1-6a1kyl)2. In certain embodiments, at least one RXc is —S(═O)2NH(C1-6alkyl).
In compounds of Formula (A), 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):
##STR00248## ##STR00249##
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(═0)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(═0)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(═0)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 Fomiula (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 (A), 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 —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 (A), 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 (A), 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 unsubstitrrted 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 (A), 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)RD4. 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 C1-6alkyl. 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 (A), RD may include a substituent RD5. In certain embodiments, RD5 is H. In certain embodiments, RD5 is substituted allyl. 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:
##STR00250##
In certain embodiments, RD is of the formula:
##STR00251##
In certain embodiments, RD is of the formula:
##STR00252##
In certain embodiments, RD is of the formula:
##STR00253##
In certain embodiments, RD is of the formula:
##STR00254##
In certain embodiments, RD is of the formula:
##STR00255##
In certain embodiments, RD is of the formula:
##STR00256##
In certain embodiments, RD is of the formula:
##STR00257##
In certain embodiments, RD is of the formula:
##STR00258##
In certain embodiments, RD is of the formula:
##STR00259##
In certain embodiments, RD is of the formula:
##STR00260##
In certain embodiments, RD is of the formula:
##STR00261##
In certain embodiments, RD is of the formula:
##STR00262##
In certain embodiments, RD is of the formula:
##STR00263##
In certain embodiments, RD is of the formula:
##STR00264##
In certain embodiments, RD is of the formula:
##STR00265##
In certain embodiments, RD is of the formula:
##STR00266##
In certain embodiments, RD is of the formula:
##STR00267##
In certain embodiments, RD is of the formula:
##STR00268##
In certain embodiments, RD is of the formula:
##STR00269##
In certain embodiments, RD is of the formula:
##STR00270##
In certain embodiments, RD is of the formula:
##STR00271##
In certain embodiments, RD is of the formula:
##STR00272##
In certain embodiments, RD is of the formula:
##STR00273##
In certain embodiments, RD is of the formula:
##STR00274##
In certain embodiments, RD is of the formula:
##STR00275##
In certain embodiments, RD is of the formula:
##STR00276##
In certain embodiments, RD is of the formula:
##STR00277##
Various combinations of certain embodiments of Formula (A) are further contemplated herein.
For example, in certain embodiments, a compound of Formula (A) is a compound of Formula (A1) or (A2):
##STR00278##
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
##STR00279##
In certain embodiments, one RB group is substituted or unsubstituted —CH2-(piperazinyl). In certain embodiments, one RB group is
##STR00280##
where the alkyl is optionally substituted. In certain embodiments, one RB group is
##STR00281##
where the alkyl is unsubstituted. In certain embodiments, one RB group is
##STR00282##
In certain embodiments, one RB groups 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
##STR00283##
where the alkyl is optionally substituted. In certain embodiments, one RB group is
##STR00284##
where the alkyl is unsubstituted. In certain embodiments, one RB group is
##STR00285##
In certain embodiments, one RB group is substituted or unsubstituted piperazinyl. In certain embodiments, one RB group is
##STR00286##
where there alkyl is optionally substituted. In certain embodiments, one RB group is
##STR00287##
where there alkyl is unsubstituted. In certain embodiments, one RB group is
##STR00288##
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 —N(RA1)N(RA1)2. In certain embodiments, RX is —N(RA1)N(RA1)2; and each instance of RA is hydrogen, methyl, or acetyl. In certain embodiments, RX is —NHNMe2 or —NHNHAc. In certain embodiments, Rx is —NH2. In certain embodiments, RX is —NH(RA1). In certain embodiments, RX is —NH(RA1); and RA1 is substituted or unsubstituted C1-6alkyl. In certain embodiments, RX is —NH(RA1); and RA1 is substituted or unsubstituted methyl. In certain embodiments, RX is —NH(RA1); and RA1 is acyl. In certain embodiments, RX is —NH(RA1); and RA1 is substituted or unsubstituted —C(═O)—(C1-6alkyl). In certain embodiments, RX is —NH(RA1); and RA1 is acetyl or propionyl. In certain embodiments, RX is —NH(RA1); and RA1 is substituted or unsubstituted —C(═O)-(carbocyclyl). In certain embodiments, RX is —NH(RA); and RA1 is substituted or unsubstituted —C(═O)-(cyclopropyl). In certain embodiments, RX is —NH(RA1); and RA1 is substituted or unsubstituted heteroaryl. In certain embodiments, RX is —NH(RA1); and RA1 is substituted or unsubstituted pyrazole. In certain embodiments, RX is —NH(RA1); and RA1 is substituted or unsubstituted isoxazole. In certain embodiments, RX is —NH(RA); and RA1 is substituted or unsubstituted pyrimidine. In certain embodiments, RX is —NH(RA1); and RA1 is substituted or unsubstituted heterocyclyl. In certain embodiments, RX is —NH(RA1); and RA1 is substituted or unsubstituted azetidine. In certain embodiments, RX is —NH(RA1); and RA1 is substituted or unsubstituted oxetane.
In certain embodiments, a compound of Formula (A1) is a compound of Formula (A1-a), (A1-b), (A1-c), or (A1-d):
##STR00289##
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
##STR00290##
In certain embodiments, one RB group is substituted or unsubstituted —CH2-(piperazinyl). In certain embodiments, one RB group is
##STR00291##
where the alkyl is optionally substituted. In certain embodiments, one RB group is
##STR00292##
where the alkyl is unsubstituted. In certain embodiments, one RB group is
##STR00293##
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
##STR00294##
where the alkyl is optionally substituted. In certain embodiments, one RB group is
##STR00295##
where the alkyl is unsubstituted. In certain embodiments, one RB group is
##STR00296##
In certain embodiments, one RB group is substituted or unsubstituted piperazinyl. In certain embodiments, one RB group is
##STR00297##
where there alkyl is optionally substituted. In certain embodiments, one RB group is
##STR00298##
where there alkyl is unsubstituted. In certain embodiments, one RB group is
##STR00299##
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 (A2) is a compound of Formula (A2-a), (A2-b), (A2-c), or (A2-d):
##STR00300##
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 C1-6 alkyl. In certain embodiments, one RB group is C1-6alkyl substituted with one —CN group. In certain embodiments, one RB group is
##STR00301##
In certain embodiments, one RB group is substituted or unsubstituted —CH2-(piperazinyl). In certain embodiments, one RB group is
##STR00302##
where the alkyl is optionally substituted. In certain embodiments, one RB group is
##STR00303##
where the alkyl is unsubstituted. In certain embodiments, one RB group is
##STR00304##
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
##STR00305##
where the alkyl is optionally substituted. In certain embodiments, one RB group is
##STR00306##
where the alkyl is unsubstituted. In certain embodiments, one RB group is
##STR00307##
In certain embodiments, one RB group is substituted or unsubstituted piperazinyl. In certain embodiments one RB group is
##STR00308##
where there alkyl is optionally substituted. In certain embodiments, one RB group is
##STR00309##
where there alkyl is unsubstituted. In certain embodiments, one RB group is
##STR00310##
In certain embodiments, one RB group is substituted or unsubstituted morpholine. In certain emodiments, 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 (A1) is a compound of Formula (A1-e)-(A1-p):
##STR00311##
##STR00312##
where RXa, RXc, RA, and RB are defined herein. In certain embodiments RA is substituted or unsubstituted C1-6alkyl. 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
##STR00313##
In certain embodiments, one RB group is substituted or unsubstituted —CH2-(piperazinyl). In certain embodiments, one RB group is
##STR00314##
where the alkyl is optionally substituted. In certain embodiments, one RB group is
##STR00315##
where the alkyl is unsubstituted. In certain embodiments, one RB group is
##STR00316##
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
##STR00317##
where the alkyl is optionally substituted. In certain embodiments, one RB group is
##STR00318##
where the alkyl is unsubstituted. In certain embodiments, one RB group is
##STR00319##
In certain embodiments, one RB group is substituted or unsubstituted piperazinyl. In certain embodiments, one RB group is
##STR00320##
where the alkyl is optionally substituted. In certain embodiments, one RB group is
##STR00321##
where the alkyl is unsubstituted. In certain embodiments, one RB group is
##STR00322##
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 (A2) is a compound of Formula (A2-e)-(A2-p):
##STR00323##
##STR00324##
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
##STR00325##
C1-6alkyl substituted with one —CN group. In certain embodiments, one RB group is NC. In certain embodiments, one RB group is substituted or unsubstituted —CH2-(piperazinyl). In certain embodiments, one RB group is
##STR00326##
where the alkyl is optionally substituted. In certain embodiments, one RB group is
##STR00327##
where the alkyl is unsubstituted. In certain embodiments, one RB group is
##STR00328##
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
##STR00329##
where the alkyl optionally substituted. In certain embodiments, one RB group is
##STR00330##
where the alkyl is unsubstituted. In certain embodiments, one RB group is
##STR00331##
In certain embodiments, one RB group is substituted or unsubstituted piperazinyl. In certain embodiments, one RB group is
##STR00332##
where there alkyl is optionally substituted. In certain embodiments, one RB group is
##STR00333##
where there alkyl is unsubstituted. In certain embodiments, one RB group is
##STR00334##
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 (A) is a compound of Formula (A3) or (A4):
##STR00335##
wherein RD, RA, RB, and l are defined herein. In certain embodiments RA is substituted or unsubstituted C1-6alkyl. 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
##STR00336##
In certain embodiments, one RB group is substituted or unsubstituted —CH2-(piperazinyl). In certain embodiments, one RB group is
##STR00337##
where the alkyl is optionally substituted. In certain embodiments, one RB group is
##STR00338##
where the alkyl is unsubstituted. In certain embodiments, one RB group is
##STR00339##
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
##STR00340##
where the alkyl is optionally substituted. In certain embodiments, one RB group is
##STR00341##
where the alkyl is unsubstituted. In certain embodiments, one RB group is
##STR00342##
In certain embodiments, one RB group is substituted or unsubstituted piperazinyl. In certain embodiments, one RB group is
##STR00343##
where there alkyl is optionally substituted. In certain embodiments, one RB group is
##STR00344##
alkyl where there alkyl is unsubstituted. In certain embodiments, one RB group is
##STR00345##
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, RD is RD is
##STR00346##
In certain embodiments, RD is
##STR00347##
In certain embodiments, RD is
##STR00348##
In certain embodiments, RD is
##STR00349##
In certain embodiments, a compound of Formula (A3) is a compound of Formula (A3-a), (A3-b), or (A3-c).
##STR00350##
wherein RD, RA, RB, and l are defined herein. In certain embodiments RA is substituted or unsubstituted C1-6alkyl. 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
##STR00351##
In certain embodiments, one RB group is substituted or unsubstituted —CH2-(piperazinyl). In certain embodiments, one RB group is
##STR00352##
where the alkyl is optionally substituted. In certain embodiments, one RB group is
##STR00353##
where the alkyl is unsubstituted. In certain embodiments, one RB group is
##STR00354##
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
##STR00355##
where the alkyl is optionally substituted. In certain embodiments, one RB group is
##STR00356##
where the alkyl where the alkyl is unsubstituted. In certain embodiments, one RB group is
##STR00357##
In certain embodiments, one RB group is substituted or unsubstituted piperazinyl. In certain embodiments, one RB group is
##STR00358##
where there alkyl is optionally substituted. In certain embodiments, one RB group is
##STR00359##
where there alkyl is unsubstituted. In certain embodiments, one RB group is
##STR00360##
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, RD is
##STR00361##
In certain embodiments, RD is
##STR00362##
In certain embodiments, RD is
##STR00363##
In certain embodiments, RD is
##STR00364##
In certain embodiments, a compound of Formula (A4) is a compound of Formula (A4-a), (A4-b), or (A4-c):
##STR00365##
wherein RD, 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
##STR00366##
In certain embodiments, one RB group is substituted or unsubstituted —CH2-(piperazinyl). In certain embodiments, one RB group is
##STR00367##
where the alkyl is optionally substituted. In certain embodiments, one RB group is
##STR00368##
where the alkyl is unsubstituted. In certain embodiments, one RB group is
##STR00369##
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
##STR00370##
where the alkyl is optionally substituted. In certain embodiments, one RB group is
##STR00371##
where the alkyl is unsubstituted. In certain embodiments, one RB group is
##STR00372##
In certain embodiments, one RB group is substituted or unsubstituted piperazinyl. In certain embodiments, one RB group is
##STR00373##
where the alkyl is optionally substituted. In certain embodiments, one RB group is
##STR00374##
where there alkyl is unsubstituted. In certain embodiments, one RB group is
##STR00375##
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, RD is
##STR00376##
In certain embodiments, RD is
##STR00377##
In certain embodiments, RD is
##STR00378##
In certain embodiments, RD is
##STR00379##
Another aspect of the invention relates to the compound of Formula (I-11):
##STR00380##
and pharmaceutically acceptable salts, solvetes, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs thereof.
In another aspect, provided are compounds of Formula (V):
##STR00381##
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′, —NRA1C′(═S)ORA1′, —NRA1C′(═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):
##STR00382##
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):
##STR00383##
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 phenyl, the invention provides compounds of Formula (V-c):
##STR00384##
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 phenyl, the invention provides compounds of Formula (V-d):
##STR00385##
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):
##STR00386##
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 pyrimidine, the invention provides compounds of Formula (V-eA):
##STR00387##
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 1H-pyrazolo[3,4-d]pyrimidin-4-amine, the invention provides compounds of Formula (V-eB):
##STR00388##
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 furo[2,3-c]pyridin-7-amine, the invention provides compounds of Formula (V-eC):
##STR00389##
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 quinazoline, the invention provides compounds of Formula (V-eD):
##STR00390##
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):
##STR00391##
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):
##STR00392##
wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, RA′, RB′, RX′, k′, and l′ are as defined herein.
In another aspect, provided herein are copounds of Formula (II):
##STR00393##
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 atached 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):
##STR00394##
##STR00395##
wherein:
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 heterycyclyl, optionally suubstituted 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 DD1′ and RD2′ are joined to form an optionally substituted carbocyclic or optionall ubstituted hereroyclic 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):
##STR00396##
wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, RA′, RB′, RD′, RX′, k′, and l′, and m′ are as defined herein.
Compounds of Formula (II) include an aryl group for Ring A′ optionally substituted with one or more RA′ groups. In certain embodiments, when Ring A′ is naphthyl, the invention provides compounds of Formula (II-b):
##STR00397##
wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, RA′, RB′, RD′, RX′, k′, and l′, and m′ are as defined herein.
Compounds of Formula (II) include an aryl group for Ring A′ optionally substituted with one or more RA′ groups. In certain embodiments, when Ring A′ is phenyl, the invention provides compounds of Formula (II-c):
##STR00398##
wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, RA′, RB′, RD′, RX′, k′, and l′ and m′ are as defined herein.
Compounds of Formula (II) include an aryl group for Ring A′ optionally substituted with one or more RA′ groups. In certain embodiments, when Ring A′ is phenyl, the invention provides compounds of Formula (II-d):
##STR00399##
wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, RA′, RB′, RD′, RX′, k′, and l′, and m′ are as defined herein.
Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more RA′ groups. In certain embodiments, when Ring A′ is pyrrolopyrimidine, the invention provides compounds of Formula (II-e):
##STR00400##
wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, RA′, RB′, RD′, RX′, k′, and l′, and m′ are as defined herein.
Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more RA′ groups. In certain embodiments, when Ring A′ is pyrimidine, the invention provides compounds of Formula (II-eA):
##STR00401##
wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, RA′, RB′, RD′, RX′, k′, and l′, and m′ are as defined herein.
Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more RA′ groups. In certain embodiments, when Ring A′ is pyrimidine, the invention provides compounds of Formula (II-eB):
##STR00402##
wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, RA′, RB′, RD′, RX′, k′, and l′, and m′ are as defined herein.
Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more 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):
##STR00403##
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 quinazoline, the invention provides compounds of Formula (II-eD):
##STR00404##
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 copounds of Formula (II-f):
##STR00405##
wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, RA′, RB′, RD′, RX′, k′, and l′, and m′ are as defined herein.
Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more 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 copounds of Formula (II-g):
##STR00406##
wherein Ring C′, Cy, Q′, U′, X′, Y′, Z′, RA′, RB′, RD′, RX′, k′, and l′, and m′ are as defined herein.
In compounds of Formula (II), RD′ is a substituent on Ring A′, Ring C′, or Cy. In certain embodiments, RD′ comprises a Michael acceptor moiety. This Michael aceptor moiety may reach with a cysteine or other nucleophilic residue to allow covalent attachment of the compound to the target. In certain embodiments, the covalent attachment is irreversible. In other embodiments, the covalent attachment is reversible. In certain embodiments, 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 Fomrula (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), 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, RD′ 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), RD′ may include a substituent RD2′. In certain embodiments, RD2a′ is H. In certain embodiments, RD2a′ is halogen. In certain embodiments, RD2, is F. In certain embodiments, RD2′ is Cl. In certain embodiments, RD2a′ is Br. In certain embodiments, RD2a′ is I (iodine). In certain embodiments, RD2a′ is substituted acyl. In certain embodiments, RD2a′ is unsubstituted acyl, In certain embodiments, RD2a′ is acetyl. In certain embodiments, RD2a′ is substituted alkyl. In certain embodiments, RD2a′ is unsubstituted alkyl. In certain embodiments, RD2a′ is C1-6 alkyl. In certain embodiments, RD2a′ is methyl. In certain embodiments, RD2a′ is ethyl. In certain embodiments, RD2a′ is propyl. In certain embodiments, RD2a′ is butyl. In certain embodiments, RD2a′ is substituted alkenyl. In certain embodiments, RD2a′ is unsubstituted alkenyl. In certain embodiments, RD2a′ is substituted alkynyl. In certain embodiments, RD2a′ is unsubstituted alkynyl. In certain embodiments, RD2a′ is substituted carbocyclyl. In certain embodiments, RD2a′ is unsubstituted carbocyclyl. In certain embodiments, RD2a′ is substituted heterocyclyl. In certain embodiments, RD2a′ is unsubstituted heterocyclyl. In certain embodiments, RD2a′ is substituted aryl. In certain embodiments, RD2a′ is unsubstituted aryl. In certain embodiments, RD2a′ is substituted phenyl. In certain embodiments, RD2a′ is unsubstituted phenyl. In certain embodiments,RD2a′ is substituted heteroaryl. In certain embodiments, RD2a′ is unsubstituted heteroaryl. In certain embodiments, RD2a′, is substituted pyridyl. In certain embodiments, RD2a′ is unsubstituted pyridyl. In certain embodiments, RD2a′ is —CN. In certain embodiments, RD2a′ is —NO2. In certain embodiments, RD2a′ is —ORD2a′. In certain embodiments, RD2a′ is —N(RD2a′)2. In certain embodiments, RD2a′ is —SRD2a′. In certain embodiments, RD2a′ is —CH2ORD2a′. In certain embodiments, RD2a′ is —CH2N(RD2a′)2. In certain embodiments, RD2a′ 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), 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, RD3a′ is substituted aryl. In certain embodiments, RD3a′ is unsubstituted aryl. In certain embodiments, RD3a′ 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, RD3a′ is unsubstituted pyridyl. In certain embodiments, RD3a′ is —CN. In certain embodiments, RD3a′ is —NO2. In certain embodiments, RD3′ is —ORD3a′. In certain embodiments, RD3a′ is —N(RD3a′)2. In certain embodiments, RD3′ is —SRD3a′. In certain embodinrents, 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 Fomrula (II), 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-nitrobenzene-sulfonyloxy. 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 embodimentsRD4′ 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), 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:
##STR00407##
In certain embodiments, RD′ is of the formula:
##STR00408##
In certain embodiments, RD′ is of the formula:
##STR00409##
In certain embodiments, RD′ is of the formula:
##STR00410##
In certain embodiments, RD′ is of the formula:
##STR00411##
In certain embodiments, RD′ is of the formula:
##STR00412##
In certain embodiments, RD′ is of the formula:
##STR00413##
In certain embodiments, RD′ is of the formula:
##STR00414##
In certain embodiments, RD′ is of the formula:
##STR00415##
In certain embodiments, RD′ is of the formula:
##STR00416##
In certain embodiments, RD′ is of the formula:
##STR00417##
In certain embodiments, RD′ is of the formula:
##STR00418##
In certain embodiments, RD′ is of the formula:
##STR00419##
In certain embodiments, RD′ is of the formula:
##STR00420##
In certain embodiments, RD′ is of the formula:
##STR00421##
In certain embodiments, RD′ is of the formula:
##STR00422##
In certain embodiments, RD′ is of the formula:
##STR00423##
In certain embodiments, RD′ is of the formula:
##STR00424##
In certain embodiments, RD′ is of the formula:
##STR00425##
In certain embodiments, RD′ is of the formula:
##STR00426##
In certain embodiments, RD′ is of the formula:
##STR00427##
In certain embodiments, RD′ is of the formula:
##STR00428##
In certain embodiments, RD′ is of the formula:
##STR00429##
In certain embodiments, RD′ is of the formula:
##STR00430##
In certain embodiments, RD′ is of the formula:
##STR00431##
In certain embodiments, RD′ is of the formula:
##STR00432##
Compounds of Formula (II) or (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:
##STR00433##
In certain embodiments, Ring A′ is of the formula:
##STR00434##
In certain embodiments, k′ is 1. In certain embodiments, Ring A′ is of the formula:
##STR00435##
In certain embodiments, Ring A′ is of the formula:
##STR00436##
In certain embodiments, Ring A′ is of the formula:
##STR00437##
In certain embodiments, Ring A′ is of the formula:
##STR00438##
In certain embodiments, Ring A′ is of the formula:
##STR00439##
In certain embodiments, Ring A′ is of the formula:
##STR00440##
In certain embodiments, k′ is 2. In certain embodiments, Ring A′ is of the formula:
##STR00441##
In certain embodiments, Ring A′ is of the formula:
##STR00442##
In certain embodiments, Ring A′ is of the formula:
##STR00443##
In certain embodiments, Ring A′ is of the formula:
##STR00444##
In certain embodiments, Ring A′ is of the formula:
##STR00445##
In certain embodiments, Ring A′ is of the formula:
##STR00446##
In certain embodiments, Ring A′ is of the formula:
##STR00447##
In certain embodiments, Ring A′ is of the formula:
##STR00448##
In certain embodiments, Ring A′ is of the formula:
##STR00449##
In certain embodiments, Ring A′ is of the formula:
##STR00450##
In certain embodiments, k′ is 3. In certain embodiments, Ring A′ is of the formula:
##STR00451##
In certain embodiments, Ring A′ is of the formula:
##STR00452##
In certain embodiments, Ring A′ is of the formula:
##STR00453##
In certain embodiments, Ring A′ is of the formula:
##STR00454##
In certain embodiments, Ring A′ is of the formula:
##STR00455##
In certain embodiments, k′ is 4. In certain embodiments, Ring A′ is of the formula:
##STR00456##
In certain embodiments, Ring A′ is of the formula:
##STR00457##
Compounds of Formula (II) or (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:
##STR00458##
In certain embodiments, k′ is 1. In certain embodiments, Ring A′ is of the formula:
##STR00459##
In certain embodiments, Ring A′ is of the formula:
##STR00460##
In certain embodiments, Ring A′ is of the formula:
##STR00461##
In certain embodiments, k′ is 2. In certain embodiments, Ring A′ is of the formula:
##STR00462##
In certain embodiments, Ring A′ is of the formula:
##STR00463##
In certain embodiments, Ring A′ is of the formula:
##STR00464##
In certain embodiments, Ring A′ is of the formula:
##STR00465##
In certain embodiments, Ring A′ is of the formula:
##STR00466##
In certain embodiments, Ring A′ is of the formula:
##STR00467##
In certain embodiments, Ring A′ is of the formula:
##STR00468##
In certain embodiments, Ring A′ is of the formula:
##STR00469##
In compounds of Formula (II) or (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(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). 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
##STR00470##
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(RA1′)2. In certain embodiments, at least one RA′ is —NHC(═O)N(RA1′)2. In certain embodiments, at least one 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 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 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 Formula (II) or (V), Ring C′ may be substituted with one or more one 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)NHRA1′. 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)NHRA1′. 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 diazepane. In certain embodiments, at least one RB′ is
##STR00471##
In certain embodiments, at least one RB′ is
##STR00472##
In certain embodiments, at least one RB′ is
##STR00473##
In certain embodiments, at least one RB′ is
##STR00474##
In certain embodiments, at least one RB′ is
##STR00475##
In certain embodiments, at least one RB′ is
##STR00476##
In certain embodiments, at least one RB′ is
##STR00477##
In certain embodiments, at least one RB′ is
##STR00478##
In certain embodiments, at least one RB′ is
##STR00479##
In certain embodiments, at least one RB′ is
##STR00480##
In certain embodiments, at least one RB′ is
##STR00481##
In certain embodiments, at least one RB′ is
##STR00482##
In certain embodiments, at least one RB′ is
##STR00483##
In certain embodiments, at least one RB′ is
##STR00484##
In certain embodiments, at least one RB′ is
##STR00485##
In certain embodiments, at least one RB′ is
##STR00486##
In certain embodiments, at least one RB′ is
##STR00487##
In certain embodiments, at least one RB′ is
##STR00488##
In certain embodiments, at least one RB′ is
##STR00489##
In certain embodiments, at least one RB′ is
##STR00490##
In certain embodiments, at least one RB′ is
##STR00491##
In certain embodiments, at least one RB′ is
##STR00492##
In certain embodiments, at least one RB′ is
##STR00493##
In certain embodiments, at least one RB′ is
##STR00494##
In certain embodiments, at least one RB′ is
##STR00495##
In certain embodiments, at least one RB′ is
##STR00496##
In certain embodiments, at least one RB′ is
##STR00497##
In certain embodiments, at least one RB′ is
##STR00498##
In certain embodiments, at least one RB′ is
##STR00499##
In certain embodiments, at least one RB′ is
##STR00500##
In certain embodiments, at least one RB′ is
##STR00501##
In certain embodiments, at least one RB′ is
##STR00502##
In certain embodiments, at least one RB′ is
##STR00503##
In certain embodiments, at least one RB′ is
##STR00504##
In certain embodiments, at least one RB′ is
##STR00505##
In certain embodiments, at least one RB′ is
##STR00506##
In certain embodiments, at least one RB′ is
##STR00507##
In certain embodiments, at least one RB′ is
##STR00508##
In certain embodiments, at least one RB′ is
##STR00509##
In certain embodiments, at least one RB′ is
##STR00510##
In certain embodiments, at least one RB′ is
##STR00511##
In certain embodiments, two RB′ groups are joined to form a 1,3 dioxolane. In certain embodiments, two RB′ group are joined to form a 1,3 dioxolane which is fused to aryl Ring C′, together comprising an optionally substituted benzodioxolane. In certain embodiments, two 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 Formula (II) or (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 Fomiula (II) or (V), linker X′, Y′, and Z′ are divalent linker moieties. In certain embodiments, X′ is a bond. In certain embodiments, X′ is a single bond. In certain embodiments, X′ is —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 Formula (II) or (V), linker X′, Y′, and Z′ can be taken together to represent specific linking groups. In certain embodiments, X′, Y′, and Z′ together represent
##STR00512##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00513##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00514##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00515##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00516##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00517##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00518##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00519##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00520##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00521##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00522##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00523##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00524##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00525##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00526##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00527##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00528##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00529##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00530##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00531##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00532##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00533##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00534##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00535##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00536##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00537##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00538##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00539##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00540##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00541##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00542##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00543##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00544##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00545##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00546##
In certain embodiments, X′, Y′, and Z′ together represent
##STR00547##
In certain embodiments, X′, Y′, and Z′ together represent a single bond.
In compounds of Formula (II) and (V), linker Q′ and U′ are divalent linker moieties. In certain embodiments, Q′ is —NRA′. In certain embodiments, Q′ is —NH. In certain embodiments, Q′ is —C═O. In certain embodiments, Q′ —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 copounds of Formula (II) or (V), linker Q′ and U′ can be taken together to represent specific linking groups. In certain embodiments, Q′ and U′ together represent
##STR00548##
In certain embodiments, Q′ and U′ together represent
##STR00549##
In certain embodiments, Q′ and U′ together represent
##STR00550##
In certain embodiments, Q′ and U′ together represent
##STR00551##
In certain embodiments, Q′ and U′ together represent
##STR00552##
In certain embodiments, Q′ and U′ together represent
##STR00553##
In certain embodiments, Q′ and U′ together represent
##STR00554##
In certain embodiments, Q′ and U′ together represent
##STR00555##
In certain embodiments, Q′ and U′ together represent
##STR00556##
In certain embodiments, Q′ and U′ together represent
##STR00557##
In certain embodiments, Q′ and U′ together represent
##STR00558##
In certain embodiments, Q′ and U′ together represent
##STR00559##
Cy of Formula (II) or (V) may be an optionally substituted aryl ring. In certain embodiments, Ring Cy is a substituted aryl ring. In certain embodiments, Cy is an unsubstituted aryl ring. In certain embodiments, Cy is a monocyclic aryl ring. In certain embodiments, Cy is substituted phenyl. In certain embodiments, Cy is unsubstituted phenyl. In certain embodiments, Cy is a bicyclic aryl ring. In certain embodiments, Cy is substituted naphthyl. In certain embodiments, Cy is unsubstituted naphthyl. In certain embodiments, Cy is an optionally substituted aryl ring fused with one or more optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl groups wherein the point of attachment is on the aryl ring.
Cy of Formula (II) or (V) may also be an optionally substituted heteroaryl ring. In certain embodiments, Cy is a substituted heteroaryl ring. In certain embodiments, Cy is an unsubstituted heteroaryl ring. In certain embodiments, Cy is a monocyclic heteroaryl ring. In certain embodiments, Cy is a 5-membered monocyclic heteroaryl ring. In certain embodiments, Cy is a 5-membered monocyclic heteroaryl ring with one heteroatom selected from the group consisting of S, N, and O. In certain embodiments, Cy is a 5-membered monocyclic heteroaryl ring with two heteroatoms selected from the group consisting of S, N, and O. In certain embodiments, Cy is a 5-membered monocyclic heteroaryl ring with three heteroatoms selected from the group consisting of S, N, and O. In certain embodiments, Cy is substituted pyrrolyl. In certain embodiments, Cy is unsubstituted pyrrolyl. In certain embodiments, Cy is substituted furanyl. In certain embodiments, Cy is unsubstituted furanyl. In certain embodiments, Cy is substituted thienyl. In certain embodiments, Cy is unsubstituted thienyl. In certain embodiments, Cy is substituted pyrazolyl. In certain embodiments, Cy is unsubstituted pyrazolyl. In certain embodiments, Cy is substituted imidazolyl. In certain embodiments, Cy is unsubstituted imidazolyl. In certain embodiments, Cy is substituted oxazolyl. In certain embodiments, Cy is unsubstituted oxazolyl. In certain embodiments, Cy is substituted isoxazolyl. In certain embodiments, Cy is unsubstituted isoxazolyl. In certain embodiments, Cy is substituted thiazolyl. In certain embodiments, Cy is unsubstituted thiazoIyl. In certain embodiments, Cy is substituted isothiazolyl. In certain embodiments, Cy is unsubstituted isothiazolyl. In certain embodiments, Cy is substituted triazolyl. In certain embodiments, Cy is unsubstituted triazolyl. In certain embodiments, Cy is substituted oxadiazolyl. In certain embodiments, Cy is unsubstituted oxadiazolyl. In certain embodiments, Cy is substituted thiadiazolyl. In certain embodiments, Cy is unsubstituted thiadiazolyl. In certain embodiments, Cy is a 6-membered monocyclic heteroaryl ring. In certain embodiments, Cy is a 6-membered monocyclic heteroaryl ring with one heteroatom selected from the group consisting of S, N, and O. In certain embodiments, Cy is a 6-membered monocyclic heteroaryl ring with two heteroatoms selected from the group consisting of S, N, and O. In certain embodiments, Cy is a 6-membered monocyclic heteroaryl ring with three heteroatoms selected from the group consisting of S, N, and O. In certain embodiments, Cy is substituted pyridyl. In certain embodiments, Cy is unsubstituted pyridyl. In certain embodiments, Cy is substituted pyridazinyl. In certain embodiments, Cy is unsubstituted pyridazinyl. In certain embodiments, Cy is substituted pyrimidinyl. In certain embodiments, Cy is unsubstituted pyrimidinyl. In certain embodiments, Cy is substituted pyrazinyl. In certain embodiments, Cy is unsubstituted pyrazinyl. In certain embodiments, Cy is substituted triazinyl. In certain embodiments, Cy is unsubstituted triazinyl. In certain embodiments, Cy is an optionally substituted heteroaryl ring fused with one or more optionally substituted carbocyclic, optionally substituted heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl groups wherein the point of attachment is on any one of the heteroaryl ring, or carbocyclic, heterocyclic, aryl, or heteroaryl groups, as valency permits. In certain embodiments, Cy is a bicyclic heteroaryl ring. In certain embodiments, Cy is an optionally substituted heteroaryl ring fused with an optionally substituted phenyl ring. In certain embodiments, Cy is substituted indolyl. In certain embodiments, Cy is unsubstituted indolyl. In certain embodiments, Cy is substituted isoindolyl. In certain embodiments, Cy is unsubstituted isoindolyl. In certain embodiments, Cy is substituted indazolyl. In certain embodiments, Cy is unsubstituted indazolyl. In certain embodiments, Cy is substituted benzothienyl. In certain embodiments, Cy is unsubstituted benzothienyl. In certain embodiments, Cy is substituted isobenzothienyl. In certain embodiments, Cy is unsubstituted isobenzothienyl. In certain embodiments, Cy is substituted benzofuranyl. In certain embodiments, Cy is unsubstituted benzofuranyl. In certain embodiments, Cy is substituted benzoisofuranyl. In certain embodiments, Cy is unsubstituted benzoisofuranyl. In certain embodiments, Cy is substituted benzimidazolyl. In certain embodiments, Cy is unsubstituted benzimidazolyl. In certain embodiments, Cy is substituted benzoxazolyl. In certain embodiments, Cy is unsubstituted benzoxazolyl. In certain embodiments, Cy is substituted benzisoxazolyl. In certain embodiments, Cy is unsubstituted benzisoxazolyl. In certain embodiments, Cy is substituted benzothiazolyl. In certain embodiments, Cy is unsubstituted benzothiazolyl. In certain embodiments, Cy is substituted benzisothiazolyl. In certain embodiments, Cy is unsubstituted benzisothiazolyl. In certain embodiments, Cy is substituted benzotriazolyl. In certain embodiments, Cy is unsubstituted benzotriazolyl. In certain embodiments, Cy is substituted benzoxadiazolyl. In certain embodiments, Cy is unsubstituted benzoxadiazolyl. In certain embodiments, Cy is substituted quinolinyl. In certain embodiments, Cy is unsubstituted quinolinyl. In certain embodiments, Cy is substituted isoquinolinyl. In certain embodiments, Cy is unsubstituted isoquinolinyl. In certain embodiments, Cy is substituted cinnolinyl. In certain embodiments, Cy is unsubstituted cinnolinyl. In certain embodiments, Cy is substituted quinoxalinyl. In certain embodiments, Cy is unsubstituted quinoxalinyl. In certain embodiments, Cy is substituted phthalazinyl. In certain embodiments, Cy is unsubstituted phthalazinyl. In certain embodiments, Cy is substituted quinazolinyl. In certain embodiments, Cy is unsubstituted quinazolinyl. In certain embodiments, Cy is
##STR00560##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00561##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00562##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00563##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00564##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00565##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00566##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00567##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00568##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00569##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00570##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00571##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00572##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00573##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00574##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00575##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00576##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00577##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00578##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00579##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00580##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00581##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00582##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00583##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00584##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00585##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00586##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00587##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00588##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00589##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00590##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00591##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00592##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00593##
wherein X′ may link to any freely valent position. In certain embodiments, Cy is
##STR00594##
wherein X′ may link to any freely valent position.
In compounds of Formula (II) or (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(C1-6alkyl)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
##STR00595##
In certain embodiments, at least one RX′ is
##STR00596##
In certain embodiments, at least one RX′ is
##STR00597##
In certain embodiments, at least one RX′ is
##STR00598##
In certain embodiments, at least one RX′ is
##STR00599##
In certain embodiments, at least one RX′ is
##STR00600##
In certain embodiments, at least one RX′ is
##STR00601##
In certain embodiments, at least one RX′ is
##STR00602##
In certain embodiments, at least one RX′ is
##STR00603##
In certain embodiments, at least one RX′ is
##STR00604##
In certain embodiments, at least one RX′ is
##STR00605##
In certain embodiments, at least one RX′ is
##STR00606##
In certain embodiments, at least one RX′ is
##STR00607##
In certain embodiments, at least one RX′ is
##STR00608##
In certain embodiments, at least one RX′ is
##STR00609##
In certain embodiments, at least one RX′ is
##STR00610##
In certain embodiments, at least one RX′ is
##STR00611##
In certain embodiments, at least one RX′ is
##STR00612##
In certain embodiments, at least one RX′ is
##STR00613##
In certain embodiments, at least one RX′ is
##STR00614##
In certain embodiments, at least one RX′ is
##STR00615##
In certain embodiments, at least one RX′ is
##STR00616##
In certain embodiments, at least one RX′ is
##STR00617##
In certain embodiments, at least one RX′ is
##STR00618##
In certain embodiments, at least one RX′ is
##STR00619##
In certain embodiments, at least one RX′ is
##STR00620##
In certain embodiments, at least one RX′ is
##STR00621##
In certain embodiments, at least one RX′ is
##STR00622##
In certain embodiments, at least one RX′ is
##STR00623##
In certain embodiments, at least one RX′ is
##STR00624##
In certain embodiments, at least one RX′ is
##STR00625##
In certain embodiments, at least one RX′ is
##STR00626##
In certain embodiments, at least one RX′ is
##STR00627##
In certain embodiments, at least one RX′ is
##STR00628##
In certain embodiments, at least one RX′ is
##STR00629##
In certain embodiments, at least one RX′ is
##STR00630##
In certain embodiments, at least one RX′ is
##STR00631##
In certain embodiments, at least one RX′ is
##STR00632##
In certain embodiments, at least one RX′ is
##STR00633##
In certain embodiments, at least one RX′ is
##STR00634##
In certain embodiments, at least one RX′ is
##STR00635##
In certain embodiments, at least one RX′ is
##STR00636##
In certain embodiments, at least one RX′ is
##STR00637##
In certain embodiments, at least one RX′ is
##STR00638##
In certain embodiments, at least one RX′ is
##STR00639##
In certain embodiments, at least one RX′ is
##STR00640##
In certain embodiments, at least one RX′ is
##STR00641##
In certain embodiments, at least one RX′ is
##STR00642##
In certain embodiments, at least one RX′ is
##STR00643##
In certain embodiments, at least one RX′ is
##STR00644##
In certain embodiments, at least one RX′ is
##STR00645##
In certain embodiments, at least one RX′ is
##STR00646##
In certain embodiments, at least one RX′ is
##STR00647##
In certain embodiments, at least one RX′ is
##STR00648##
In certain embodiments, at least one RX′ is
##STR00649##
In certain embodiments, at least one RX′ is
##STR00650##
In certain embodiments, at least one RX′ is
##STR00651##
In certain embodiments, at least one RX′ is
##STR00652##
In certain embodiments, at least one RX′ is
##STR00653##
In certain embodiments, at least one RX′ is
##STR00654##
In certain embodiments, at least one RX′ is
##STR00655##
In certain embodiments, at least one RX′ is
##STR00656##
In certain embodiments, at least one RX′ is
##STR00657##
In certain embodiments, at least one RX′ is
##STR00658##
In certain embodiment, a compound of the invention is a compound of Formula (A), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiment, a compound of the invention is a compound of Formula (A), or a pharmaceutically acceptable salt thereof. In certain embodiment, a compound of the invention is a compound of Formula (I-11), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiment, a compound of the invention is a compound of Formula (I-11), or a pharmaceutically acceptable salt thereof. In certain embodiment, a compound of the invention is a compound of Formula (II), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer. isotopically labeled derivative, or prodrug thereof. In certain embodiment, a compound of the invention is a compound of Formula (II), or a pharmaceutically acceptable salt thereof. In certain embodiment, a compound of the invention is a compound of Formula (V), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. In certain embodiment, a compound of the invention is a compound of Formula (V), or a pharmaceutically acceptable salt thereof.
In certain embodiments, compounds of the present invention include those which:
As used herein “kinase” refers to a large class of enzymes which catalyze the transfer of the γ-phosphate from ATP to the hydroxyl group on the side chain of Ser/Thr or Tyr in proteins and peptides and are intimately involved in the control of various important cell functions, perhaps most notably: signal transduction, differentiation and proliferation. There are estimated to be about 2,000 distinct protein kinases in the human body and although each of these phosphorylates particular protein/peptide substrates, they all bind the same second substrate ATP in a highly conserved pocket. About 50% of the known oncogene products are protein tyrosine kinases PTKs and their kinase activity has been shown to lead to cell transformation.
In certain embodiments, the kinase to be inhibited is involved in the myeloid differentiation primary response gene (88) (MYD88) signaling pathway. For example, the kinase is Transforming growth factor b-activated kinase-1 (TAK1) or Hemopoietic cell kinase (HCK). In certain embodiments, the compound of the invention inhibits TAK1, HCK, or both TAK1 and HCK.
Myeloid differentiation primary response gene (88) (MYD88) L265P is a widely expressed somatic mutation in WM patients that supports NF-NFκB signaling through stimulation of BTK, IRAK1/4, TAK1. MYD88 is an adaptor molecule for Toll-like receptors (TLR) with the exception of TLR-3 and interleukin-1 receptor (IL-1R) signaling. Following TLR or IL-1R stimulation, MYD88 is recruited to the activated receptor complex as a homodimer which then complexes with interleukin-1 receptor-associated kinase 4 (IRAK4) and activates IRAK1 and IRAK2. Tumor necrosis factor receptor associated factor 6 (TRAF6) is then activated by IRAK1 leading to NFκB activation via IκBα phosphorylation and TAK1 activation.
Transforming growth factor b-activated kinase-1 (TAK1; also known as MAP3K7) is a member of the serine/threonine protein kinase family. This kinase mediates the signaling transduction induced by TGF beta and morphogenetic protein (BMP), and controls a variety of cell functions including transcription regulation and apoptosis. TAK1 knockout is embryonic lethal to mice. Conditional knockdown of TAK1 in adult mice results in systemic inflammation, spenomegaly, degeneration in heart, kidneys and liver and increased proliferation and differentiation of myeloid progenitor cells. TAK1 is located downstream of Myd88, Bruton's tyrosine kinase (BTK), and interleukin-1 receptor-associated kinase (IRAK), and is being investigated for its role in innate immunity, inflammatory response, and Ras-dependent cancers.
Hemopoietic cell kinase (HCK) is a non-receptor tyrosine-protein kinase found in hematopoietic cells and is known to interact with Bruton's tyrosine kinase (BTK) upon activation by B cell receptors (Proc. Natl. Acad. Sci. USA. 1994, 91(17), 8152-55). HCK transmits signals from cell surface receptors and plays an important role in the regulation of innate immune responses, including neutrophil, monocyte, macrophage and mast cell functions, phagocytesis, cell survival and proliferation, cell adhesion and migration. It acts downstream of receptors that bind the Fc region of immunoglobulins, such as FCGR1A and FCGR2A, but also CSF3R, PLAUR, the receptors for IFNG, IL2, IL6 and IL8, and integrins, such as ITGB1 and ITGB2. During the phagocytic process, it mediates mobilization of secretory lysosomes, degranulation, and activation of NADPH oxidase to bring about the respiratory burst. It also plays a role in the release of inflammatory molecules, promotes reorganization of the actin cytoskeleton and actin polymerization, and formation of podosomes and cell protrusions.
Hematopoietic progenitor kinase 1 (HPK1) is a hematopoietic cell-restricted member of the Ste20 serine/threonine kinase super family. HPK1 is also known as mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1). HPK1 is a tissue-specific upstream activator of the MEKK/JNK/SAPK signaling pathway. HPK1 diminishes T cell receptor (TCR) signaling activity and T cell proliferation by phosphorylating the adaptor protein SLP-76. Cytosolic HPK1 is recruited to the TCR complex, and its kinase activity is induced upon the engagement of the TCR. Overexpression of HPK1 suppresses TCR-induced activation of AP-1-dependent gene transcription in a kinase-dependent manner, suggesting that the kinase activity of HPK1 is required to inhibit the Erk MAPK pathway. This blockage of the Erk MAPK pathway is thought to be the inhibitory mechanism that negatively regulates TCR-induced IL-2 gene transcription (Immunol. Res. 2012, 54(1-3), 262-65). In certain embodiments, the compounds of the invention, such as the compounds of Formula (A), (I-11), (II), or (V) (e.g., compounds of Formula (A-1)-(A-18)), inhibit HPK1.
In certain embodiments, the compounds of the invention are selective inhibitors of TAK1, HCK, or HPK1. The term “selective inhibitor” as used herein is understood to mean that in contrast to many kinase inhibitors of the prior art, the compounds do not act on a variety of kinases but act specifically on TAK1, HCK, or HPK1. In certain embodiments, the compounds of the invention inhibit one or more kinases in addition to TAK1, HCK, or HPK1 such as BTK or the SRC family of kinases. In certain embodiments of the invention, the specificity of the inhibitors is given by the IC50 value. In some embodiments, 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 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.
In certain embodiments, the compounds of the invention (e.g., the compounds of Formula (A), (I-11), (II), or (V)) inhibit HCK selectively. In certain embodiments, the compounds of the invention (e.g., the compounds of Formula (A), (I-11), (II), or (V)) inhibit TAK1 selectively. A non-limiting example of a selective TAK1 inhibitor is:
##STR00659##
In certain embodiments, the compounds of the invention (e.g., the compounds of Formula (A), (I-11), (II), or (V)) inhibit both TAK1 and HCK. A non-limiting example of a dual TAK1/HCK inhibitor is:
##STR00660##
In certain embodiments, the compounds of the invention (e.g., the compounds of Formula (A), (I-11), (II), or (V)) inhibit HPK1 selectively. A non-limiting example of a selective HPK1 inhibitor is:
##STR00661##
Also, provided are methods to treat B cell neoplasms using compounds of the invention in combination with inhibitors of Bruton's tyrosine kinase (BTK), interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), bone marrow on X chromosome kinase (BMX), phosphoinositide 3-kinase (PI3K), transforming growth factor b-activated kinase-1 (TAK1), and/or a Src family kinase. In certain embodiments, one or more compounds of the invention are used in combination with an inhibitor of the phosphoinositide 3-kinase delta isoform (PI3Kδ). In certain embodiments, combinations of 2, 3, 4, 5. 6, 7, 8, 9, 10, or more of the agents described herein are used for treating WM. In certain embodiments, the agents described herein are used in combination with inhibitors of Bruton's tyrosine kinase (BTK), interleukin-1 receptor-associated kinase 1 (IRAK1), interleukin-1 receptor-associated kinase 4 (IRAK4), bone marrow on X chromosome kinase (BMX), phosphoinositide 3-kinase (PI3K), transforming growth factor b-activated kinase-1 (TAK1), and/or a Src family kinase.
Bruton's tyrosine kinase (BTK) is a key signaling enzyme expressed in all hematopoietic cells types except T lymphocytes and natural killer cells. BTK plays an essential role in the B cell signaling pathway linking cell surface B cell receptor BCR stimulation to downstream intracellular responses. BTK is a key regulator of B cell development activation signaling and survival (Kurosaki, Curr. Op. Imm, 2000, 276-281; Schaeffer and Schwartzberg, Curr. Op. Imm., 2000, 282-288). In addition BTK plays a role in a number of other hematopoietic cell signaling pathways, e.g., Toll like receptor (TLR) and cytokine receptor-mediated TNF-α production in macrophages, IgE receptor (FcepsilonRI) signaling in mast cells, inhibition of Fas/APO-1 apoptotic signaling in B-lineage lymphoid cells, and collagen stimulated platelet aggregation. See e.g., C. A. Jeffries, et al., J. Biol. Chem., 2003, 278, 26258-26264: N. J. Horwood, et al., J. Exp. Med., 2003, 197, 1603-1611; Iwaki et al., J. Biol. Chem., 2005, 280(48), 40261-40270; Vassilev et al., J. Biol. Chem., 1999, 274(3), 1646-1656; and Quek et al., Curr. Biol., 1998, 8(20), 1137-1140. Activated Btk interacts with MyD88 and TRIF, promoting the activation of MyD88-dependent and TRIF-dependent pathways (Nature Immunology, 2011, 12, 416-424).
BTK inhibitors are well-known in the art, and include, for example, ibrutinib and benzonaphthyridinones (see U.S. provisional patent application U.S. Ser. No. 61/716,273, filed Oct. 19, 2012), Additional non-limiting examples of BTK inhibitors are disclosed in WO 1999/054286, WO 2013/010380, WO 2009/137596, WO 2011/029043, WO 2010/056875, WO 2000/056737, and WO 2013/067277.
IRAK1 and 4 are serine/threonine-protein kinases that play a critical role in initiating innate immune response against foreign pathogens. They are involved in Toll-like receptor (TLR) and IL-1R signaling pathways, and are rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent auto-phosphorylation and kinase activation of IRAK1 (Immunity, 1997, 7(6), 837-47). IRAK4−/− mice have abolished cellular responses to various IL-1 and TLR ligands and are severely impaired in their response to viral and bacterial challenges. IRAK1−/− mice show a similar but partial response.
IRAK1 and lRAK4 inhibitors are well-known in the art, and include, for example, those disclosed in WO 2003/030902, WO 2012/007375, G. M. Buckely et al., Biorg. Med. Chem. Lett. 2008, 18, 3211-3214, and G. M. Buckely et al., Biorg. Med. Chem. Lett. 2008, 18, 3656-3660, WO2013/074986, and U.S. provisional patent application, U.S. Ser. No. 61/727,640, filed Nov. 16, 2012.
In certain embodiments, the IRAK4 inhibitor is of formula:
##STR00662##
or an analog thereof.
“Bone Marrow on X chromosome” kinase (BMX, also termed ETK) is a non-receptor tyrosine kinase and is activated downstream of phosphatidylinositol-3 kinase (PI-3K) and v-src sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (SRC), but its substrates are unknown. Positional scanning peptide library screening revealed a marked preference for a priming phosphotyrosine (pY) in the −1 position. Potential substrates include multiple tyrosine kinases with kinase domain pYpY sites required for full activity. BMX has been found to phosphorylate residue Y577 of focal adhesion kinase (FAK) subsequent to Y576 phosphorylation by SRC. In addition, BMX loss by RNA interference and mouse embryonic fibroblasts (MEFs) from Bmx negative (Bmx−) mice displayed impaired FAK signaling. Insulin receptor (IR) phosphorylation similarly was decreased by BMX loss, as was hepatic IR phosphorylation in Bmx− mice. However, glucose tolerance was increased, reflecting a marked compensatory decrease in the activity of the AKT phosphatase PHLPP. These findings reveal a mechanism through which BMX functions as a central regulator of multiple kinase pathways.
BMX inhibitors are well-known in the art, and include, for example, those disclosed in U.S. Ser. No. 61/716,273 and 61/717,345, the contents of both of which are incorporated herein by reference. In certain embodiments, the BMX inhibitor is of formula:
##STR00663##
or an analog thereof.
Phosphatidylinositol 3-kinases (PI3-kinases or PI3Ks) are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. PI3Ks are a family of related intracellular signal transducer enzymes capable of phosphorylating the 3 position hydroxyl group of the inositol ring of phosphatidylinositol (Ptdlns). Phosphatidylinositol 3-kinase is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by PI3KCA gene represents the catalytic subunit, which uses ATP to phosphorylate phosphatidylinositols (Ptdlns), Ptdlns4P and Ptdlns(4,5)P2. Of particular interest is the PI3K delta isoform, which is expressed in white blood cells and is mainly involved in the signaling, development, and survival of B cells.
PI3K inhibitors are well-known in the art, and include, for example, those disclosed in International PCT Publications WO 2013/088404, WO 2012/068096, and WO 2013/052699, which are incorporated herein by reference.
In certain embodiments, the PI3K inhibitor is
##STR00664##
or its analogs.
Compounds of the invention may be combined with other kinase inhibitors to treat WM or other B cell neoplasms. In certain embodiments, a compound of the invention is administered with an inhibitor of Bruton's tyrosine kinase (BTK) to treat WM or other B cell neoplasm. In certain embodiments, a compound of the invention is administered with an inhibitor of interleukin-1 receptor-associated kinase 1 (IRAK1) to treat WM or otherB cell neoplasm. In certain embodiments, a compound of the invention is administered with an inhibitor of phosphoinositide 3-kinase (PI3K) to treat WM or other B cell neoplasm. In certain embodiments, a compound of of the invention is administered with an inhibitor of the phosphoinositide 3-kinase delta isoform (PI3Kδ) to treat WM or other B cell neoplasm. In certain embodiments, a compound of of the invention is administered with two of any inhibitors of BTK, IRAK1, or PI3K to treat WM or other B cell neoplasm. In certain embodiments, a compound of the invention is administered with more than two of any inhibitors of BTK, IRAK1, or PI3K to treat WM or other B cell neoplasm.
The BTK inhibitors, the IRAK1 inhibitors, the IRAK4 inhibitors, and/or the PI3K inhibitors can be administered to the subject simultaneously or sequentially.
A “subject” or “patient” to which administration is contemplated includes, any animal. In some embodiments, a subject includes but is not limited to, humans, commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and/or dogs), birds (e.g., commercially relevant birds such as chickens, ducks, geese, and/or turkeys) and experimental animals (e.g., mice, rats, non-human primates). A subject in need of treatment is a subject identified as having a B cell neoplasm, i.e,. the subject has been diagnosed by a physician (e.g., using methods well known in the art) as having a B cell neoplasm. In certain embodiments, the subject in need of treatment is a subject suspected of having or developing a B cell neoplasm, such as a subject presenting one or more symptoms indicative of a B cell neoplasm. The term “subject in need of treatment” further includes people who once had a B cell neoplasm but whose signs and/or symptoms have been ameliorated (i.e., their cancer is in remission). The one or more symptoms or clinical features of B cell neoplasms include, but are not limited to, asymptomatic localized or generalized peripheral lymphadenopathy, plasmacytic difference, bone marrow involvement, autoimmune thrombocytopenia, peripheral blood villous lymphocytes, end organ damage (hypercalcemia, renal insufficiency, bone lesions), recurrent infections, elevated creatine, hyperuricemia, and hypoalbunemia.
In certain embodiments, the subject is diagnosed as having Waldenström's macroglobulinemia (WM). The subject may present one or more signs, symptoms, or clinical features of WM including anemia, hyper-viscosity, neuropathy, coagulopathies, splenomegaly, hepatomegaly, adenopathy, and an IgM serum paraprotein, In certain embodiments, the subject is diagnosed as having WM on the basis that the subject has a mutation at position 38182641 of chromosome 3p22.2. In some embodiments, the mutation results in a single nucleotide change from T to C in the MYD88 gene. In some embodiments, the mutation results in an amino acid change from leucine to proline at position 265 in the MYD88 gene. The mutation may be detected in a biological sample obtained from the subject using any suitable method known in the art, including but not limited to, direct sequencing of nucleic acid molecules, HPLC analysis, DNA chip technologies, and mass spectroscopy. Non-limiting examples of the biological sample include bone marrow, lymph node, spleen, or blood.
The terms “administer,” “administering,” or “administration,” as used he rein refers to implanting, absorbing, ingesting, injecting, or inhaling an inventive compound, or a pharmaceutical composition thereof.
As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a B cell neoplasm. In certain embodiments, treatment may be administered after one or more signs or symptoms have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the B cell neoplasm. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and/or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example, to delay or prevent recurrence.
An “effective amount” of compounds of the invention refers to an amount sufficient to elicit the desired biological response, i.e., treating the B cell neoplasm. As will be appreciated by those of ordinary skill in this art, the effective amount of compounds of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. An eifective amount includes, but is not limited to, that amount necessary to slow, reduce, inhibit, ameliorate or reverse one or more signs and/or symptoms associated with a B cell neoplasm. In the treatment of Waldenström's macroglobulinemia, this may refer to a reduction in the levels of IgM serum paraprotein, reduction in anemia, reduction in hyper-viscosity, reduction in neuropathy, reduction in coagulopathies, reduction in splenomegaly, reduction in hepatomegaly, and reduction in adenopathy.
An effective amount of a compound may vary from about 0.001 mg/kg to about 1000 mg/kg in one or more dose administrations, for one or several days (depending on the mode of administration). In certain embodiments, the effective amount varies from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kg to about 750 mg/kg, from about 0.1 mg/kg to about 500 mg/kg, from about 1.0 mg/kg to about 250 mg/kg, from about 1.0 mg/kg to about 100 mg/kg, and from about 10.0 mg/kg to about 150 mg/kg.
One or more additional pharmaceutical agents, such as anti-cancer agents (e.g., chemotherapeutics), anti-inflammatory agents, steroids, immunosuppressants, radiation therapy, or other agents, can be used in combination with the compounds of of the invention in the treatment of a B cell neoplasm. The one or more additional pharmaceutical agents can be administered to the subject simultaneously or sequentially.
Exemplary chemotherapeutic agents include alkylating agents such as nitrogen mustards, ethylenimines, methylmelamines, alkyl sulfonates, nitrosuoureas, and triazenes; antimetabolites such as folic acid analogs, pyrimidine analogs, in particular fluorouracil and cytosine arabinoside, and purine analogs; natural products such as vinca alkaloids epi-podophyllotoxins, antibiotics, enzymes, and biological response modifiers; and miscellaneous products such as platinum coordination complexes, anthracenedione, substituted urea such as hydroxyurea, methyl hydrazine derivatives, and adrenocorticoid suppressant.
Exemplary chemotherapeutic agents also include anthracycline antibiotic, actinomycin D, plicamycin, puromycin, gramicidin D, paclitaxel, colchicine, cytochalasin B, emetine, maytansine, amsacrine, cisplatin, carboplatin, mitomycin, altretamine, cyclophosphamide, lomustine, and carmustine.
In yet another aspect, the present invention provides pharmaceutical compositions comprising an effective amount of a compound of of the invention, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, and prodrugs, and optionally a pharmaceutically acceptable excipient, for use in the treatment of a B cell neoplasm. In certain embodiments, provided by the invention are the compounds of of the invention, and pharmaceutically acceptable salts and compositions thereof, for use in the treatment of a B cell neoplasm. In certain embodiments, the effective amount is a therapeutically effective amount. In certain embodiments, the therapeutically effective amount is an amount useful for the treatment and/or prevention of a B cell neoplasm. In certain embodiments, the B cell neoplasm is, but is not limited to, Hodgkin's lymphomas and most non-Hodgkins lymphomas, such as, diffuse large B cell lymphoma, Follicular lymphoma, Mucosa-Associated Lymphatic Tissue lymphoma (MALT), small cell lymphocytic lymphoma (overlaps with Chronic lymphocytic leukemia), Mantle cell lymphoma (MCL), Burkitt lymphoma, Mediastinal large B cell lymphoma, Waldenström's macroglobulinemia, Nodal marginal zone B cell lymphoma (NMZL), Splenic marginal zone lymphoma (SMZL), Intravascular large B-cell lymphoma, Primary effusion lymphoma and Lymphomatoid granulomatosis. An etfective amount of a compound may vary from about 0.001 mg/kg to about 1000 mg/kg in one or more dose administrations, for one or several days (depending on the mode of administration). In certain embodiments, the effective amount varies from about 0.001 mg/kg to about 1000 mg/kg, from about 0.01 mg/kg to about 750 mg/kg, from about 0.1 mg/kg to about 500 mg/kg, from about 1.0 mg/kg to about 250 mg/kg, and from about 10.0 mg/kg to about 150 mg/kg.
Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing a compound of of the invention (the “active ingredient”) into association with a carrier or excipient, and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.
Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. As used herein, a “unit dose” is a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as, for example, one-half or one-third of such a dosage.
The pharmaceutical preparations of the present invention may include or be diluted into a pharmaceutically acceptable carrier. The term “pharmaceutically acceptable carrier” as used herein means one or more compatible fillers, diluents or other such substances, which are suitable for administration to a human or other mammal, such as a dog, cat, rat, mouse, or horse. The term “carrier” denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. The carriers are capable of being commingled with the preparations of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy or stability. Carriers suitable for oral, subcutaneous, intravenous, intramuscular, etc. formulations can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa.
The compounds and compositions provided herein can be administered by any route, including enteral (e.g., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the subject (e.g., whether the subject is able to tolerate oral administration).
The exact amount of a compound required to achieve an effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound, mode of administration, and the like. The desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., two, thRee, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.
In certain embodiments, the compound of the invention is administered at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more preferably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.
It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.
The present invention is further illustrated by the following Example, which in no way should be construed as further limiting. The entire contents of all of the references (including literature references, issued patents, published patent applications, and co pending patent applications) cited throughout this application are hereby expressly incorporated by reference.
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.
Preparation of I-11
##STR00665##
4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (284 mg, 1.0 mmol), 3-hydroxy-4-methylbenzoic acid (152 mg, 1.0 mmol) and K2CO3 (414 mg, 3.0 mmol) were combined in DMSO (5 mL) and stirred overnight at 100° C. The reaction mixture was then cooled to room temperature. The mixture was acidified with 1N HCl solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography to yield 296 mg of product as a colorless oil. Ms (ESI) m/z 400 (M+H)+.
##STR00666##
To a solution of 4-methyl -3-((7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)benzoic acid (200 mg, 0.5 mmol), HATU (230 mg, 0.6 mmol), DMAP (73 mg, 0.6 mmol) and iPr2NEt (220 uL, 1.25 mmol) in CH2Cl2 (3 mL) was added 2-(3-aminophenyl)-2-methyl-propanenitrile (80 mg, 0.5 mmol) and the resulting mixture was stirred at room temperature for 24 hours. The solution was filtered to remove solids, concentrated and purified with column chromatography (dichloromethane:methanol=10:1) to afford 455 mg of product as a colorless oil. To the solution of the obtained oil in CH2Cl2 (5 mL) was added TFA (0.5 mL) and the resulting mixture was stirred at room temperature for 5 hours. The solution was concentrated and dried with vacuum, then dissolved in THF (4 mL) and 1 N NaOH solution (4 mL). The reaction mixture was stirred for 24 h and extracted with ethyl acetate. The combined organic phase was washed with brine and dried with Na2SO4, then filtered and concentrated, and purified by reverse phase HPLC to give 185 mg (90%) of title compound as a white solid.
Preparation of A-17
##STR00667## ##STR00668##
Sodium hydroxide (2 ml of 1N solution) was added to a solution of 4,6-dichloropyrimidine (150 mg, 1.0 mmol) and 3-hydroxy-4-methylbenzoic acid (152 mg, 1.0 mmol) in acetone (2 mL) and the reaction mixture as stirred at room temperature for 1 hour at which point LC-MS analysis indicated complete consumption of starting material. The reaction mixture was extracted with ethyl acetate. The combined organic phase was washed with brine and dried with Na2SO4, then filtered and concentrated, and purified by colunm chromatography to yield 250 mg of product as a white solid. MS (ESI) m/z 265 (M+H)+.
##STR00669##
To a solution of 3-((6 -chloropyrimidin-4-yl)oxy)-4-methylbenzoic acid (210 mg, 0.8 mmol), HATU (365 mg 0.96 mmol), DMAP (117 mg, 0.96 mmol) and iPr2NEt (350 uL, 2.0 mmol) in CH2Cl2 (4 mL) was added 4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (230 mg, 0.8 mmol) and the resulting mixture was stirred at room temperature for 24 hours The solution was filtered to remove solids, concentrated and purified column chromatography to yield 360 mg (84%) of product as a pale yellow oil. MS (ESI) m/z 534 (M+H)+.
##STR00670##
10 mL of a 2N solution of NH3 in i-PrOH was added to 3-((6-chloropyrimidin-4-yl)oxy)-N-(4-((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide (270 mg, 0.5 mmol) and the reaction mixture was stirred for 48 hours at 75° C. then cooled to room temperature and concentrated. The crude product was purified by column chromatography to yield 120 mg of product as a colorless oil. MS (ESI) m/z 515 (M+H)+.
##STR00671##
To a solution of 3-((6-aminopyrimidin-4-yl)oxy)-N-(4((4-ethylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-4-methylbenzamide (51 mg, 0.1 mmol) in DMF cooled in a dry ice/SOLVENT bath was added acryloyl chloride (8.9 uL, 0.11 mmol). The cooling bath was removed allowing the mixture to warm to room temperature and continue stirring for an half hour. The solution was then diluted in DMSO and purified by reverse phase HPLC to afford 45 mg (80%) of A-17 as a white solid.
Compounds (A-1)-(A-16) and (A-18) were prepared similarly to A-17.
Characterization data for all final compounds is in the table below.
ID #
Structure
Name
1H NMR and or MS (m/z)
A-1
##STR00672##
N-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl) phenyl)-4-methyl- 3-((6-(methylamino) pyrimidin-4-yl)oxy) benzamide
1H NMR (400 MHz, DMSO) δ 10.39 (s, 1H), 8.11 (s, 1H), 9.00 (d, J = 8.4) Hz, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.33 (bs, 1H), 3.60 (s, 2H), 3.38 (m, 2H), 2.97-2.79 (m, 6H), 2.71 (bs, 3H), 2.37-2.22 (m, 2H), 2.09 (s, 3H), 1.12 (t, J = 6.8 Hz, 3H). MS (ESI) m/z 529 (M + H)+.
A-2
##STR00673##
N-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl) phenyl)-4-methyl- 3-((6-(propionamido- pyrimidin)-4-yl)oxy) benzamide
1H NMR (600 MHz, TFA salt, DMSO) δ 10.89 (s, 1H), 10.42 (s, 1H), 9.36 (br, 1H), 8.42 (s, 1H), 8.13 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), 7.80 (d, J = 7.8 Hz, 1H), 7.71 (s, 1H), 7.64 (d, J = 9.0 Hz, 1H), 7.57 (s, 1H), 7.46 (d, J = 7.8 Hz, 1H), 3.61 (s, 2H), 3.38 (m, 2H), 3.07 (m, 2H), 2.92 (m, 2H), 2.85 (m, 2H), 2.37 (q, J = 7.2 Hz, 2H), 2.32 (m, 2H), 2.10 (s, 3H), 1.34 (t, J = 7.2 Hz, 3H), 0.98 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 571 (M + H)+.
A-3
##STR00674##
3-((6-(cyclopropane- carboxamido) pyrimidin-4-yl)oxy)- N-(4-((4-ethylpiperazin- 1-yl)methyl)-3- (trifluoromethyl) phenyl)-4-methyl- benzamide
1H NMR (600 MHz, DMSO) δ 11.25 (s, 1H), 10.36 (s, 1H), 8.43 (s, 1H), 8.11 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.70 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.54 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 3.49 (s, 2H), 2.32 (m, 8H), 2.24 (m, 2H), 2.09 (s, 3H), 1.97 (m, 1H), 0.91 (t, J = 7.2 Hz, 3H), 0.79 (m, 4H). MS (ESI) m/z 583 (M + H)+.
A-4
##STR00675##
3-((6-aminopyrimidin- 4-yl)oxy)-N-(4-((4- ethylpiperazin-1- yl)methyl)-3- (trifluoromethyl) phenyl)-4-methyl- benzamide
1H NMR (600 MHz, TFA salt, DMSO) δ 8.06 (s, 1H), 8.03 (s, 1H), 7.92 (d, J = 8.4 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.63 (s, 1H), 7.43 (d, J = 7.2 Hz, 1H), 5.78 (s, 1H), 3.70 (s, 2H), 3.47 (m, 2H), 3.15 (q, J = 7.2 Hz, 2H), 3.01 (m, 4H), 2.42 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 515 (M + H)+.
A-5
##STR00676##
N-(4-((4-ethylpiperazin- 1-yl)methyl)-3-(trifluoro- methyl)phenyl)-4- methyl-3-((6-((1- methyl-1H-pyrazol- 4-yl)amino)pyrimidin- 4-yl)oxy)benzamide
1H NMR (600 MHz, DMSO) δ 10.36 (s, 1H), 9.37 (br, 1H), 8.20 (s, 1H), 8.11 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H), 7.63 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 5.94 (s, 1H), 3.74 (s, 3H), 3.50 (s, 2H), 2.18-2.42 (m, 10H), 2.12 (s, 3H), 0.92 (m, 3H). MS (ESI) m/z 595 (M + H)+.
A-6
##STR00677##
3-((6-((1H-pyrazol-5-yl) amino)pyrimidin-4-yl) oxy)-N-(4-((4-ethyl- piperazin-1-yl)methyl)- 3-(trifluoromethyl) phenyl)-4-methyl- benzamide
1H NMR (600 MHz, TFA salt, DMSO) δ 10.45 (s, 1H), 9.92 (s, 1H), 9.33 (br, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.74 (s, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.62 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 3.66 (s, 2H), 3.44 (m, 2H), 3.12 (m, 2H), 2.97 (m, 2H), 2.91 (m, 2H), 2.37 (m, 2H), 2.17 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 581 (M + H)+.
A-7
##STR00678##
3-((6-((1H-pyrazol-4- yl)amino)pyrimidin-4- yl)oxy)-N-(4-((4- ethylpiperazin-1-yl) methyl)-3-(trifluoro- methyl)phenyl)-4- methylbenzamide
1H NMR (600 MHz, DMSO) δ 12.63 (br, 1H), 10.44 (s, 1H), 9.42 (br, 1H), 8.26 (br, 1H), 8.19 (s, 1H), 8.06 (d, J = 9.0 Hz, 1H), 7.90 (br, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.76 (s, 1H), 7.70 (d, J = 9.0 Hz, 1H), 7.53 (br, 1H), 7.51 (d, J = 8.4 Hz, 1H), 6.00 (s, 1H), 3.60 (s, 2H), 2.25-2.86 (m, 10H), 2.19 (s, 3H), 1.05, (m, 3H). MS (ESI) m/z 581 (M + H)+.
A-8
##STR00679##
N-(4-((4-ethylpiperazin- 1-yl)methyl)-3-(tri- fluoromethyl)phenyl)- 4-methyl-3-((6- (pyrimidin-5-ylamino) pyrimidin-4-yl)oxy) benzamide
1H NMR (600 MHz, TFA salt, DMSO) δ 10.49 (s, 1H), 10.02 (s, 1H), 9.44 (br, 1H), 9.08 (s, 2H), 8.82 (s, 1H), 8.42 (s, 1H), 8.19 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.79 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.54 (d, J = 8.4 Hz, 1H), 6.27 (s, 1H), 3.66 (s, 2H), 3.44 (m, 2H), 3.13 (m, 2H), 2.98 (m, 2H), 2.91 (m, 2H), 2.38 (m, 2H), 2.20 (s, 3H), 1.20 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 593 (M + H)+.
A-9
##STR00680##
3-((6-(2-acetylhydra- zinyl)pyrimidin-4- yl)oxy)-N-(4-((4- ethylpiperazin-1-yl) methyl)-3-(trifluoro- methyl)phenyl)-4- methylbenzamide
1H NMR (600 MHz, DMSO) δ 10.43 (s, 1H), 9.88 (s, 1H), 9.20 (s, 1H), 8.19 (s, 1H), 8.17 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.73 (s, 1H), 7.70 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 5.99 (s, 1H), 3.56 (s, 2H), 3.32 (m, 4H), 2.29-2.48 (m, 4H), 2.32 (q, J = 7.2 Hz, 2H), 2.17 (s, 3H), 1.92 (s, 3H), 0.97 (J = 7.2 Hz, 3H). MS (ESI) m/z 572 (M + H)+.
A-10
##STR00681##
3-((6-(azetidin-3- ylamino)pyrimidin- 4-yl)oxy)-N-(4-((4- ethylpiperazin-1-yl) methyl)-3-(trifluoro- methyl)phenyl)-4- methylbenzamide
1H NMR (600 MHz, TFA salt, DMSO) δ 10.56 (s, 1H), 10.05 (s, 1H), 9.47 (br, 1H), 8.76 (s, 1H), 8.20 (s, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.93 (d, J = 8.4 Hz, 7.77 (s, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 6.35 (s, 1H), 4.60 (m, 1H), 4.38 (m, 2H), 3.68 (s, 2H), 3.57 (m, 2H), 3.46 (m, 2H), 3.12 (m, 2H), 2.98 (m, 2H), 2.92 (m, 2H), 2.39 (m, 2H), 2.21 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 570 (M + H)+.
A-11
##STR00682##
3-((6-(2,2-dimethyl- hydrazinyl)pyrimidin- 4-yl)oxy)-N-(4-((4- ethylpiperazin-1-yl) methyl)-3-(trifluoro- methyl)phenyl)-4- methylbenzamide
1H NMR (600 MHz, TFA salt, DMSO) δ 10.58 (s, 1H), 9.48 (br, 1H), 8.95 (s, 1H), 8.20 (s, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 7.95 (d, J = 7.2 Hz, 1H), 7.79 (s, 1H), 7.72 (d, J = 9.0 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 6.84 (br, 2H), 3.71 (s, 6H), 3.68 (s, 2H), 3.46 (m, 2H), 3.15 (m, 2H), 2.98 (m, 2H), 2.92 (m, 2H), 2.39 (m, 2H), 2.21 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 558 (M + H)+.
A-12
##STR00683##
N-(4-((4-ethylpiperazin- 1-yl)methyl)-3-(tri- fluoromethyl)phenyl)- 4-methyl-3-((6-((1- methyl-1H-pyrazol- 3-yl)amino)pyrimidin- 4-yl)oxy)benzamide
1H NMR (600 MHz, TFA salt, DMSO) δ 10.47 (s, 1H), 9.94 (s, 1H), 9.36 (br, 1H), 8.26 (s, 1H), 8.20 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.76 (s, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.58 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 6.16 (br, 1H), 3.75 (s, 3H), 3.68 (s, 2H), 3.45 (m, 2H), 3.14 (m, 2H), 2.99 (m, 2H), 2.94 (m, 2H), 2.37 (m, 2H), 2.19 (s, 3H), 1.19 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 595 (M + H)+.
A-13
##STR00684##
N-(4-((4-ethylpiperazin- 1-yl)methyl)-3-(tri- fluoromethyl)phenyl)- 4-methyl-3-((6- (oxetan-3-ylamino) pyrimidin-4-yl) oxy)benzamide
1H NMR (600 MHz, TFA salt, DMSO) δ 10.46 (s, 1H), 9.32 (br, 1H), 8.24 (s, 1H), 8.19 (s, 1H), 8.15 (br, 1H), 8.09 (d, J = 8.4 Hz, 1H), 8.03 (d, J = 6.6 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.72 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 7.2 Hz, 1H), 5.88 (br, 1H), 4.15 (m, 2H), 3.70 (m, 2H), 3.68 (s, 2H), 3.46 (m, 2H), 3.14 (m, 2H), 2.99 (m, 2H), 2.93 (m, 2H), 2.38 (m, 2H), 2.17 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 571 (M + H)+.
A-14
##STR00685##
N-(4-((4-ethylpiperazin- 1-yl)methyl)-3-(tri- fluoromethyl)phenyl)- 4-methyl-3-((2-((1- methyl-1H-pyrazol-4- yl)amino)pyrimidin-4- yl)oxy)benzamide
1H NMR (600 MHz, DMSO) δ 10.45 (s, 1H), 9.60 (br, 1H), 8.33 (s, 1H), 8.17 (s, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.98 (m, 1H), 7.88 (m, 1H), 7.69 (d, J = 9.0 Hz, 1H), 7.61 (m, 1H), 7.05 (m, 1H), 6.73 (m, 1H), 6.46 (m, 1H), 3.55 (s, 3H), 3.49 (br, 2H), 2.20-2.58 (m, 10H), 2.18 (s, 3H), 0.97 (t, J = 7.2 Hz, 3H), MS (ESI) m/z 595 (M + H)+.
A-15
##STR00686##
N-(4-((4-ethylpiperazin- 1-yl)methyl)-3- (trifluoromethyl) phenyl)-3-((2-(isoxazol- 4-ylamino)pyrimidin- 4-yl)oxy)-4- methylbenzamide
1H NMR (600 MHz, TFA salt, DMSO) δ 10.51 (s,1H), 9.90 (m, 1H), 9.31 (br, 1H), 8.44 (d, J = 5.4 Hz, 1H), 8.32 (m, 1H), 8.20 (s, 1H), 8.11 (d, J = 8.4 Hz, 1H), 7.97 (m, 1H), 7.87 (s, 1H), 7.71 (d, J = 8.4 Hz, 1H), 7.61 (s, 1H), 6.62 (s, 1H), 3.69 (s, 2H), 3.46 (m, 2H), 3.15 (m, 2H), 2.99 (m, 2H), 2.94 (m, 2H), 2.39 (m, 2H), 2.19 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 582 (M + H)+.
A-16
##STR00687##
N-(4-((4-ethylpiperazin- 1-yl)methyl)-3- (trifluoromethyl) phenyl)-3-((6-(isoxazol- 4-ylamino)pyrimidin- 4-yl)oxy)-4- methylbenzamide
MS (ESI) m/z 582 (M + H)+.
A-17
##STR00688##
3-((6-acrylamido- pyrimidin-4-yl)oxy)- N-(4-((4-ethyl-piperazin- 1-yl)methyl)-3-(tri- fluoromethyl)phenyl)- 4-methylbenzamide
1H NMR (600 MHz, DMSO) δ 11.16 (s, 1H), 10.37 (s, 1H), 8.46 (s, 1H), 8.11 (s, 1H), 7.97 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.73 (s, 1H), 7.68 (s, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.47 (d, J = 7.8 Hz, 1H), 6.54 (dd, J = 16.8, 10.8 Hz, 1H), 6.30 (d, J = 16.8 Hz, 1H), 5.81 (d, J = 10.8 Hz, 1H), 3.49 (s, 2H), 2.32 (m, 8H), 2.23 (q, J = 7.2 Hz, 2H), 2.11 (s, 3H), 0.91 (t, J = 7.2 Hz, 3H). MS (ESI) m/z 569 (M + H)+.
I-11
##STR00689##
3-((7H-pyrrolo[2,3-d] pyrimidin-4-yl)oxy)-N- (3-(2-cyanopropan-2-yl) phenyl)-4-methyl- benzamide
1H NMR (400 MHz, DMSO) δ 10.23 (s, 1H), 8.22 (s, 1H), 7.86 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.46 (d, J = 8.0, 1H), 7.43 (d, J = 3.2 Hz, 1H), 7.33 (dd, J = 8.0, 8.0 Hz, 1H), 7.17 (d, J = 8.0 Hz, 1H), 6.48 (d, J = 3.2 Hz, 1H), 2.10 (s, 3H), 1.61 (s, 6H). MS (ESI) m/z 412 (M + H)+.
In Vitro Activity Assays
The in vitro activity of the compounds described herein in inhibiting TAK1, HCK and other kinases were obtained using an Invitrogen Select Screening assay as known in the art. The IC50 values determined from this assay are shown below.
Cell Proliferation Analysis
CellTiter-Glo® Luminescent cell viability assay (Pro-mega) was used to assess cell survival following treatment with the compounds described. Cells were seeded into 384 well plates with the EL406 Combination Washer Dispenser (BioTek Instruments, Inc.) and the compounds were injected into the cells culture media with the JANUS Automated Workstation (PerkinElmer Inc.). Cells were treated with a series diluted inhibitors (20-0.04 μM) for 72 hours at 37° C. Luminescent measurement is performed using the 2104 Envision® Multilabel Reader (PerkinElmer Inc.).
Apoptosis Analysis for Primary Patient Bone Marrow Tumor Cells
WM cells were treated with and without the compounds described herein. Cells were incubated at 37° C. with 0.01-4 uM of the compounds described herein. Apoptosis analysis was performed using Annexin V/Propidium iodide staining with the Apoptosis Detection Kit I (BD Pharmingen). 1×106/well cells were treated in 24 well plates for ˜24 hours with inhibitors or corresponding controls. A minimum of 10,000 events were acquired using a BD™ FACSCanto II flow cytometer and analyzed with BD FACS DIVA Software.
Results
A number ofcompounds described herein show inhibitory activity against TAK1, HCK, BTK and other kinases. Shown in Table 1 and 1a are exemplary in vitro IC50 data of these compounds. Table 2 and 2a shows the in vitro EC50 values of these compounds.
TABLE 1
HCK
Com-
BTK
IC50
TAK1
GCK
pound
IC50
(nM)
IC50
IC50
Structure
ID
(nM)
Inv
(nM)
(nM)
##STR00690##
(A-1)
—
275
364
31
##STR00691##
(A-17)
3380
28
45
17
##STR00692##
(A-2)
—
253
100
28
##STR00693##
(A-3)
—
185
92
—
##STR00694##
(A-4)
—
382
591
—
##STR00695##
(I-11)
—
—
—
—
TABLE 1a
HCK
BTK
IC50
TAK1
Cpd.
IC50
(nM)
IC50
Structure
ID
(nM)
Inv
(nM)
##STR00696##
(A-5)
>10000
61.8
100
##STR00697##
(A-6)
—
38.4
63.5
##STR00698##
(A-7)
—
33.8
71.7
##STR00699##
(A-8)
—
889
487
##STR00700##
(A-9)
—
>10000
7310
##STR00701##
(A-10)
—
>10000
>10000
##STR00702##
(A-18)
—
6980
1750
##STR00703##
(A-11)
—
>10000
>10000
##STR00704##
(A-12)
—
18
76.2
##STR00705##
(A-13)
—
392
400
##STR00706##
(A-14)
—
27.4
53.8
##STR00707##
(A-15)
—
116
136
##STR00708##
(A-16)
—
—
—
TABLE 2
BCWM.1
MWCL-1
RPCIWM-1
OCI-Ly3
Ramos
OCI-Ly19
Mec1 EC50
Cpd. ID
EC50 (nM)
EC50 (nM)
EC50 (nM)
EC50 (nM)
EC50 (nM)
EC50 (nM)
(nM)
(A-1)
1720
3990
—
11500
9480
4980
—
(A-2)
42
1350
—
2960
5340
1750
—
(A-3)
50
910
—
480
2680
600
—
(A-4)
3010
1150
—
31900
21100
9430
14300
(A-17)
8
202
—
247
389
188
—
TABLE 2a
BCWM.1
MWCL-1
TMD8
OCI-Ly7
OCI-Ly3
Ramos
OCI-Ly19
Cpd. ID
EC50 (nM)
EC50 (nM)
EC50 (nM)
EC50 (nM)
EC50 (nM)
EC50 (nM)
EC50 (nM)
(A-5)
51
73
132
655
4710
3000
173
72
242
6060
417
(A-6)
86
118
—
—
4770
3080
302
(A-7)
48
71
—
—
4000
3020
192
(A-8)
980
2660
—
—
>10000
6180
1700
(A-9)
10800
18700
—
—
19600
>20000
>20000
6460
>20000
>20000
(A-10)
8250
24800
—
—
8370
>20000
>20000
>20000
>20000
>20000
(A-11)
19700
>20000
—
—
>20000
>20000
>20000
(A-12)
38
75
—
—
156
2960
209
71
71
472
(A-13)
361
1760
—
—
1200
3260
2280
964
2860
1730
(A-14)
33
128
45
173
—
2090
179
(A-15)
185
718
392
786
—
4680
307
(A-16)
610
1710
856
1030
—
1310
777
(A-18)
1980
4090
—
—
1860
7240
2780
3750
6740
5030
(I-11)
4950
1440
3460
1120
9690
3890
—
Kinome Scan
Compounds (A-2) and (A-17) were run in the Kinome Scan™ (DiscoverRx) assay to determine the inhibition against a broad panel of known kinases.
Results
Table 3 shows the KinomeScan (an active site-directed competition binding assay to measure interactions between test compounds and individual kinases) data of each compound, II-1 and I-13. Lower values indicate a greater inhibition for a given kinase by the test compound. As is shown, II-1 and I-13 inhibited several other kinases include LOK, DDR1, JNK2, ZAK, IKK-alpha, BLK, p38-alpha, ABL1, LYN, and STK36 along with the key target HCK.
TABLE 3
Kinases
A-2 (1 μM)
A-17 (1 μM)
TAOK1
0.45
0.05
LOK
0.05
0.1
TAOK3
0.45
0.1
DDR1
0.35
0.25
HCK
1.5
0.3
JNK2
0.15
0.3
ZAK
1.6
0.4
IKK-alpha
13
0.55
BLK
0.65
0.6
p38-alpha
0
0.75
ABL1-nonphosphorylated
1
0.8
LYN
3.6
0.8
STK36
1
0.9
LCK
1.6
1
FLT3
1.8
1.2
MKK7
11
1.2
MAP4K2
2.8
1.4
p38-beta
1.8
2.1
PDGFRB
5.1
2.5
CSF1R
3.2
2.6
RET(M918T)
7.4
2.8
ABL2
2.9
2.9
ABL1(E255K)-phosphorylated
3.3
3
CDC2L1
0.45
3.2
EPHA8
5.4
3.6
RET
9.9
3.6
CDC2L2
0.4
3.8
KIT(L576P)
2.2
3.9
CDK8
12
4
MAP4K4
6.4
4
KIT(V559D)
3.4
4.2
MINK
18
4.6
MAP3K3
21
4.8
TAOK2
0.15
4.8
JAK3(JH1domain-catalytic)
47
4.9
JNK1
6.8
5
KIT
5.6
5.1
FES
4.1
5.2
CDKL2
1.4
5.5
TIE1
5.5
5.5
ULK3
71
6
HPK1
30
6.2
CDK11
1.6
6.6
CDKL3
1.6
6.8
FGR
13
7.7
TNIK
20
9
CDC2L5
19
10
MST3
36
10
ABL1(M351T)-phosphorylated
6
11
DDR2
3
11
FGFR1
21
12
FLT3(N841I)
14
12
HIPK2
29
12
NLK
29
12
SRC
5.9
12
HIPK3
13
13
MAP4K5
29
14
p38-gamma
6.6
14
RSK2(Kin. Dom. 2-C-terminal)
97
15
KIT(A829P)
32
16
KIT(V559D, T670I)
11
16
OSR1
79
16
TNK1
33
16
EPHB2
69
17
YSK1
21
17
EGFR(L747-E749del, A750P)
21
18
EPHA3
32
18
FRK
19
18
MST4
38
18
PCTK1
45
18
RET(V804M)
26
18
TIE2
13
18
PCTK2
10
20
ULK1
100
20
FGFR4
32
21
BRAF(V600E)
23
22
HIPK1
32
22
EGFR(L747-S752del, P753S)
19
23
FLT3(D835Y)
23
23
JNK3
15
23
p38-delta
15
23
FLT3(D835H)
23
24
CAMK1
38
26
CTK
40
26
FLT1
38
26
MYO3A
59
26
SGK3
97
26
YES
24
27
FGFR2
34
28
NEK4
59
30
SBK1
89
31
ABL1(F317L)-phosphorylated
3.9
33
AURKA
95
33
MEK3
84
33
CAMK1D
73
34
HIPK4
14
34
ZAP70
69
35
MUSK
43
37
ASK2
65
38
EGFR(E746-A750del)
28
38
FLT4
54
38
STK39
23
38
TTK
39
38
FLT3(R834Q)
64
39
PAK3
61
39
SLK
17
39
ABL1(T315I)-phosphorylated
37
40
CDK3
58
40
CSK
69
40
PFTK1
27
40
BRAF
42
41
FER
30
42
IKK-beta
48
42
PIK3CA(Q546K)
85
42
ABL1(T315I)-nonphosphorylated
0
44
MYLK2
63
44
PRKCD
39
44
ROCK1
97
44
CDKL1
45
45
TYK2(JH1domain-catalytic)
90
45
GRK7
68
46
PLK4
78
46
ROCK2
100
46
CDK2
43
47
MAST1
59
47
ABL1(F317I)-nonphosphorylated
0
48
EIF2AK1
62
48
AURKB
77
50
MEK6
77
50
ERBB2
46
51
ERN1
58
51
RET(V804L)
62
51
RPS6KA5(Kin. Dom. 1-N-terminal)
78
51
KIT(V559D, V654A)
50
52
PCTK3
32
52
EGFR(L747-T751del, Sins)
18
53
EPHA2
40
53
EGFR(L861Q)
56
54
MAP3K15
100
54
SGK
100
54
FYN
52
55
PDGFRA
25
55
PIK3CA(C420R)
100
55
SRMS
66
55
CDK5
67
56
IRAK1
97
56
PIK3C2G
81
56
PKNB(M. tuberculosis)
100
56
QSK
69
56
YSK4
89
57
CIT
56
58
EGFR(T790M)
83
58
JAK2(JH1domain-catalytic)
74
58
MAP3K1
60
58
PIK3CA(E545A)
89
58
PIK3CG
94
58
NDR1
87
59
PFPK5(P. falciparum)
100
59
SRPK1
70
59
DYRK2
99
60
EGFR
55
60
GSK3A
40
60
ABL1(F317L)-nonphosphorylated
0
61
CLK1
85
61
PRKCQ
55
61
PAK1
96
62
STK35
80
62
ABL1(F317I)-phosphorylated
7.9
63
CAMK1G
61
64
CAMK4
100
64
CDKL5
93
64
CDK7
33
66
PLK3
100
66
PRKD1
87
66
IRAK4
99
67
PIK3CA(E545K)
88
67
EGFR(S752-I759del)
37
68
INSRR
71
68
PFTAIRE2
100
68
MYLK
100
69
PIK3CA(I800L)
83
70
SYK
21
70
AURKC
100
71
CASK
60
71
CDK9
46
71
CSNK1A1
83
71
EPHB6
92
71
PIK3CA
100
71
BMPR1B
99
72
FLT3-autoinhibited
68
72
PIK3CA(E542K)
87
72
PRKCI
65
73
ANKK1
100
74
EPHA4
64
75
EGFR(G719C)
60
76
EPHA5
86
76
JAK1(JH1domain-catalytic)
86
76
MST2
82
76
PRKCH
94
76
ARK5
96
77
CLK4
66
77
FGFR3
80
77
GAK
77
77
MEK1
100
77
MYO3B
76
77
WNK3
95
77
DCAMKL1
77
78
EPHA6
68
78
FGFR3(G697C)
81
78
KIT(D816H)
82
78
RIPK5
90
78
SNRK
68
78
ERBB4
88
79
EGFR(L858R)
83
80
IKK-epsilon
100
80
TLK1
100
80
TRKC
100
80
ERK2
100
81
PRKD2
73
81
ACVRL1
83
82
BMPR2
86
82
NEK10
100
82
PAK2
78
82
S6K1
54
82
SIK
73
82
GSK3B
83
83
HUNK
100
83
MERTK
100
83
NIK
62
83
PIP5K2B
100
83
RIOK1
100
83
VRK2
96
83
CAMK2D
92
84
PAK6
100
84
TBK1
95
84
GCN2(Kin. Dom. 2, S808G)
84
85
PKN1
100
85
SGK2
100
85
TGFBR2
100
85
WNK1
100
85
ALK
92
86
DCAMKL3
97
86
MEK2
83
86
PIM1
100
86
PRKCE
92
86
TAK1
3.2
86
YANK2
100
86
AXL
68
87
MKNK2
72
87
NEK6
91
87
PIP5K1A
100
87
ADCK3
100
88
CLK2
100
88
ERK8
100
88
PIK3CB
66
88
PIM3
93
88
RAF1
75
88
AKT1
82
89
BUB1
80
89
MAP4K3
100
89
BTK
65
90
ICK
65
90
PAK7
100
90
PIK3CD
100
90
RIOK3
83
90
BMX
79
91
CDK4-cyclinD1
94
91
SNARK
100
91
TRKA
90
91
ALK(L1196M)
90
92
LATS2
100
92
PRKG2
74
92
NEK2
98
93
TRKB
85
93
AAK1
94
94
EGFR(L858R, T790M)
80
94
ERK3
93
94
LRRK2(G2019S)
100
94
PAK4
95
94
PIK3CA(H1047L)
97
94
RIPK4
88
94
RPS6KA4(Kin. Dom. 1-N-terminal)
96
94
TESK1
81
94
CSF1R-autoinhibited
96
95
LIMK2
94
95
LRRK2
95
95
PIK3CA(M1043I)
83
95
RPS6KA4(Kin. Dom. 2-C-terminal)
100
95
TNNI3K
64
95
HASPIN
84
96
MAP3K4
80
96
PRP4
94
96
YANK1
73
96
ABL1(Y253F)-phosphorylated
4.8
97
EGFR(G719S)
65
97
MLK1
91
97
NEK1
93
97
PIK4CB
98
97
BIKE
92
98
RSK2(Kin. Dom. 1-N-terminal)
100
98
SRPK2
100
98
STK16
100
98
AMPK-alpha2
95
99
CAMKK2
79
99
EPHB4
87
99
RSK4(Kin. Dom. 1-N-terminal)
92
99
ABL1(Q252H)-phosphorylated
11
100
ACVR1
100
100
ACVR1B
100
100
ACVR2A
100
100
ACVR2B
95
100
ADCK4
100
100
AKT2
90
100
AKT3
100
100
ALK(C1156Y)
49
100
AMPK-alpha1
85
100
ASK1
96
100
BMPR1A
100
100
BRK
100
100
BRSK1
100
100
BRSK2
100
100
CAMK2A
92
100
CAMK2B
100
100
CAMK2G
86
100
CAMKK1
100
100
CDK4-cyclinD3
100
100
CHEK1
100
100
CHEK2
100
100
CLK3
100
100
CSNK1A1L
99
100
CSNK1D
100
100
CSNK1E
100
100
CSNK1G1
100
100
CSNK1G2
100
100
CSNK1G3
93
100
CSNK2A1
100
100
CSNK2A2
100
100
DAPK1
100
100
DAPK2
93
100
DAPK3
100
100
DCAMKL2
74
100
DLK
100
100
DMPK
100
100
DMPK2
88
100
DRAK1
100
100
DRAK2
85
100
DYRK1A
92
100
DYRK1B
77
100
EPHA1
90
100
EPHA7
75
100
EPHB1
78
100
EPHB3
100
100
ERBB3
100
100
ERK1
100
100
ERK4
96
100
ERK5
98
100
FAK
100
100
GRK1
77
100
GRK4
100
100
IGF1R
100
100
INSR
100
100
IRAK3
100
100
ITK
95
100
JAK1(JH2domain-pseudokinase)
90
100
KIT(D816V)
96
100
KIT-autoinhibited
65
100
LATS1
100
100
LIMK1
100
100
LKB1
100
100
LTK
100
100
LZK
100
100
MAK
93
100
MAP3K2
90
100
MAPKAPK2
100
100
MAPKAPK5
94
100
MARK1
83
100
MARK2
100
100
MARK3
94
100
MARK4
92
100
MEK4
82
100
MEK5
37
100
MELK
89
100
MET
100
100
MET(M1250T)
89
100
MET(Y1235D)
100
100
MKNK1
94
100
MLCK
100
100
MLK2
100
100
MLK3
62
100
MRCKA
100
100
MRCKB
100
100
MST1
80
100
MST1R
100
100
MTOR
86
100
MYLK4
100
100
NDR2
100
100
NEK11
100
100
NEK3
65
100
NEK5
85
100
NEK7
100
100
NEK9
100
100
NIM1
100
100
PDPK1
69
100
PHKG1
100
100
PHKG2
100
100
PIK3C2B
100
100
PIK3CA(H1047Y)
79
100
PIM2
71
100
PIP5K1C
50
100
PIP5K2C
82
100
PKAC-alpha
72
100
PKAC-beta
100
100
PKMYT1
100
100
PKN2
89
100
PLK1
100
100
PLK2
100
100
PRKD3
100
100
PRKG1
100
100
PRKR
100
100
PRKX
100
100
PYK2
97
100
RIOK2
100
100
RIPK1
54
100
RIPK2
86
100
ROS1
75
100
RPS6KA5(Kin. Dom. 2-C-terminal)
100
100
RSK1(Kin. Dom. 1-N-terminal)
100
100
RSK1(Kin. Dom. 2-C-terminal)
100
100
RSK3(Kin. Dom. 1-N-terminal)
100
100
RSK3(Kin. Dom. 2-C-terminal)
100
100
RSK4(Kin. Dom. 2-C-terminal)
100
100
SgK110
100
100
SIK2
100
100
SRPK3
100
100
STK33
97
100
TEC
82
100
TGFBR1
100
100
TLK2
100
100
TNK2
100
100
TRPM6
58
100
TSSK1B
83
100
TXK
89
100
TYK2(JH2domain-pseudokinase)
87
100
TYRO3
92
100
ULK2
81
100
VEGFR2
28
100
WEE1
100
100
WEE2
100
100
YANK3
88
100
Kinative
The kinase selectivity of compounds (A-5) and (A-14) were evaluated using a chemical proteomic approach named KiNativ which detects 260 kinases in A375 cells (ActivX Biosciences). To probe the intracellular targets of the compounds, A375 cells were incubated with the inhibitor at 1 μM final concentration and then looked for protection of labeling by an ATP-biotin probe that non-specifically labels conserved lysines on kinases and other nucleotide-dependent enzymes.
Results
Table 4 shows that compound (A-5) inhibits a number of kinases at 1 μM, including Ab1 (>90%), FYN (71.2%), LYN (87.8%), and ZAK (75.7%). Table 5 shows that compound (A-14) inhibits a number of kinases at 1 μM, including Ab1 (>90%), FYN (88.2%), LYN (85.7%), and ZAK (75.8%).
TABLE 4
SEQ
Compound
ID
Labeling
A-4
Kinase
Reference
Sequence
NO:
Site
(1.0 μM)
ABL, ARG
UniRef100_P00519,
LMTGDTYTAHAGAKFPIK
1
Activation
95.5
UniRef100_P42684
Loop
ACK
UniRef100_Q07912
TVSVAVKCLKPDVLSQPEA
2
Lys1
4.9
MDDFIR
AGK
UniRef100_Q53H12
ATVFLNPAACKGK
3
ATP
−31.4
AMPKa1,
UniRef100_P54646,
DLKPENVLLDAHMNAK
4
Lys2
16.3
AMPKa2
UniRef100_Q13131
ARAF
UniRef100_P10398
DLKSNNIFLHEGLTVK
5
Lys2
12.2
ATR
UniRef100_Q13535
FYIMMCKPK
6
ATP
23.0
AurA
UniRef100_O14965
FILALKVLFK
7
Lys1
−16.0
AurB
UniRef100_Q96GD4
SHFIVALKVLFK
8
Lys1
−51.1
BARK1
UniRef100_P25098
DLKPANILLDEHGHVR
9
Lys2
−13.4
BRAF
UniRef100_P15056
DLKSNNIFLHEDLTVK
10
Lys2
18.9
BTK
UniRef100_Q06187
YVLDDEYTSSVGSKFPVR
11
Activation
−18.8
Loop
CaMK1a
UniRef100_Q14012
LVAIKCIAK
12
Lys1
12.4
CaMK1d
UniRef100_Q8IU85
LFAVKCIPK
13
Lys1
−6.0
CaMK2d
UniRef100_Q13557
IPTGQEYAAKIINTKK
14
Lys1
−8.1
CaMK2g
UniRef100_Q13555
TSTQEYAAKIINTK
15
Lys1
−23.1
CaMK4
UniRef100_Q16566
DLKPENLLYATPAPDAPLK
16
Lys2
5.9
CaMKK2
UniRef100_Q96RR4
DIKPSNLLVGEDGHIK
17
Lys2
6.2
CASK
UniRef100_O14936,
ETGQQFAVKIVDVAK
18
Lys1
−28.1
UniRef100_C9JGY0
CDC2
UniRef100_P06493
DLKPQNLLIDDKGTIK
19
Lys2
−2.3
CDK11,
UniRef100_P49336,
DLKPANILVMGEGPER
20
Lys2
50.0
CDK8
UniRef100_Q9BWU1
CDK2
UniRef100_P24941
DLKPQNLLINTEGAIK
21
Lys2
−3.5
CDK4
UniRef100_P11802
DLKPENILVTSGGTVK
22
Lys2
17.4
CDK5
UniRef100_Q00535
DLKPQNLLINR
23
Lys2
−27.3
CDK6
UniRef100_Q00534
DLKPQNILVTSSGQIK
24
Lys2
13.1
CDK7
UniRef100_P50613
DLKPNNLLLDENGVLK
25
Lys2
3.9
CDK9
UniRef100_P50750
DMKAANVLITR
26
Lys2
−16.2
CHK1
UniRef100_B5BTY6,
DIKPENLLLDER
27
Lys2
−5.0
UniRef100_O14757
CHK2
UniRef100_O96017
DLKPENVLLSSQEEDCLIK
28
Lys2
−7.8
CK1a
UniRef100_P48729,
DIKPDNFLMGIGR
29
Lys2
−0.6
UniRef100_B4E1D9
CK1g2
UniRef100_P78368
DVKPENFLVGRPGTK
30
Lys2
−9.1
CK2a2
UniRef100_P19784
DVKPHNVMIDHQQK
31
Lys2
−18.2
CLK3
UniRef100_P49761
YEIVGNLGEGTFGKVVECL
32
ATP Loop
−52.8
DHAR
CSK
UniRef100_P41240
VSDFGLTKEASSTQDTGKL
33
Activation
15.3
PVK
Loop
DGKA
UniRef100_P23743
IDPVPNTHPLLVFVNPKSG
34
ATP
−4.8
GK
DGKH
UniRef100_Q86XP1
ATFSFCVSPLLVFVNSKSG
35
ATP
−6.3
DNQGVK
DGKQ
UniRef100_P52824
GRLLTALVLPDLLHAKLPP
36
ATP
11.0
DSCPLLVFVNPKSGGLK
DNAPK
UniRef100_P78527
KGGSWIQEINVAEK
37
ATP
−61.5
DNAPK
UniRef100_P78527
EHPFLVKGGEDLR
38
ATP
−64.6
eEF2K
UniRef100_O00418
YIKYNSNSGFVR
39
ATP
−30.5
EphB1
UniRef100_P54762
YLQDDTSDPTYTSSLGGKI
40
Activation
−1.7
PVR
Loop
EphB2
UniRef100_P29323
FLEDDTSDPTYTSALGGKI
41
Activation
−12.8
PIR
Loop
Erk1
UniRef100_P27361
DLKPSNLLINTTCDLK
42
Lys2
−9.0
Erk2
UniRef100_P28482
DLKPSNLLLNTTCDLK
43
Lys2
−3.8
Erk5
UniRef100_Q13164
DLKPSNLLVNENCELK
44
Lys2
25.9
FER
UniRef100_P16591
TSVAVKTCKEDLPQELK
45
Lys1
91.4
FES
UniRef100_P07332
LRADNTLVAVKSCR
46
Lys1
89.1
FGR
UniRef100_P09769
LIKDDEYNPCQGSKFPIK
47
Activation
31.9
Loop
FRAP
UniRef100_P42345
IQSIAPSLQVITSKQRPR
48
ATP
−7.5
FRK
UniRef100_P42685
HEIKLPVK
49
Activation
91.1
Loop
FYN, SRC,
UniRef100_P12931,
QGAKFPIKWTAPEAALYG
50
Activation
71.2
YES
UniRef100_P07947,
R
Loop
UniRef100_P06241
GCK
UniRef100_Q12851
DIKGANLLLTLQGDVK
51
Lys2
94.9
GCN2
UniRef100_Q9P2K8
DLKPVNIFLDSDDHVK
52
Lys2
20.8
GSK3A
UniRef100_P49840
DIKPQNLLVDPDTAVLK
53
Lys2
36.0
GSK3B
UniRef100_P49841
DIKPQNLLLDPDTAVLK
54
Lys2
0.5
HPK1
UniRef100_Q92918
DIKGANILINDAGEVR
55
Lys2
68.1
IKKa
UniRef100_O15111
DLKPENIVLQDVGGK
56
Lys2
−17.0
IKKb
UniRef100_O14920
DLKPENIVLQQGEQR
57
Lys2
−12.6
IKKe
UniRef100_Q14164
SGELVAVKVFNTTSYLRPR
58
Lys1
−9.9
ILK
UniRef100_Q13418
WQGNDIVVKVLK
59
Lys1
5.2
IRAK1
UniRef100_P51617
AIQFLHQDSPSLIHGDIKSS
60
Lys2
−3.5
NVLLDER
IRAK4
UniRef100_Q9NWZ3
DIKSANILLDEAFTAK
61
Lys2
1.9
IRE1
UniRef100_O75460
DLKPHNILISMPNAHGK
62
Lys2
−2.2
ITPK1
UniRef100_Q13572
ESIFFNSHNVSKPESSSVLT
63
ATP
1.2
ELDKIEGVFERPSDEVIR
JAK1
UniRef100_P23458
QLASALSYLEDKDLVHGN
64
Protein
4.3
VCTKNLLLAR
Kinase
Domain
JAK1
UniRef100_P23458
IGDFGLTKAIETDKEYYTVK
65
Activation
−6.2
domain2
Loop
JAK3
UniRef100_P52333
IADFGLAKLLPLDKDYYVV
66
Activation
7.7
domain2
R
Loop
JNK1,
UniRef100_P45983,
DLKPSNIVVK
67
Lys2
77.2
JNK2,
UniRef100_P53779,
JNK3
UniRef100_P45984
KHS1
UniRef100_Q9Y4K4
NVHTGELAAVKIIK
68
Lys1
15.8
KSR1
UniRef100_Q8IVT5
SKNVFYDNGKVVITDFGLF
69
Activation
−22.0
GISGVVR
Loop
KSR1,
UniRef100_Q6VAB6,
SKNVFYDNGK
70
Activation
−10.0
KSR2
UniRef100_Q8IVT5
Loop
LATS1
UniRef100_095835
ALYATKTLR
71
Lys1
5.4
LATS2
UniRef100_Q9NRM7
DIKPDNILIDLDGHIK
72
Lys2
−1.9
LCK
UniRef100_P06239
EGAKFPIKWTAPEAINYGT
73
Activation
92.3
FTIK
Loop
LKB1
UniRef100_Q15831
DIKPGNLLLTTGGTLK
74
Lys2
−6.0
LOK
UniRef100_O94804
DLKAGNVLMTLEGDIR
75
Lys2
19.9
LRRK2
UniRef100_Q5S007
DLKPHNVLLLYPNAAIIA
76
Lys2
−15.9
K
LYN
UniRef100_P07948
VAVKTLKPGTMSVQAFLE
77
Lys1
87.8
EANLMK
MAP2K1
UniRef100_Q02750
IMHRDVKPSNILVNSR
78
Lys2
11.4
MAP2K1,
UniRef100_P36507,
DVKPSNILVNSR
79
Lys2
−16.3
MAP2K2
UniRef100_Q02750
MAP2K3
UniRef100_P46734
DVKPSNVLINK
80
Lys2
−1.0
MAP2K4
UniRef100_P45985
DIKPSNILLDR
81
Lys2
−14.1
MAP2K5
UniRef100_Q13163
DVKPSNMLVNTR
82
Lys2
20.5
MAP2K6
UniRef100_P52564
DVKPSNVLINALGQVK
83
Lys2
0.5
MAP2K7
UniRef100_O14733
DVKPSNILLDER
84
Lys2
−38.2
MAP3K1
UniRef100_Q13233
DVKGANLLIDSTGQR
85
Lys2
26.9
MAP3K2
UniRef100_Q9Y2U5
ELAVKQVQFDPDSPETSK
86
Lys1
4.2
EVNALECEIQLLK
MAP3K2,
UniRef100_Q9Y2U5,
DIKGANILR
87
Lys2
3.2
MAP3K3
UniRef100_Q99759
MAP3K3
UniRef100_Q99759
ELASKQVQFDPDSPETSKE
88
Lys1
3.7
VSALECEIQLLK
MAP3K4
UniRef100_Q9Y6R4
DIKGANIFLTSSGLIK
89
Lys2
19.2
MAP3K5
UniRef100_Q99683
DIKGDNVLINTYSGVLK
90
Lys2
−30.4
MAP3K6
UniRef100_O95382
DIKGDNVLINTFSGLLK
91
Lys2
−25.0
MARK2,
UniRef100_P27448,
DLKAENLLLDADMNIK
92
Lys2
4.6
MARK3
UniRef100_Q7KZI7
MARK3
UniRef100_P27448
EVAIKIIDKTQLNPTSLQK
93
Lys1
−26.1
MARK3,
UniRef100_Q96L34,
EVAIKIIDK
94
Lys1
−16.2
MARK4
UniRef100_P27448
MARK4
UniRef100_Q96L34
DLKAENLLLDAEANIK
95
Lys2
2.9
MAST1,
UniRef100_Q6P0Q8,
DLKPDNLLITSMGHIK
96
Lys2
35.6
MAST2
UniRef100_Q9Y2H9
MAST3
UniRef100_O60307
DLKPDNLLITSLGHIK
97
Lys2
−8.1
MASTL
UniRef100_Q96GX5
GAFGKVYLGQK
98
ATP Loop
12.8
MASTL
UniRef100_Q96GX5
LYAVKVVK
99
Lys1
3.3
MELK
UniRef100_Q14680
DLKPENLLFDEYHK
100
Lys2
−19.6
MER
UniRef100_Q12866
NCMLRDDMTVCVADFGL
101
Activation
49.8
SKK
Loop
MER,
UniRef100_Q06418,
KIYSGDYYR
102
Activation
1.6
TYRO3
UniRef100_Q12866
Loop
MET
UniRef100_P08581
DMYDKEYYSVHNK
103
Activation
−21.0
Loop
MLK3
UniRef100_Q16584
DLKSNNILLLQPIESDDME
104
Lys2
20.7
HK
MLK4
UniRef100_Q5TCX8
DLKSSNILLLEK
105
Lys2
−1.7
MLKL
UniRef100_Q8NB16
APVAIKVFK
106
Lys1
−14.9
MPSK1
UniRef100_O75716
DLKPTNILLGDEGQPVLM
107
Lys2
16.1
DLGSMNQACIHVEGSR
MSK1
UniRef100_O75582
DIKLENILLDSNGHVVLTD
108
Lys2
5.7
domain1
FGLSK
MSK2
UniRef100_O75676
DLKLENVLLDSEGHIVLTD
109
Lys2
−64.9
domain1
FGLSK
MST1
UniRef100_Q13043
ETGQIVAIKQVPVESDLQE
110
Lys1
−4.7
IIK
MST2
UniRef100_Q13188
ESGQVVAIKQVPVESDLQ
111
Lys1
−6.2
EIIK
MST3
UniRef100_Q9Y6E0
DIKAANVLLSEHGEVK
112
Lys2
−3.7
MST4
UniRef100_Q9P289
TQQVVAIKIIDLEEAEDEIE
113
Lys1
6.2
DIQQEITVLSQCDSSYVTK
MST4,
UniRef100_000506,
DIKAANVLLSEQGDVK
114
Lys2
4.6
YSK1
UniRef100_Q9P289
MYO3A,
UniRef100_Q8NEV4,
DVKGNNILLTTEGGVK
115
Lys2
−15.3
MYO3B
UniRef100_Q8WXR4
NDR1
UniRef100_Q15208
DIKPDNLLLDSK
116
Lys2
9.3
NDR2
UniRef100_Q9Y2H1
DIKPDNLLLDAK
117
Lys2
−10.9
NEK1
UniRef100_Q96PY6
DIKSQNIFLTK
118
Lys2
−3.0
NEK2
UniRef100_P51955
DLKPANVFLDGK
119
Lys2
−22.7
NEK3
UniRef100_P51956
SKNIFLTQNGK
120
Activation
13.1
Loop
NEK4
UniRef100_P51957
DLKTQNVFLTR
121
Lys2
1.5
NEK6,
UniRef100_Q8TDX7,
DIKPANVFITATGVVK
122
Lys2
−12.5
NEK7
UniRef100_Q9HC98
NEK7
UniRef100_Q8TDX7
AACLLDGVPVALKK
123
Lys1
−7.2
NEK8
UniRef100_Q86SG6
DLKTQNILLDK
124
Lys2
−11.4
NEK9
UniRef100_Q8TD19
DIKTLNIFLTK
125
Lys2
−1.2
OSR1
UniRef100_C9JIG9,
DVKAGNILLGEDGSVQIA
126
Lys2
−11.1
UniRef100_O95747
DFGVSAFLATGGDITR
p38a
UniRef100_Q16539
DLKPSNLAVNEDCELK
127
Lys2
61.4
p38a
UniRef100_Q16539
QELNKTIWEVPER
128
Protein
92.2
Kinase
Domain
p38b
UniRef100_015759
QELNKTVWEVPQR
129
Protein
51.4
Kinase
Domain
p38d,
UniRef100_O15264,
DLKPGNLAVNEDCELK
130
Lys2
62.5
p38g
UniRef100_P53778
70SEK
UniRef100_P23443
DLKPENIMLNHQGHVK
131
Lys2
−2.3
p70S6Kb
UniRef100_Q9UBS0
DLKPENIMLSSQGHIK
132
Lys2
8.2
PAN3
UniRef100_Q58A45
VMDPTKILITGK
133
ATP
12.1
PCTAIRE1
UniRef100_Q00536
SKLTDNLVALKEIR
134
Lys1
−3.5
PCTAIRE2,
UniRef100_Q00537,
SKLTENLVALKEIR
135
Lys1
11.7
PCTAIRE3
UniRef100_Q07002
PDK1
UniRef100_O15530
EYAIKILEK
136
Lys1
18.8
PEK
UniRef100_Q9N2J5
DLKPSNIFFTMDDVVK
137
Lys2
9.4
PFTAIRE1
UniRef100_O94921
LVALKVIR
138
Lys1
4.3
PHKg1
UniRef100_Q16816
DLKPENILLDDNMNIK
139
Protein
−49.0
Kinase
Domain
PHKg2
UniRef100_P15735
ATGHEFAVKIMEVTAER
140
Lys1
15.2
PI4KA,
UniRef100_A4QPH2,
SGTPMQSAAKAPYLAK
141
ATP
19.3
PI4KAP2
UniRef100_P42356
PI4KB
UniRef100_Q9UBF8
VPHTQAVVLNSKDK
142
ATP
−0.2
PIK3C2B
UniRef100_O00750
VIFKCGDDLRQDMLTLQ
143
ATP
24.0
MIR
PIK3C3
UniRef100_Q8NEB9
TEDGGKYPVIFKHGDDLR
144
ATP
−5.1
PIK3CB
UniRef100_Q9BTS4,
VFGEDSVGVIFKNGDDLR
145
ATP
27.8
UniRef100_P42338
QDMLTLQMLR
PIK3CD
UniRef100_O00329
VNWLAHNVSKDNRQ
146
ATP
2.2
PIK3CG
UniRef100_P48736
KKPLWLEFK
147
ATP
−21.1
PIP4K2A
UniRef100_P48426
AKELPTLKDNDFINEGQK
148
ATP
−26.7
PIP4K2B
UniRef100_P78356
AKDLPTFKDNDFLNEGQK
149
ATP
−44.7
PIP4K2C
UniRef100_Q8TBX8
TLVIKEVSSEDIADMHSNL
150
ATP
5.2
SNYHQYIVK
PIP5K3
UniRef100_Q9Y217
GGKSGAAFYATEDDRFILK
151
ATP
0.9
PITSLRE
UniRef100_P21127
DLKTSNLLLSHAGILK
152
Lys2
−10.4
PKCa,
UniRef100_P17252,
DLKLDNVMLDSEGHIK
153
Lys2
2.3
PKCb
UniRef100_P05771,
UniRef100_B5BU22
PKD2
UniRef100_Q9BZL6
DVAVKVIDK
154
Lys1
−6.9
PKN1
UniRef100_Q16512
VLLSEFRPSGELFAIKALK
155
Lys1
−32.1
PKR
UniRef100_P19525
DLKPSNIFLVDTK
156
Lys2
−28.4
PLK1
UniRef100_P53350
CFEISDADTEVFAGKIVP
157
Lys1
−9.1
K
PRP4
UniRef100_Q13523
CNILHADIKPDNILVNESK
158
Lys2
−20.1
PRPK
UniRef100_Q96S44
FLSGLELVKQGAEAR
159
ATP Loop
−13.7
PYK2
UniRef100_Q14289
YIEDEDYYKASVTR
160
Activation
10.9
Loop
RAF1
UniRef100_P04049
DMKSNNIFLHEGLTVK
161
Lys2
36.6
RIPK3
UniRef100_Q9Y572
DLKPSNVLLDPELHVK
162
Lys2
32.6
ROCK1,
UniRef100_O75116,
DVKPDNMLLDK
163
Lys2
22.0
ROCK2
UniRef100_Q13464
RSK1
UniRef100_Q15418
DLKPENILLDEEGHIKLTDF
164
Lys2
−20.9
domain1
GLSKEAIDHEK
RSK1
UniRef100_Q15418,
DLKPENILLDEEGHIK
165
Lys2
−17.7
domain1,
UniRef100_P51812,
RSK2
UniRef100_Q15349
domain1,
RSK3
domain1
RSK1
UniRef100_Q15418
DLKPSNILYVDESGNPECL
166
Lys2
−16.3
domain1
R
RSK2
UniRef100_P51812
DLKPENILLDEEGHIKLTDF
167
Lys2
−3.3
domain1
GLSKESIDHEK
RSK2
UniRef100_P51812
DLKPSNILYVDESGNPESIR
168
Lys2
−24.1
domain2
RSK3
UniRef100_015349
DLKPENILLDEEGHIKITDF
169
Lys2
−32.6
domain1
GLSK
RSK4
UniRef100_Q9UK32
DLKPENILLDEIGHIK
170
Lys2
27.6
domain1
RSKL1
UniRef100_Q96S38
VLGVIDKVLLVMDTR
171
ATP
31.5
SGK3
UniRef100_Q96BR1
FYAVKVLQK
172
Lys1
−10.2
SLK
UniRef100_Q9H2G2
DLKAGNILFTLDGDIK
173
Lys2
−14.3
SMG1
UniRef100_Q96Q15
DTVTIHSVTITILPTKTK
174
ATP
−4.0
PK
SNRK
UniRef100_Q9NRH2
DLKPENVVFFEK
175
Lys2
18.0
SRC
UniRef100_P12931
VAIKTLKPGTMSPEAFLQE
176
Lys1
76.1
AQVMKK
SRPK1
UniRef100_Q96SB4
IIHTDIKPENILLSVNEQYIR
177
Lys2
−34.1
STK33
UniRef100_Q9BYT3
DLKLENIMVK
178
Lys2
12.9
STLK5
UniRef100_Q7RTN6
YSVKVLPWLSPEVLQQNL
179
Activation
5.0
QGYDAK
Loop
SYK
UniRef100_P43405
ISDFGLSKALR
180
Activation
17.4
Loop
TAK1
UniRef100_043318
DLKPPNLLLVAGGTVLK
181
Lys2
32.0
TAO1,
UniRef100_Q9H2K8,
DIKAGNILLTEPGQVK
182
Lys2
76.5
TAO3
UniRef100_Q7L7X3
TAO2
UniRef100_Q9UL54
DVKAGNILLSEPGLVK
183
Lys2
86.0
TBK1
UniRef100_Q9UHD2
TGDLFAIKVFNNISFLRPV
184
Lys1
18.2
DVQMR
TEC
UniRef100_P42680
YVLDDQYTSSSGAKFPVK
185
Activation
−12.8
Loop
TLK1
UniRef100_Q9UKI8
YLNEIKPPIIHYDLKPGNILL
186
Lys2
4.9
VDGTACG
TLK2
UniRef100_Q86UE8
YLNEIKPPIIHYDLKPGNILL
187
Lys2
7.1
VNGTACGEIK
TYK2
UniRef100_P29597
IGDFGLAKAVPEGHEYYR
188
Activation
−18.1
domain2
Loop
ULK1
UniRef100_075385
DLKPQNILLSNPAGR
189
Lys2
−6.0
ULK3
UniRef100_D3DW67,
NISHLDLKPQNILLSSLEKP
190
Lys2
−4.4
UniRef100_Q6PHR2
HLK
VRK2
UniRef100_Q86Y07
MLDVLEYIHENEYVHGDIK
191
Lys2
27.9
AANLLLGYK
Wee1
UniRef100_P30291
YIHSMSLVHDIKPSNIFIS
192
Lys2
23.2
R
Wnk1,
UniRef100_Q9Y3S1,
GSFKTVYK
193
ATP Loop
24.2
Wnk2
UniRef100_D3DUP1,
UniRef100_Q9H4A3
Wnk1,
UniRef100_Q9Y3S1,
DLKCDNIFITGPTGSVK
194
Lys2
0.2
Wnk2,
UniRef100_D3DUP1,
Wnk3
UniRef100_Q9BYP7,
UniRef100_Q9H4A3
YANK3
UniRef100_Q86UX6
DVKPDNILLDER
195
Lys2
27.7
ZAK
UniRef100_Q9NYL2
WISQDKEVAVKK
196
Lys1
75.7
ZAP70
UniRef100_P43403
ISDFGLSKALGADDSYYTA
197
Activation
49.2
R
Loop
ZC1/HGK,
UniRef100_O95819,
DIKGQNVLLTENAEVK
198
Lys2
19.2
ZC2/TNIK,
UniRef100_Q9UKE5,
ZC3/MINK
UniRef100_Q8N4C8
ZC2/TNIK
UniRef100_Q9UKE5
TGQLAAIKVMDVTGDEEE
199
Lys1
23.9
EIKQEINMLKK
TABLE 5
SEQ
Cmpd.
ID
Labeling
A-14
Kinase
Reference
Sequence
NO:
Site
(1.0 μM)
ABL, ARG
UniRef100_P00519,
LMTGDTYTAHAGAKFPIK
200
Activation
98.4
UniRef100_P42684
Loop
ACK
UniRef100_Q07912
TVSVAVKCLKPDVLSQPEA
201
Lys1
8.5
MDDFIR
AGK
UniRef100_Q53H12
ATVFLNPAACKGK
202
ATP
5.9
AKT1
UniRef100_P31749
GTFGKVILVK
203
ATP Loop
−23.9
AKT2,
UniRef100_Q9Y243,
GTFGKVILVR
204
ATP Loop
−19.7
AKT3
UniRef100_P31751
AMPKa1,
UniRef100_P54646,
DLKPENVLLDAHMNAK
205
Lys2
−17.5
AMPKa2
UniRef100_Q96E92
ANPa
UniRef100_P16066
GMLFLHNGAICSHGNLKS
206
Lys2
−5.3
SNCVVDGR
ARAF
UniRef100_P10398
DLKSNNIFLHEGLTVK
207
Lys2
2.0
ATR
UniRef100_Q13535
FYIMMCKPK
208
ATP
−20.3
AurA
UniRef100_O14965
FILALKVLFK
209
Lys1
14.6
AurA
UniRef100_O14965
DIKPENLLLGSAGELK
210
Lys2
6.1
AurA,
UniRef100_O14965,
GKFGNVYLAR
211
ATP Loop
−2.4
AurB,
UniRef100_Q9UQB9,
AurC
UniRef100_Q96GD4
AurB
UniRef100_Q96GD4
SHFIVALKVLFK
212
Lys1
3.3
BARK1
UniRef100_P25098
DLKPANILLDEHGHVR
213
Lys2
−13.6
BRAF
UniRef100_P15056
DLKSNNIFLHEDLTVK
214
Lys2
18.9
BTK
UniRef100_006187
YVLDDEYTSSVGSKFPVR
215
Activation
−10.2
Loop
CaMK1a
UniRef100_Q14012
LVAIKCIAK
216
Lys1
−5.4
CaMK1d
UniRef100_Q8IU85
LFAVKCIPK
217
Lys1
−1.8
CaMK2d
UniRef100_Q13557
IPTGQEYAAKIINTKK
218
Lys1
−7.3
CaMK2g
UniRef100_Q13555
TSTQEYAAKIINTK
219
Lys1
2.0
CaMK4
UniRef100_Q16566
DLKPENLLYATPAPDAPLK
220
Lys2
−2.0
CaMKK2
UniRef100_Q96RR4
DIKPSNLLVGEDGHIK
221
Lys2
16.2
CASK
UniRef100_014936
ETGQQFAVKIVDVAK
222
Lys1
7.1
CDC2
UniRef100_Q5H9N4
DLKPQNLLIDDKGTIK
223
Lys2
9.0
CDK11,
UniRef100_P49336,
DLKPANILVMGEGPER
224
Lys2
49.2
CDK8
UniRef100_Q9BWU1
CDK2
UniRef100_P24941
DLKPQNLLINTEGAIK
225
Lys2
34.5
CDK4
UniRef100_P11802
DLKPENILVTSGGTVK
226
Lys2
11.4
CDKS
UniRef100_Q00535
DLKPQNLLINR
227
Lys2
11.3
CDK6
UniRef100_Q00534
DLKPQNILVTSSGQIK
228
Lys2
13.6
CDK7
UniRef100_P50613
DLKPNNLLLDENGVLK
229
Lys2
−7.3
CDK9
UniRef100_P50750
DMKAANVLITR
230
Lys2
−13.1
CHK1
UniRef100_B4DT73
DIKPENLLLDER
231
Lys2
12.2
CHK2
UniRef100_O96017
DLKPENVLLSSQEEDCLIK
232
Lys2
−1.6
CK1a
UniRef100_P48729
DIKPDNFLMGIGR
233
Lys2
−19.6
CK1d,
UniRef100_P49674,
DVKPDNFLMGLGKK
234
Lys2
−9.3
CK1e
UniRef100_P48730
CK1g1,
UniRef100_Q9Y6M4,
KIGCGNFGELR
235
ATP Loop
1.3
CK1g2,
UniRef100_P78368,
CK1g3
UniRef100_Q9HCP0
CK1g2
UniRef100_P78368
DVKPENFLVGRPGTK
236
Lys2
−23.3
CLK2
UniRef100_P49760
LTHTDLKPENILFVNSDYEL
237
Lys2
−30.3
TYNLEK
CLK3
UniRef100_P49761
YEIVGNLGEGTFGKVVECL
238
ATP Loop
−4.0
DHAR
CSK
UniRef100_P41240
VSDFGLTKEASSTQDTGKL
239
Activation
20.0
PVK
Loop
DGKA
UniRef100_P23743
IDPVPNTHPLLVFVNPKSG
240
ATP
−16.3
GK
DGKH
UniRef100_Q86XP1
ATFSFCVSPLLVFVNSKSG
241
ATP
32.6
DNQGVK
DGKQ
UniRef100_P52824
GRLLTALVLPDLLHAKLPP
242
ATP
−23.2
DSCPLLVFVNPKSGGLK
DNAPK
UniRef100_P78527
KGGSWIQEINVAEK
243
ATP
−35.9
DNAPK
UniRef100_P78527
EHPFLVKGGEDLR
244
ATP
−63.7
eEF2K
UniRef100_O00418
YIKYNSNSGFVR
245
ATP
−22.0
Erk1
UniRef100_P27361
DLKPSNLLINTTCDLK
246
Lys2
−16.3
Erk2
UniRef100_P28482
DLKPSNLLLNTTCDLK
247
Lys2
−2.7
Erk3
UniRef100_Q16659
DLKPANLFINTEDLVLK
248
Lys2
31.8
ErkS
UniRef100_Q13164
DLKPSNLLVNENCELK
249
Lys2
−42.7
FER
UniRef100_P16591
TSVAVKTCKEDLPQELK
250
Lys1
74.0
FES
UniRef100_P07332
LRADNTLVAVKSCR
251
Lys1
36.1
FGR
UniRef100_P09769
LIKDDEYNPCQGSKFPIK
252
Activation
70.3
Loop
FRAP
UniRef100_P42345
IQSIAPSLQVITSKQRPR
253
ATP
−3.3
FRK
UniRef100_P42685
HEIKLPVK
254
Activation
98.0
Loop
FYN, SRC,
UniRef100_P12931,
QGAKFPIKWTAPEAALYG
255
Activation
88.2
YES
UniRef100_P07947,
R
Loop
UniRef100_P06241
GCK
UniRef100_Q12851
DIKGANLLLTLQGDVK
256
Lys2
96.3
GCN2
UniRef100_Q9P2K8
DLKPVNIFLDSDDHVK
257
Lys2
5.4
GPRK6
UniRef100_P43250
DLKPENILLDDHGHIR
258
Lys2
−1.9
GSK3A
UniRef100_P49840
DIKPQNLLVDPDTAVLK
259
Lys2
25.5
GSK3B
UniRef100_P49841
DIKPQNLLLDPDTAVLK
260
Lys2
−3.5
HPK1
UniRef100_Q92918
DIKGANILINDAGEVR
261
Lys2
88.2
IKKa
UniRef100_O15111
DLKPENIVLQDVGGK
262
Lys2
−3.1
IKKb
UniRef100_O14920
DLKPENIVLQQGEQR
263
Lys2
−12.2
IKKe
UniRef100_Q14164
SGELVAVKVFNTTSYLRPR
264
Lys1
−3.9
ILK
UniRef100_Q13418
WQGNDIVVKVLK
265
Lys1
−0.4
ILK
UniRef100_Q13418
ISMADVKFSFQCPGR
266
Protein
6.8
Kinase
Domain
IRAK1
UniRef100_P51617
AIQFLHQDSPSLIHGDIKSS
267
Lys2
7.6
NVLLDER
IRAK3
UniRef100_Q9Y616
VEIQNLTYAVKLFK
268
Lys1
−7.1
IRAK4
UniRef100_Q9NWZ3
DIKSANILLDEAFTAK
269
Lys2
6.3
IRE1
UniRef100_O75460
DLKPHNILISMPNAHGK
270
Lys2
−0.6
ITPK1
UniRef100_Q13572
ESIFFNSHNVSKPESSSVLT
271
ATP
−16.2
ELDKIEGVFERPSDEVIR
JAK1
UniRef100_P23458
QLASALSYLEDKDLVHGN
272
Protein
9.0
domain1
VCTKNLLLAR
Kinase
Domain
JAK1
UniRef100_P23458
IGDFGLTKAIETDKEYYTVK
273
Activation
29.3
domain2
Loop
JAK1
UniRef100_P23458
YDPEGDNTGEQVAVKSLK
274
Lys1
24.0
domain2
PESGGNHIADLKK
JAK3
UniRef100_P52333
IADFGLAKLLPLDKDYYVV
275
Activation
−4.3
domain2
R
Loop
JNK1,
UniRef100_P45983,
DLKPSNIVVK
276
Lys2
31.5
JNK2,
UniRef100_P53779,
JNK3
UniRef100_P45984
KHS1
UniRef100_Q9Y4K4
NVHTGELAAVKIIK
277
Lys1
33.9
KHS2
UniRef100_Q8IVH8
NVNTGELAAIKVIK
278
Lys1
3.8
KSR1
UniRef100_Q8IVT5
SKNVFYDNGKVVITDFGLF
279
Activation
−0.2
GISGVVR
Loop
KSR1,
UniRef100_Q6VAB6,
SKNVFYDNGK
280
Activation
1.4
KSR2
UniRef100_Q8IVT5
Loop
LATS1
UniRef100_O95835
ALYATKTLR
281
Lys1
15.8
LATS2
UniRef100_Q9NRM7
DIKPDNILIDLDGHIK
282
Lys2
0.8
LCK
UniRef100_P06239
EGAKFPIKWTAPEAINYGT
283
Activation
83.8
FTIK
Loop
LKB1
UniRef100_Q15831
DIKPGNLLLTTGGTLK
284
Lys2
3.6
LOK
UniRef100_O94804
DLKAGNVLMTLEGDIR
285
Lys2
28.8
LRRK2
UniRef100_Q5S007
DLKPHNVLLLYPNAAIIA
286
Lys2
−11.8
K
LYN
UniRef100_P07948
VAVKTLKPGTMSVQAFLE
287
Lys1
85.7
EANLMK
MAP2K1
UniRef100_Q02750
IMHRDVKPSNILVNSR
288
Lys2
6.6
MAP2K1,
UniRef100_P36507,
KLIHLEIKPAIR
289
Lys1
9.4
MAP2K2
UniRef100_Q02750
MAP2K1,
UniRef100_P36507,
DVKPSNILVNSR
290
Lys2
2.2
MAP2K2
UniRef100_Q02750
MAP2K2
UniRef100_P36507
HQIMHRDVKPSNILVNSR
291
Lys2
3.9
MAP2K3
UniRef100_P46734
DVKPSNVLINK
292
Lys2
−1.0
MAP2K4
UniRef100_P45985
DIKPSNILLDR
293
Lys2
0.4
MAP2K5
UniRef100_Q13163
DVKPSNMLVNTR
294
Lys2
−46.0
MAP2K6
UniRef100_P52564
DVKPSNVLINALGQVK
295
Lys2
2.0
MAP2K7
UniRef100_O14733
DVKPSNILLDER
296
Lys2
19.3
MAP3K1
UniRef100_Q13233
DVKGANLLIDSTGQR
297
Lys2
27.5
MAP3K2
UniRef100_Q9Y2U5
ELAVKQVQFDPDSPETSK
298
Lys1
−1.1
EVNALECEIQLLK
MAP3K2,
UniRef100_Q9Y2U5,
DIKGANILR
299
Lys2
8.4
MAP3K3
UniRef100_Q99759
MAP3K3
UniRef100_Q99759
ELASKQVQFDPDSPETSKE
300
Lys1
10.0
VSALECEIQLLK
MAP3K4
UniRef100_Q9Y6R4
DIKGANIFLTSSGLIK
301
Lys2
17.3
MAP3K5
UniRef100_Q99683
DIKGDNVLINTYSGVLK
302
Lys2
−10.2
MAP3K6
UniRef100_095382
DIKGDNVLINTFSGLLK
303
Lys2
2.1
MARK2,
UniRef100_P27448,
DLKAENLLLDADMNIK
304
Lys2
−15.6
MARK3
UniRef100_Q7KZI7
MARK3
UniRef100_P27448
EVAIKIIDKTQLNPTSLQK
305
Lys1
2.6
MARK3,
UniRef100_Q96L34,
EVAIKIIDK
306
Lys1
−7.5
MARK4
UniRef100_P27448
MARK4
UniRef100_Q96L34
DLKAENLLLDAEANIK
307
Lys2
−28.5
MAST1,
UniRef100_Q6P0Q8,
DLKPDNLLITSMGHIK
308
Lys2
−24.8
MAST2
UniRef100_Q9Y2H9
MAST3
UniRef100_O60307
DLKPDNLLITSLGHIK
309
Lys2
−4.7
MASTL
UniRef100_Q96GX5
GAFGKVYLGQK
310
ATP Loop
1.1
MASTL
UniRef100_Q96GX5
LYAVKVVK
311
Lys1
−7.6
MELK
UniRef100_Q14680
DLKPENLLFDEYHK
312
Lys2
−3.0
MER,
UniRef100_Q06418,
KIYSGDYYR
313
Activation
21.2
TYRO3
UniRef100_Q12866
Loop
MET
UniRef100_P08581
DMYDKEYYSVHNK
314
Activation
5.7
Loop
MLK3
UniRef100_Q16584
DLKSNNILLLQPIESDDME
315
Lys2
−0.2
IIK
MLK4
UniRef100_Q5TCX8
DLKSSNILLLEK
316
Lys2
1.5
MLKL
UniRef100_Q8NB16
APVAIKVFK
317
Lys1
−5.5
MPSK1
UniRef100_O75716
DLKPTNILLGDEGQPVLM
318
Lys2
−2.3
DLGSMNQACIHVEGSR
MSK1
UniRef100_O75582
DIKLENILLDSNGHVVLTD
319
Lys2
−21.5
domain1
FGLSK
MSK2
UniRef100_O75676
DLKLENVLLDSEGHIVLTD
320
Lys2
−8.1
domain1
FGLSK
MST1
UniRef100_Q13043
ETGQIVAIKQPVESDLQE
321
Lys1
7.5
IIK
MST2
UniRef100_Q13188
ESGQVVAIKQVPVESDLQ
322
Lys1
8.6
EIIK
MST3
UniRef100_Q9Y6E0
DIKAANVLLSEHGEVK
323
Lys2
−8.9
MST4
UniRef100_Q9P289
TQQVVAIKIIDLEEAEDEIE
324
Lys1
−37.3
DIQQEITVLSQCDSSYVTK
MST4,
UniRef100_O00506,
DIKAANVLLSEQGDVK
325
Lys2
−2.4
YSK1
UniRef100_Q9P289
MYO3A,
UniRef100_Q8NEV4,
DVKGNNILLTTEGGVK
326
Lys2
22.9
MYO3B
UniRef100_Q8WXR4
NDR1
UniRef100_Q15208
DIKPDNLLLDSK
327
Lys2
2.3
NDR2
UniRef100_Q9Y2H1
DIKPDNLLLDAK
328
Lys2
9.8
NEK1
UniRef100_Q96PY6
DIKSQNIFLTK
329
Lys2
−7.1
NEK2
UniRef100_P51955
DLKPANVFLDGK
330
Lys2
12.5
NEK3
UniRef100_P51956
SKNIFLTQNGK
331
Activation
−8.6
Loop
NEK4
UniRef100_P51957
DLKTQNVFLTR
332
Lys2
2.8
NEK6,
UniRef100_Q8TDX7,
DIKPANVFITATGVVK
333
Lys2
−1.8
NEK7
UniRef100_Q9HC98
NEK7
UniRef100_Q8TDX7
AACLLDGVPVALKK
334
Lys1
2.7
NEK8
UniRef100_Q86SG6
DLKTQNILLDK
335
Lys2
−7.8
NEK9
UniRef100_Q8TD19
DIKTLNIFLTK
336
Lys2
−10.7
NLK
UniRef100_Q9UBE8
DIKPGNLLVNSNCVLK
337
Lys2
22.3
OSR1
UniRef100_C9JIG9,
DVKAGNILLGEDGSVQIA
338
Lys2
32.2
UniRef100_095747
DFGVSAFLATGGDITR
p38a
UniRef100_Q16539
DLKPSNLAVNEDCELK
339
Lys2
76.1
p38a
UniRef100_Q16539
QELNKTIWEVPER
340
Protein
88.4
Kinase
Domain
p38d,
UniRef100_O15264,
DLKPGNLAVNEDCELK
341
Lys2
51.5
p38g
UniRef100_P53778
p70S6K
UniRef100_P23443
DLKPENIMLNHQGHVK
342
Lys2
−74.1
p70S6Kb
UniRef100_Q9UBS0
DLKPENIMLSSQGHIK
343
Lys2
3.5
PAN3
UniRef100_Q58A45
VMDPTKILITGK
344
ATP
7.3
PCTAIRE1
UniRef100_Q00536
SKLTDNLVALKEIR
345
Lys1
53.3
PCTAIRE2,
UniRef100_Q00537,
SKLTENLVALKEIR
346
Lys1
72.9
PCTAIRE3
UniRef100_Q07002
PDHK1
UniRef100_Q15118
SPGQPIQVVYVPSHLYHM
347
ATP
−23.7
VFELFKNAMR
PEK
UniRef100_Q9NZJ5
DLKPSNIFFTMDDVVK
348
Lys2
−21.9
PFTAIRE1
UniRef100_O94921
LVALKVIR
349
Lys1
64.0
PHKg1
UniRef100_Q16816
DLKPENILLDDNMNIK
350
Protein
−0.9
Kinase
Domain
PHKg2
UniRef100_P15735
ATGHEFAVKIMEVTAER
351
Lys1
7.1
PI4K2B
UniRef100_Q8TCG2
SEEPYGQLNPKWTK
352
ATP
33.4
PI4KA,
UniRef100_A4QPH2,
SGTPMQSAAKAPYLAK
353
ATP
2.1
PI4KAP2
UniRef100_P42356
P14KB
UniRef100_Q9UBF8
VPHTQAVVLNSKDK
354
ATP
23.7
PIK3C2B
UniRef100_O00750
VIFKCGDDLRQDMLTLQ
355
ATP
−15.7
MIR
PIK3C3
UniRef100_Q8NEB9
TEDGGKYPVIFKHGDDLR
356
ATP
−29.7
PIK3CB
UniRef100_P42338
VFGEDSVGVIFKNGDDLR
357
ATP
−3.9
QDMLTLQMLR
PIK3CD
UniRef100_O00329
VNWLAHNVSKDNRQ
358
ATP
−22.8
PIK3CG
UniRef100_P48736
KKPLWLEFK
359
ATP
−20.1
PIP4K2A
UniRef100_P48426
AKELPTLKDNDFINEGQK
360
ATP
−19.5
PIP4K2C
UniRef100_Q8TBX8
TLVIKEVSSEDIADMHSNL
361
ATP
−7.3
SNYHQYIVK
PIP5K3
UniRef100_Q9Y217
GGKSGAAFYATEDDRFILK
362
ATP
21.7
PITSLRE
UniRef100_P21127
DLKTSNLLLSHAGILK
363
Lys2
10.2
PKCa,
UniRef100_P05771,
DLKLDNVMLDSEGHIK
364
Lys2
−86.4
PKCb
UniRef100_P17252
PKCe
UniRef100_Q02156
DLKLDNILLDAEGHCK
365
Lys2
27.7
PKCi
UniRef100_P41743
IYAMKVVK
366
Lys1
−54.3
PKD2
UniRef100_Q9BZL6
DVAVKVIDK
367
Lys1
−5.4
PKN1
UniRef100_Q16512
VLLSEFRPSGELFAIKALK
368
Lys1
1.8
PKR
UniRef100_P19525
DLKPSNIFLVDTK
369
Lys2
−1.7
K
PLK1
UniRef100_P53350
CFEISDADTKEVFAGKIVP
370
Lys1
18.8
K
PLK4
UniRef100_O00444
AESIHTGLEVAIKMIDKK
371
Lys1
−17.3
PRP4
UniRef100_Q13523
CNILHADIKPDNILVNESK
372
Lys2
−5.5
PRPK
UniRef100_Q96544
FLSGLELVKQGAEAR
373
ATP Loop
−16.0
PYK2
UniRef100_Q14289
YIEDEDYYKASVTR
374
Activation
30.5
Loop
RIPK1
UniRef100_Q13546
DLKPENILVDNDFHIK
375
Lys2
23.1
RIPK3
UniRef100_Q9Y572
DLKPSNVLLDPELHVK
376
Lys2
70.2
ROCK1,
UniRef100_O75116,
DVKPDNMLLDK
377
Lys2
−0.2
ROCK2
UniRef100_Q13464
RSK1
UniRef100_Q15418
DLKPENILLDEEGHIKLTDF
378
Lys2
−29.6
domain1
GLSKEAIDHEK
RSK1
UniRef100_P51812,
DLKPENILLDEEGHIK
379
Lys2
−25.1
domain1,
UniRef100_Q15418,
RSK2
UniRef100_Q15349
domain1,
RSK3
domain1
RSK1
UniRef100_Q15418
DLKPSNILYVDESGNPECL
380
Lys2
1.0
domain2
R
RSK2
UniRef100_P51812
DLKPENILLDEEGHIKLTDF
381
Lys2
−36.7
domain1
GLSKESIDHEK
RSK2
UniRef100_P51812
DLKPSNILYVDESGNPESIR
382
Lys2
2.8
domain2
RSK3
UniRef100_015349
DLKPENILLDEEGHIKITDF
383
Lys2
−37.8
domain1
GLSK
RSKL1
UniRef100_Q96S38
VLGVIDKVLLVMDTR
384
ATP
21.8
SGK3
UniRef100_Q96BR1
FYAVKVLQK
385
Lys1
16.6
SLK
UniRef100_Q9H2G2
DLKAGNILFTLDGDIK
386
Lys2
13.8
SMG1
UniRef100_Q96Q15
DTVTIHSVTITILPTKTK
387
ATP
−3.6
PK
SNRK
UniRef100_Q9NRH2
DLKPENVVFFEK
388
Lys2
24.5
SRC
UniRef100_P12931
VAIKTLKPGTMSPEAFLQE
389
Lys1
82.7
AQVMKK
SRPK1
UniRef100_Q96SB4
IIHTDIKPENILLSVNEQYIR
390
Lys2
−9.1
SRPK1,
UniRef100_P78362,
FVAMKVVK
391
Lys1
−38.7
SRPK2
UniRef100_Q96SB4
STK33
UniRef100_Q9BYT3
DLKLENIMVK
392
Lys2
−8.0
STLK5
UniRef100_Q7RTN6
YSVKVLPWLSPEVLQQNL
393
Activation
12.0
QGYDAK
Loop
SYK
UniRef100_P43405
ISDFGLSKALR
394
Activation
6.6
Loop
TAK1
UniRef100_043318
DLKPPNLLLVAGGTVLK
395
Lys2
0.4
TAO1,
UniRef100_Q7L7X3,
DIKAGNILLTEPGQVK
396
Lys2
87.1
TAO3
UniRef100_Q9H2K8
TAO2
UniRef100_Q9UL54
DVKAGNILLSEPGLVK
397
Lys2
92.0
TBK1
UniRef100_Q9UHD2
TGDLFAIKVFNNISFLRPV
398
Lys1
−18.0
DVQMR
TEC
UniRef100_P42680
YVLDDQYTSSSGAKFPVK
399
Activation
20.6
Loop
TLK1
UniRef100_Q9UKI8
YLNEIKPPIIHYDLKPGNILL
400
Lys2
11.5
VDGTACGEIK
TLK2
UniRef100_Q86UE8
YLNEIKPPIIHYDLKPGNILL
401
Lys2
10.2
VNGTACGEIK
ULK1
UniRef100_O75385
DLKPQNILLSNPAGR
402
Lys2
8.8
ULK3
UniRef100_D3DW67
NISHLDLKPQNILLSSLEKP
403
Lys2
27.1
HLK
VRK2
UniRef100_Q86Y07
MLDVLEYIHENEYVHGDIK
404
Lys2
−1.2
AANLLLGYK
Wnk1,
UniRef100_Q9Y3S1,
GSFKTVYK
405
ATP Loop
11.2
Wnk2
UniRef100_D3DUP1
Wnk1,
UniRef100_Q9Y3S1,
DLKCDNIFITGPTGSVK
406
Lys2
−1.1
Wnk2,
UniRef100_D3DUP1,
Wnk3
UniRef100_Q9BYP7
YANK3
UniRef100_Q86UX6
DVKPDNILLDER
407
Lys2
−43.1
ZAK
UniRef100_Q9NYL2
WISQDKEVAVKK
408
Lys1
75.8
ZAP70
UniRef100_P43403
ISDFGLSKALGADDSYYTA
409
Activation
10.7
R
Loop
ZC1/HGK,
UniRef100_095819,
DIKGQNVLLTENAEVK
410
Lys2
57.5
ZC2/TNIK,
UniRef100_Q9UKE5,
ZC3/MINK
UniRef100_Q8N4C8
ZC2/TNIK
UniRef100_Q9UKE5
TGQLAAIKVMDVTGDEEE
411
Lys1
46.0
EIKQEINMLKK
Protocol for PhosFlow Studies
PhosFlow was performed to detect levels of phosphorylation for BTK-pY223 (BD Biosciences) and Hck-pY410 (Abcam) in BCWM.1 cells, in BCWM cells that stably overexpress HCK (BCWM.1_HCK-wt) and in BCWM.1 cells that stably overexpress the T338M mutant of HCK (BCWM.1_HCK-mu). Cells were fixed with BD Phosflow Fix Buffer I (BD Biosciences) at 37° C. for 10 min, then washed twice with BD Phosflow Perm/Wash Buffer I (BD Biosciences). Cells were suspended in BD Phosflow Perm/Wash Buffer I at 10 million/ml and antibodies aliquoted to flow tubes with 100 μl cells. Cells were incubated at room temperature for 30 min in the dark. Cells were washed twice with ED Phosflow Perm/Wash Buffer I before performing flow analysis using a BD™ FACSCanto II flow cytometer.
Protocol for Apoptosis Analysis
Apoptosis analysis of WM patient primary lymphoplasmacytic cells (LPCs) was preformed following A-5 and A-14 treatment of Bone marrow mononuclear cells (BMMC) from WM patients for 24 hours. Apoptosis analysis was performed using Annexin V/Propidium iodide staining with the Apoptosis Detection Kit I (BD Pharmingen) in CD19-APC-cy7 antibody (BD Pharmingen) gated LPCs population.
Results
PhosFlow studies indicate both A-5 and A-14 inhibit Hck and BTK phosphorylation in BCWM.1 cells and BCWM.1 cells with genetic engineered expression of Hck wild type (-wt) and T338M gatekeeper mutant (-mu) with both 0.5 μuM and 0.1 μM doses (shown by Table 6 and Table 7, respectively). In addition, the expression of Hck-wt or Hck-mu increased the resistance to the inhibition of both Hck and BTK phosphorylations by A-5 and A-14, with more resistance presented in Hck-mu expressing BCWM.1 cells. Both A-5 and A-14 induced significant apoptosis in WM patient primary LPCs compared with DMSO control, as shown in Table 8.
TABLE 6
Relative
p-BTK
p-Hck
MFI %
_Hck-
_Hck-
_Hck-
_Hck-
(0.5 μM
BCW M.1
BCWM.1 wt
BCWM.1 mu
BCW M.1
BCWM.1 wt
BCWM.1 mu
drugs)
15 min
90 min
15 min
90 min
15 min
90 min
15 min
90 min
15 min
90 min
15 min
90 min
DMSO
100
100
100
100
100
100
100
100
100
100
100
100
A-5
56.3
42.3
73.6
69.9
100.7
90.4
68.2
49
80.4
77.7
102.2
81.1
A-14
51.5
27.4
65.6
29.7
112.1
83.9
59.3
35.6
68.6
41.5
89.7
52.3
TABLE 7
Relative
p-BTK
p-Hck
MFI %
_Hck-
_Hck-
_Hck-
_Hck-
(0.1 μM
BCW M.1
BCWM.1 wt
BCWM.1 mu
BCW M.1
BCWM.1 wt
BCWM.1 mu
drugs)
15 min
90 min
15 min
90 min
15 min
90 min
15 min
90 min
15 min
90 min
15 min
90 min
DMSO
100
100
100
100
100
100
100
100
100
100
100
100
A-5
68.1
52.7
82.1
78.3
70.9
70.4
76.3
50.5
76
80.6
95.3
69.6
A-14
81.8
50.1
76.3
72
75.3
61.2
73.6
57.8
75.8
78.9
83.1
63.7
TABLE 8
Dose (1.0 μM)
Dose (0.5 μM)
Dose (0.2 μM)
Apoptosis
Apoptosis Relative
Apoptosis
Apoptosis Relative
Apoptosis
Apoptosis Relative
Treatments
(%)
to DMSO
(%)
to DMSO
(%)
to DMSO
Patient 1
Untreated
40.9
114.30%
DMSO
39.2
100%
A-5
57.7
147.20%
Patient 2
N
14.2
97.30%
DMSO
14.6
100%
A-5
28.9
197.90%
Patient 3
N
14.529
95.49%
DMSO
15.216
100.00%
A-5
29.48
193.70%
Patient 4
N
29.83
103.00%
DMSO
29.75
100.00%
A-5
48.56
163.20%
Patient 5
N
18.69
110.70%
DMSO
16.89
100%
A-5
30.5
180.60%
23.25
137.70%
A-14
46.86
277.40%
39.24
232.30%
Patient 6
N
8.66
117.50%
DMSO
7.37
100%
A-5
17.82
241.80%
A-14
20.88
283.30%
Patient 7
DMSO
6.46
100.00%
A-5
18.2
281.70%
17.23
266.70%
A-14
31.51
487.80%
22.62
350.20%
Patient 8
DMSO
5.38
100.00%
A-5
17.31
321.75%
11.04
205.20%
A-14
31.58
586.99%
12.9
239.78%
Patient 9
DMSO
7.6
100.00%
A-14
43.7
575.00%
24.8
326.32%
Patient
N
17.6
113.50%
10
DMSO
15.5
100%
A-5
28.7
185.20%
21.5
138.70%
A-14
52
335.50%
27.9
180.00%
Patient
N
26.2
112.70%
11
DMSO
25.5
100%
A-5
47
184.30%
30.2
118.40%
A-14
71.8
281.60%
53.1
208.20%
In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in. employed in, or otherwise relevant to a given product or process.
Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.
This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. lf there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.
Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.
Yang, Guang, Gray, Nathanael S., Buhrlage, Sara Jean, Treon, Steven P., Tan, Li
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| Jun 29 2016 | YANG, GUANG | DANA-FARBER CANCER INSTITUTE, INC | ASSIGNMENT OF ASSIGNORS INTEREST SEE DOCUMENT FOR DETAILS | 066137 | /0779 | |
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