USRE50030E1 - Methods to treat lymphoplasmacytic lymphoma - Google Patents

Methods to treat lymphoplasmacytic lymphoma Download PDF

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USRE50030E1
USRE50030E1 US17/534,896 US201417534896A USRE50030E US RE50030 E1 USRE50030 E1 US RE50030E1 US 201417534896 A US201417534896 A US 201417534896A US RE50030 E USRE50030 E US RE50030E
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certain embodiments
optionally substituted
alkyl
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Steven P. Treon
Sara Jean Buhrlage
Nathanael S. Gray
Li Tan
Guang Yang
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Dana Farber Cancer Institute Inc
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Dana Farber Cancer Institute Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • WM Waldenström's macroglobulinemia
  • LPL lymphoplasmacytic lymphoma
  • 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.
  • the kits further include instructions for using the kit (e.g., for administering a compound described herein, or a pharmaceutical composition thereof).
  • haloalkyl hydrogen atoms are replaced with chloro to provide a “perchloroalkyl” group.
  • haloalkyl groups include —CF 3 , —CF 2 CF 3 , —CF 2 CF 2 CF 3 , —CCl 3 , —CFCl 2 , —CF 2 Cl, and the like.
  • 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.
  • a heteroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-10 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-9 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-8 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-7 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more heteroatoms within the parent chain (“heteroC 1-6 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 1-5 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 1-4 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1-3 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain (“heteroC 1-2 alkyl”). In certain embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroC 1 alkyl”).
  • a heteroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms within the parent chain (“heteroC 2-6 alkyl”). Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an “unsubstituted heteroalkyl”) or substituted (a “substituted heteroalkyl”) with one or more substituents. In certain embodiments, the heteroalkyl group is an unsubstituted heteroC 1-10 alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroC 1-10 alkyl.
  • alkynyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) (“C 2-10 alkynyl”). In certain embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2-9 alkynyl”). In certain embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2-8 alkynyl”). In certain embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2-7 alkynyl”).
  • 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”).
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • partially unsaturated refers to a ring moiety that includes at least one double or triple bond.
  • 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.
  • alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are, in certain embodiments, optionally substituted.
  • each instance of R gg is, independently, halogen, —CN, —NO 2 , —N 3 , —SO 2 H, —SO 3 H, —OH, —OC 1-6 alkyl, —ON(C 1-6 alkyl) 2 , —N(C 1-6 alkyl) 2 , —N(C 1-6 alkyl) 3 + X ⁇ , —NH(C 1-6 alkyl) 2 + X ⁇ , —NH 2 (C 1-6 alkyl) + X ⁇ , —NH 3 + X ⁇ , —N(OC 1-6 alkyl)(C 1-6 alkyl), —N(OH)(C 1-6 alkyl), —NH(OH), —SH, —SC 1-6 alkyl, —SS(C 1-6 alkyl), —C( ⁇ O)(C 1-6 alkyl), —CO 2 H, —CO 2 (C 1-6 alkyl), —OC( ⁇ O)
  • Suitable leaving groups include, but are not limited to, halides (such as chloride, bromide, or iodide), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, alkyl-carbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, N,O-dimethylhydroxylamino, pixyl, haloformates, —NO 2 , trialkylammonium, and aryliodonium salts.
  • the leaving group is a sulfonic acid ester.
  • 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).
  • R D is an electrophilic moiety as described herein.
  • each instance of R X is independently selected from the group consisting of R D , optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, and —N(R A1 )(R Xa );
  • each instance of R Xa is selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —C( ⁇ O)R A1 , —C( ⁇ O)OR A1 , —C( ⁇ O)N(R A1 ) 2 , —S( ⁇ O)R A1 , —S( ⁇ O)N(R A1 ) 2 , —S( ⁇ O) 2 R A1 , —S( ⁇ O) 2 OR A1 , —S( ⁇ O) 2 N(R A1 ) 2 , —S( ⁇ O) 2 N(R A1 ) 2 , —N(R A1 ) 2 , and a nitrogen protecting group;
  • k 0, 1, 2, 3, or 4;
  • l is 1, 2, 3, 4, or 5;
  • Q and U are taken together to be —NR A (C ⁇ O)— or —(C ⁇ O)NR A —;
  • the subject is adminstered compound (A-1):
  • the subject is adminstered compound (A-4):
  • the subject is adminstered compound (A-5):
  • the subject is adminstered compound (A-6):
  • the subject is adminstered compound (A-7):
  • the subject is adminstered compound (A-8):
  • the subject is adminstered compound (A-9):
  • the subject is adminstered compound (A-10):
  • the subject is adminstered compound (A-11):
  • the subject is adminstered compound (A-13):
  • the subject is adminstered compound (A-14):
  • the subject is adminstered compound (A-17):
  • the subject is adminstered compound (A-18):
  • k is 2. In certain embodiments, Ring A is of the formula:
  • Ring A is of the formula:
  • Ring A is of the formula:
  • l is 5. In certain embodiments, Ring C is of the formula:
  • At least one R B is
  • At least one R B is
  • At least one R B is
  • At least one R B is
  • At least one R B is —NO 2 . In certain embodiments, at least one R B is —NR A1 C( ⁇ O)R A1 . In certain embodiments, at least one R B is —NR A1 C( ⁇ O) OR A1 . In certain embodiments, at least one R B is —NR A1 S ( ⁇ O) 2 R A1 . In certain embodiments, at least one R B is —NHS( ⁇ O) 2 R A1 . In certain embodiments, at least one R B is —NHS( ⁇ O) 2 (C 1-6 alkyl) where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R B is —NHS( ⁇ O) 2 Me.
  • At least one R B is —S( ⁇ O) 2 R A1 . In certain embodiments, at least one R B is —S( ⁇ O) 2 N(R A1 ) 2 . In certain embodiments, at least one is —S( ⁇ O) 2 N( A1 ) 2 . In certain embodiments, at least one R B is —S( ⁇ O) 2 N(C 1-6 alkyl) 2 . In certain embodiments, at least one R B is —S( ⁇ O) 2 NH(C 1-6 alkyl). In certain embodiments, at least one R B is —S( ⁇ O) 2 NH(t-Bu). In certain embodiments, at least one R B is —S( ⁇ O) 2 NH 2 .
  • R B is substituted or unsubstituted C 1-6 alkyl; and l is 1. In certain embodiments, R B is substituted or unsubstituted C 1-6 alkyl; l is 1; and R B is meta to the point of attachment of U. In certain embodiments, R B is substituted or unsubstituted C 1-6 alkyl; l is 1; R B is para to the point of attachment of U. In certain embodiments, R B is C 1-6 alkyl substituted with one —CN group; and l is 1. In certain embodiments, R B is C 1-6 alkyl substituted with one —CN group; l is 1; and R B is meta to the point of attachment of U. In certain embodiments, R B is C 1-6 alkyl substituted with one —CN group; l is 1; and R B is para to the point of attachment of U. In certain embodiments, R B is R B is
  • R B is
  • R B is substituted or unsubstituted —CH 2 -(piperazinyl); and l is 1.
  • R B is substitued to unsubstituted —CH 2 -(piperazinyl); l is 1; and R B is meta to the point of attachment of U.
  • R B is substituted or unsubstituted —CH 2 -piperazinyl); l is 1; and R B is para to the point of attachment of U.
  • R B is
  • R B is
  • R B is meta to the point of attachment of U. In certain embodiments, R B is
  • R B is
  • R B is substituted or unsubstituted piperazinyl; and l is 1. In certain embodiments, R B is substituted or unsubstituted piperazinyl; l is 1; and R B is meta to the point of attachment of U. In certain embodiments, R B is substituted or unsubstituted piperazinyl; l is 1; and R B is para to the point of attachment of U. In certain embodiments, R B is substituted or unsubstituted piperazinyl; l is 1; and R B is para to the point of attachment of U. In certain embodiments, R B is
  • R B is
  • R B is meta to the point of attachment of U. In certain embodiments, R B is
  • R B is para to the point of attachment of U.
  • R B is substituted or unsubstituted morpholine; and l is 1.
  • R B is substituted or unsubstituted morpholine; l is 1; and R B is meta to the point of attachment of U.
  • R B is substituted or unsubstituted morpholine; l is 1; and R B is para to the point of attachment of U.
  • At least one R B group is substituted or unsubstituted C 1-6 alkyl; and l is 2. In certain embodiments, at least one R B group is substituted or unsubstituted C 1-6 alkyl; l is 2; and at least one R B is meta to the point of attachment of U. In certain embodiments, at least one R B group is substituted or unsubstituted C 1-6 alkyl; l is 2; and one R B is para to the point of attachment of U. In certain embodiments, at least one R B group is C 1-6 alkyl substituted with one —CN group; and l is 2.
  • At least one R B group is C 1-6 alkyl substituted with one —CN group; l is 2; and at least one R B is meta to the point of attachment of U. In certain embodiments, at least one R B group is C 1-6 alkyl substituted with one —CN group; l is 2; and one R B is para to the point of attachment of U. In certain embodiments, at least one R B group is
  • At least one R B group is
  • l is 2; and at least one R B is meta to the point of attachment of U.
  • at least one R B group is
  • At least one R B group is substituted or unsubstituted —CH 2 -(piperazinyl); and l is 2. In certain embodiments, at least one R B group is substituted or unsubstituted —CH 2 -(piperazinyl): l is 2; and at least one R B is meta to the point of attachment of U. In certain embodiments, at least one R B group is substituted or unsubstituted —CH 2 -(piperazinyl); l is 2; and one R B is para to the point of attachment of U. In certain embodiments, at least one R B group is
  • At least one R B group is
  • l is 2; and at least one R B is meta to the point of attachment of U.
  • at least one R B group is
  • l is 2; and one R B is para to the point of attachment of U.
  • at least one R B group is haloalkyl; and l is 2.
  • at least one R B group is haloalkyl; l is 2; and at least one R B is meta to the point of attachment of U.
  • at least one R B group is haloalkyl; l is 2; and one R B is para to the point of attachment of U.
  • at least one R B group is —CF 3 ; and l is 2.
  • at least one R B group is —CF 3 ; l is 2; and at least one R B is meta to the point of attachment of U.
  • At least one R B group is —CF 3 ; l is 2; and one R B is para to the point of attachment of U.
  • at least one R B group is substituted or unsubstituted imidazoyl; and l is 2.
  • at least one R B group is substituted or unsubstituted imidazoyl; l is 2; and at least one R B is meta to the point of attachment of U.
  • at least one R B group is substituted or unsubstituted imidazoyl; l is 2; and one R B is para to the point of attachment of U.
  • at least one R B group is
  • At least one R B group is
  • l is 2; and at least one R B is meta to the point of attachment of U.
  • at least one R B group is
  • l is 2; and at least one R B is meta to the point of attachment of U.
  • at least one R B group is
  • l is 2; and one R B is para to the point of attachment of U.
  • at least one R B group is substituted or unsubstituted morpholine; and l is 2.
  • at least one R B group is substituted or unsubstituted morpholine; l is 2; and at least one R B is meta to the point of attachment of U.
  • at least one R B group is substituted or unsubstituted morpholine; l is 2; and one R B is para to the point of attachment of U.
  • two R B groups are substituted or unsubstituted morpholine; l is 2; and both R B groups are meta to the point of attachment of U.
  • Q and U are taken together to represent a divalent linker moiety. In certain embodiments, Q and U are taken together to represent
  • Q and U are taken together to represent
  • Q and U are taken together to represent
  • Formula (A) includes a pyridine or pyrimidine ring as Ring B.
  • each instance of A included in Ring B is carbon.
  • one instance of A included in Ring B is carbon, and the other instance of A included in Ring B is nitrogen.
  • Ring B is of the formula:
  • Ring B is of the formula:
  • Formula (A) may include one or more R Y groups.
  • the two instances of R Y may be the same or different from each other.
  • at least one instance of R Y is H.
  • each instance of R Y is H.
  • at least one instance of R Y is halogen (e.g., F, Cl, Br, or I).
  • at least one instance of R Y is substituted or unsubstituted C 1-6 alkyl.
  • at least one instance of R Y is Me.
  • at least one instance of R Y is substituted methyl (e. g., —CF 3 or Bn).
  • R Y is Et, substituted ethyl (e.g., perfluoroethyl), Pr, substituted propyl (e.g., perfluoropropyl), Bu, or substituted butyl (e.g., perfluorobutyl).
  • the pyridine or pyrimidine ring may be substituted with one or more R X groups.
  • R X groups When Formula (A) includes two instances of R X , the two instances of R X may be the same or different from each other.
  • at least one R X is substituted carbocyclyl.
  • at least one R X is unsubstituted carbocyclyl.
  • at least one R X is
  • At least one R X is
  • At least one R X is
  • At least one R X is
  • At least one R X is
  • At least one R X is
  • At least one R X is
  • At least one R X is
  • At least one R X is
  • At least one R X is
  • At least one R X is
  • At least one R X is
  • At least one R X is —NH(acyl). In certain embodiments, at least one R X is
  • At least one R X is
  • At least one R X is
  • At least one R X is
  • At least one R X is
  • At least one R X is
  • At least one R X is
  • At least one R X is
  • At least one R X is
  • At least one R X is
  • At least one R X is —N(R A1 )N(R A1 ) 2 . In certain embodiments, at least one R X is —NHN(R A1 ) 2 . In certain embodiments, at least one R X is —NHNH(acyl). In certain embodiments, at least one R X is —NHNHC( ⁇ O)Me. In certain embodiments, at least one R X is —NHN(C 1-6 alkyl) 2 where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R X is —NHNMe 2 .
  • At least one R Xa is H. In certain embodiments, all R Xa groups are H. In certain embodiments, at least one R Xa is substituted alkyl. In certain embodiments, at least one R Xa is substituted C 1-6 alkyl. In certain embodiments, at least one R Xa is substituted methyl. In certain embodiments, at least one R Xa is unsubstituted alkyl. In certain embodiments, at least one R Xa is unsubstituted C 1-6 alkyl. In certain embodiments, at least one R Xa is methyl. In certain embodiments, at least one R Xa is ethyl. In certain embodiments, at least one R Xa is propyl.
  • At least one R Xa is butyl. In certain embodiments, at least one R Xa is substituted alkenyl. In certain embodiments, at least one R Xa is unsubstituted alkenyl. In certain embodiments, at least one R Xa is substituted alkynyl. In certain embodiments, at least one R Xa is unsubstituted alkynyl. In certain embodiments, at least one R Xa is substituted carbocyclyl. In certain embodiments, at least one R Xa is unsubstituted carbocyclyl. In certain embodiments, at least one R Xa is substituted heterocyclyl.
  • At least one R Xa is unsubstituted heterocyclyl. In certain embodiments, at least one R Xa is substituted aryl. In certain embodiments, at least one R Xa is unsubstituted aryl. In certain embodiments, at least one R Xa is substituted phenyl. In certain embodiments, at least one R Xa is unsubstituted phenyl. In certain embodiments, at least one R Xa is substituted heteroaryl. In certain embodiments, at least one R Xa is unsubstituted heteroaryl. In certain embodiments, at least one R Xa is —C( ⁇ O)R A1 .
  • At least one R Xa is —C( ⁇ O)NHR A1 . In certain embodiments, at least one R Xa is —C( ⁇ O)N(C 1-6 alkyl) 2 . In certain embodiments, at least one R Xa is —C( ⁇ O)NH(C 1-6 alkyl). In certain embodiments, at least one R Xa is —C( ⁇ O)NH 2 . In certain embodiments, at least one R Xa is —S( ⁇ O)R A1 . In certain embodiments, at least one R Xa is —S( ⁇ O)(C 1-6 alkyl).
  • At least one R Xa is —S( ⁇ O)N(R A1 ) 2 . In certain embodiments, at least one R Xa is —S( ⁇ O)NH(R A1 ). In certain embodiments, at least one R Xa is —S( ⁇ O)NH 2 . In certain embodiments, at least one R Xa is —S( ⁇ O)N(C 1-6 alkyl) 2 . In certain embodiments, at least one R Xa is —S( ⁇ O)NH(C 1-6 alkyl). In certain embodiments, at least one R Xa is —S( ⁇ O) 2 R A1 .
  • At least one R Xa is —S( ⁇ O) 2 (C 1-6 alkyl). In certain embodiments, at least one R Xa is —S( ⁇ O) 2 OR A1 . In certain embodiments, at least one R Xa is —S( ⁇ O) 2 OH. In certain embodiments, at least one R Xa is —S( ⁇ O) 2 N(R A1 ) 2 . In certain embodiments, at least one R Xa is —S( ⁇ O) 2 NH (R A1 ). In certain embodiments, at least one R Xa is —S( ⁇ O) 2 NH 2 .
  • At least one R Xa is —S( ⁇ O) 2 N(C 1-6 alkyl) 2 . In certain embodiments, at least one R Xa is —S( ⁇ O) 2 NH(C 1-6 alkyl). In certain embodiments, at least one R Xa is —N(R A1 ) 2 . In certain embodiments, at least one R Xa is —NH(R A1 ). In certain embodiments, at least one R Xa is —NH(acyl). In certain embodiments, at least one R Xa is —NHC(—O)Me. In certain embodiments, at least one R Xa is —N(C 1-6 alkyl) 2 where the alkyl is substituted or unsubstituted. In certain embodiments, at least one R Xa is —NMe 2 .
  • At least one R Xc is H. In certain embodiments, all R Xc groups are H. In certain embodiments, at least one R Xc is substituted alkyl. In certain embodiments, at least one R Xc is substituted C 1-6 alkyl. In certain embodiments, at least one R Xc is substituted methyl. In certain embodiments, at least one R Xc is unsubstituted alkyl. In certain embodiments, at least one R Xc is unsubstituted C 1-6 alkyl. In certain embodiments, at least one R Xc is methyl. In certain embodiments, at least one R Xc is ethyl. In certain embodiments, at least one R Xc is propyl.
  • At least one R Xc is butyl. In certain embodiments, at least one R Xc is substituted alkenyl. In certain embodiments, at least one R Xc is unsubstituted alkenyl. In certain embodiments, at least one R Xc is substituted alkynyl. In certain embodiments, at least one R Xc is unsubstituted alkynyl. In certain embodiments, at least one R Xc is substituted carbocyclyl. In certain embodiments, at least one R Xc is unsubstituted carbocyclyl. In certain embodiments, at least one R Xc is substituted heterocyclyl.
  • At least one R Xc is unsubstituted heterocyclyl. In certain embodiments, at least one R Xc is substituted aryl. In certain embodiments, at least one R Xc is unsubstituted aryl. In certain embodiments, at least one R Xc is substituted phenyl. In certain embodiments, at least one R Xc is unsubstituted phenyl. In certain embodiments, at least one R Xc is substituted heteroaryl. In certain embodiments, at least one R Xc is unsubstituted heteroaryl. In certain embodiments, at least one R Xc is —OR A1 . In certain embodiments, at least one R Xc is —OH.
  • At least one R Xc is —O(C 1-6 alkyl). In certain embodiments, at least one R Xc is —N(R A1 ) . In certain embodiments, at least one R Xc is —NH(R A1 ). In certain embodiments, at least one R Xc is —N(C 1-6 alkyl) 2 . In certain embodiments, at least one R Xc is —NH(C 1-6 alkyl). In certain embodiments, at least one R Xc is —NH 2 . In certain embodiments, at least one R Xc is —SR A1 . In certain embodiments, at least one R Xc is —SH.
  • At least one R Xc is —S(C 1-6 alkyl). In certain embodiments, at least one R Xc is —CN. In certain embodiments, at least one R Xc is —NO 2 . In certain embodiments, at least one R Xc is —N 3 . In certain embodiments, at least one R Xc is —NR A1 C( ⁇ O)R A1 . In certain embodiments, at least one R Xc is —NHC( ⁇ O)R A1 . In certain embodiments, at least one R Xc is —NHC( ⁇ O)(C 1-6 alkyl). In certain embodiments, at least one R Xc is —NR A1 C( ⁇ O)OR A1 .
  • At least one R Xa is —NHC( ⁇ O)OR A1 . In certain embodiments, at least one R Xc is —NR A1 C( ⁇ O)O(C 1-6 alkyl). In certain embodiments, at least one R Xc is —NR A1 C( ⁇ O)N(R A1 ) 2 . In certain embodiments, at least one R Xc is —NHC( ⁇ O)N(C 1-6 alkyl) 2 . In certain embodiments, at least one R Xc is —NHC( ⁇ O)NH 2 . In certain embodiments, at least one R Xc is —NR A1 S( ⁇ O) 2 R A1 .
  • At least one R Xc is —NHS( ⁇ O) 2 R A1 . In certain embodiments, at least one R Xc is —NHS( ⁇ O) 2 (C 1-6 alkyl). In certain embodiments, at least one R Xc is —NR A1 S( ⁇ O)R A1 . In certain embodiments, at least one R Xc is —NR A1 S( ⁇ O)(C 1-6 alkyl). In certain embodiments, at least one R Xc is —NHS( ⁇ O)(C 1-6 alkyl). In certain embodiments, at least one R Xc is —OC( ⁇ O)R A1 .
  • At least one R Xc is —C( ⁇ O)R A1 . In certain embodiments, at least one R Xc is —C( ⁇ O)H. In certain embodiments, at least one R Xc is acetyl. In certain embodiments, at least one R Xc is —C( ⁇ O)(C 1-6 alkyl). In certain embodiments, at least one R Xc is —C( ⁇ O)OR A1 In certain embodiments, at least one R Xc is —C( ⁇ O)OH. In certain embodiments, at least one R Xc is —C( ⁇ O)O(C 1-6 alkyl).
  • At least one R Xc is —C( ⁇ O)N(R A1 ) 2 . In certain embodiments, at least one R Xc is —C( ⁇ )NHR A1 . In certain embodiments, at least one R Xc is —C( ⁇ O)N(C 1-6 alkyl) 2 . In certain embodiments, at least one R Xc is —C( ⁇ O)NH(C 1-6 alkyl). In certain embodiments, at least one R Xc is —C( ⁇ O)NH 2 . In certain embodiments, at least one R Xc is —S( ⁇ O)R A1 .
  • At least one R Xc is —S( ⁇ O)(C 1-6 alkyl). In certain embodiments, at least one R Xc is —S( ⁇ O)N(R A1 ) 2 . In certain embodiments, at least one R Xc is —S( ⁇ O)NH(R A1 ). In certain embodiments, at least one R Xc is —S( ⁇ O)NH 2 . In certain embodiments, at least one R Xc is —S( ⁇ O)N(C 1-6 alkyl) 2 . In certain embodiments, at least one R Xc is —S( ⁇ O)NH(C 1-6 alkyl).
  • At least one R Xc is —S( ⁇ O) 2 R A1 . In certain embodiments, at least one R Xc is —S( ⁇ O) 2 (C 1-6 alkyl). In certain embodiments, at least one R Xc is —S( ⁇ O) 2 OR A1 . In certain embodiments, at least one R Xc is —S( ⁇ O) 2 OH. In certain embodiments, at least one R Xc is —S( ⁇ O) 2 N(R A1 ) 2 . In certain embodiments, at least one R Xc is —S( ⁇ O) 2 NH(R A1 ). In certain embodiments, at least one R Xc is —S( ⁇ O) 2 NH 2 .
  • At least one R Xc is —S( ⁇ O) 2 N(C 1-6 a 1 kyl) 2 . In certain embodiments, at least one R Xc is —S( ⁇ O) 2 NH(C 1-6 alkyl).
  • R D is an optional electrophilic moiety that is attached to the pyridyl ring.
  • R D is any one of Formulae (i-1)-(i-18):
  • R D3 is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO 2 , —OR D3a , —N(R D3a ) 2 , —SR D3a , —CH 2 OR D3a , —CH 2 N(R D3a ) 2 , —CH 2 SR D3a , —C( ⁇ O)R D3a , —C( ⁇ 0 )OR D3a , —C( ⁇ O)SR D3a , —C( ⁇ O)N(R D3a ) 2 , —C( ⁇ S)R D3a , —C( ⁇ S)OR D3a , —C( ⁇ S)
  • R D1 and R D3 , or R D2 and R D3 , or R D1 and R D2 are joined to form an optionally substituted carbocyclic or optionally substituted heterocyclic ring;
  • z 0, 1, 2, 3, 4, 5, or 6;
  • R D5 and one R C are joined to form an optionally substituted heterocyclic ring.
  • R D1 is methyl. In certain embodiments, R D1 is ethyl. In certain embodiments, R D1 is propyl. In certain embodiments, R D1 is butyl. In certain embodiments, R D1 is substituted alkenyl. In certain embodiments, R D1 is unsubstituted alkenyl. In certain embodiments, R D1 is substituted alkynyl. In certain embodiments, R D1 is unsubstituted alkynyl. In certain embodiments, R D1 is substituted carbocyclyl. In certain embodiments, R D1 is unsubstituted carbocyclyl. In certain embodiments, R D1 is substituted heterocyclyl.
  • R D1 is unsubstituted heterocyclyl. In certain embodiments, R D1 is substituted aryl. In certain embodiments, R D1 is unsubstituted aryl. In certain embodiments, R D1 is substituted phenyl. In certain embodiments, R D1 is unsubstituted phenyl. In certain embodiments, R D1 is substituted heteroaryl. In certain embodiments, R D1 is unsubstituted heteroaryl. In certain embodiments, R D1 is substituted pyridyl. In certain embodiments, R D1 is unsubstituted pyridyl. In certain embodiments, R D1 is —CN. In certain embodiments, R D1 is —NO 2 .
  • R D1 is —OR D1a . In certain embodiments, R D1 is —N(R D1a ) 2 . In certain embodiments, R D1 is —SR D1a . In certain embodiments, R D1 is —CH 2 OR D1a . In certain embodiments, R D1 is —CH 2 N(R D1a ) 2 . In certain embodiments, R D1 is —CH 2 SR D1a .
  • At least one R D1a is H. In certain embodiments, at least one R D1a is substituted acyl. In certain embodiments, at least one R D1a is unsubstituted acyl. In certain embodiments, at least one R D1a is acetyl. In certain embodiments, at least one R D1a is substituted alkyl. In certain embodiments, at least one R D1a is unsubstituted alkyl. In certain embodiments, at least one R D1a is C 1-6 alkyl. In certain embodiments, at least one R D1a is methyl. In certain embodiments, at least one R D1a is ethyl. In certain embodiments, at least one R D1a is propyl.
  • R D1a is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom.
  • R D1a is a sulfur protecting group when attached to a sulfur atom.
  • R D1a is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom.
  • two R D1a groups are joined to form a substituted heterocyclic ring.
  • two R D1a groups are joined to form an unsubstituted heterocyclic ring.
  • R D2 is methyl. In certain embodiments, R D2 is ethyl. In certain embodiments, R D2 is propyl. In certain embodiments, R D2 is butyl. In certain embodiments, R D2 is substituted alkenyl. In certain embodiments, R D2 is unsubstituted alkenyl. In certain embodiments, R D2 is substituted alkynyl. In certain embodiments, R D2 is unsubstituted alkynyl. In certain embodiments, R D2 is substituted carbocyclyl. In certain embodiments, R D2 is unsubstituted carbocyclyl. In certain embodiments, R D2 is substituted heterocyclyl.
  • R D2 is unsubstituted heterocyclyl. In certain embodiments, R D2 is substituted aryl. In certain embodiments, R D2 is unsubstituted aryl. In certain embodiments, R D2 is substituted phenyl. In certain embodiments, R D2 is unsubstituted phenyl. In certain embodiments, R D2 is substituted heteroaryl. In certain embodiments, R D2 is unsubstituted heteroaryl. In certain embodiments, R D2 is substituted pyridyl. In certain embodiments, R D2 is unsubstituted pyridyl. In certain embodiments, R D2 is —CN. In certain embodiments, R D2 is —NO 2 .
  • R D2 is —OR D2a . In certain embodiments, R D2 is —N(R D2a ) 2 . In certain embodiments, R D2 is —SR D2a . In certain embodiments, R D2 is —CH 2 OR D2a . In certain embodiments, R D2 is —CH 2 N(R D2a ) 2 . In certain embodiments, R D2 is —CH 2 SR D2a .
  • At least one R D2a is H. In certain embodiments, at least one R D2a is substituted acyl. In certain embodiments, at least one R D2a is unsubstituted acyl. In certain embodiments, at least one R D2a is acetyl. In certain embodiments, at least one R D2a is substituted alkyl. In certain embodiments, at least one R D2a is unsubstituted alkyl. In certain embodiments, at least one R D2a is C 1-6 alkyl. In certain embodiments, at least one R D2a is methyl. In certain embodiments, at least one R D2a is ethyl. In certain embodiments, at least one R D2a is propyl.
  • At least one R D2a is butyl. In certain embodiments, at least one R D2a is substituted alkenyl. In certain embodiments, at least one R D2a is unsubstituted alkenyl. In certain embodiments, at least one R D2a is substituted alkynyl. In certain embodiments, at least one R D2a is unsubstituted alkynyl. In certain embodiments, at least one R D2a is substituted carbocyclyl. In certain embodiments, at least one R D2a is unsubstituted carbocyclyl. In certain embodiments, at least one R D2a is substituted heterocyclyl.
  • At least one R D2a is unsubstituted heterocyclyl. In certain embodiments, at least one R D2a is substituted aryl. In certain embodiments, at least one R D2a is unsubstituted aryl. In certain embodiments, at least one R D2a is substituted phenyl. In certain embodiments, at least one R D2a is unsubstituted phenyl. In certain embodiments, at least one R D2a is substituted heteroaryl. In certain embodiments, at least one R D2a is unsubstituted heteroaryl. In certain embodiments, at least one R D2a is substituted pyridyl.
  • At least one R D2a is unsubstituted pyridyl. In certain embodiments, at least one R D2a is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R D2a is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R D2a is an oxygen protecting group when attached to an oxygen atom.
  • R D is of the formula:
  • one R B group is
  • one R B group is substituted or unsubstituted —CH 2 -(piperazinyl). In certain embodiments, one R B group is
  • one R B group is
  • one R B group is haloalkyl. In certain embodiments, one R B group is —CF 3 . In certain embodiments, one R B group is substituted or unsubstituted imidazoyl. In certain embodiments, one R B group is
  • one R B group is
  • a compound of Formula (A2) is a compound of Formula (A2-a), (A2-b), (A2-c), or (A2-d):
  • R A is substituted or unsubstituted C 1-6 alkyl.
  • R A is methyl.
  • l is 1.
  • R B is meta to the point of attachment of the amide linker.
  • l is 2.
  • the two R B groups are meta to the point of attachment of the amide linker.
  • l is 2; one R B group is meta to the point of attachment of the amide linker; and the second R B group is para to the point of attachment of the amide linker.
  • one R B group is substituted or unsubstituted C 1-6 alkyl.
  • one R B group is C 1-6 alkyl substituted with one —CN group.
  • one R B group is
  • one R B group is substituted or unsubstituted —CH 2 -(piperazinyl). In certain embodiments, one R B group is
  • one R B group is
  • one R B group is haloalkyl. In certain embodiments, one R B group is —CF 3 . In certain embodiments, one R B group is substituted or unsubstituted imidazoyl. In certain embodiments, one R B group is
  • one R B group is
  • one R B group is
  • one R B group is substituted or unsubstituted piperazinyl. In certain embodiments one R B group is
  • one R B group is
  • one R B group is
  • one R B group is substituted or unsubstituted morpholine. In certain emodiments, two R B groups are substituted or unsubstituted morpholine. In certain embodiments, all instances of R Xc are hydrogen. In certain embodiments, R Xa is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R Xa is methyl or ethyl.
  • a compound of Formula (A1) is a compound of Formula (A1-e)-(A1-p):
  • one R B group is substituted or unsubstituted —CH 2 -(piperazinyl). In certain embodiments, one R B group is
  • one R B group is
  • one R B group is substituted or unsubstituted piperazinyl. In certain embodiments, one R B group is
  • one R B group is
  • one R B group is
  • one R B group is substituted or unsubstituted morpholine. In certain embodiments, two R B groups are substituted or unsubstituted morpholine. In certain embodiments, all instances of R Xc are hydrogen. In certain embodiments, R Xa is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R Xa is methyl or ethyl.
  • a compound of Formula (A2) is a compound of Formula (A2-e)-(A2-p):
  • R Xa , R Xc , R A , and R B are defined herein.
  • R A is substituted or unsubstituted C 1-6 alkyl.
  • R A is methyl.
  • one R B group is substituted or unsubstituted C 1-6 alkyl.
  • one R B group is
  • one R B group is NC. In certain embodiments, one R B group is substituted or unsubstituted —CH 2 -(piperazinyl). In certain embodiments, one R B group is
  • one R B group is
  • one R B group is haloalkyl. In certain embodiments, one R B group is —CF 3 . In certain embodiments, one R B group is substituted or unsubstituted imidazoyl. In certain embodiments, one R B group is
  • one R B group is
  • one R B group is
  • one R B group is substituted or unsubstituted piperazinyl. In certain embodiments, one R B group is
  • one R B group is
  • one R B group is
  • one R B group is substituted or unsubstituted morpholine. In certain embodiments, two R B groups are substituted or unsubstituted morpholine. In certain embodiments, all instances of R Xc are hydrogen. In certain embodiments, R Xa is substituted or unsubstituted C 1-6 alkyl. In certain embodiments, R Xa is methyl or ethyl.
  • a compound of Formula (A) is a compound of Formula (A3) or (A4):
  • R D , R A , R B , and l are defined herein.
  • R A is substituted or unsubstituted C 1-6 alkyl.
  • R A is methyl.
  • l is 1.
  • R B is meta to the point of attachment of the amide linker,
  • l is 2.
  • the two R B groups are meta to the point of attachment of the amide linker.
  • l is 2; one R B group is meta to the point of attachment of the amide linker; and the second R B group is para to the point of attachment of the amide linker.
  • one R B group is substituted or unsubstituted C 1-6 alkyl.
  • one R B group is C 1-6 alkyl substituted with one —CN group.
  • one R B group is
  • one R B group is substituted or unsubstituted —CH 2 -(piperazinyl). In certain embodiments, one R B group is
  • one R B group is
  • one R B group is
  • one R B group is haloalkyl. In certain embodiments, one R B group is —CF 3 . In certain embodiments, one R B group is substituted or unsubstituted imidazoyl. In certain embodiments, one R B group is
  • one R B group is
  • one R B group is
  • one R B group is substituted or unsubstituted piperazinyl. In certain embodiments, one R B group is
  • one R B group is
  • one R B group is substituted or unsubstituted morpholine. In certain embodiments, two R B groups are substituted or unsubstituted morpholine. In certain embodiments, R D is R D is
  • R D is
  • R D is
  • a compound of Formula (A3) is a compound of Formula (A3-a), (A3-b), or (A3-c).
  • R D , R A , R B , and l are defined herein.
  • R A is substituted or unsubstituted C 1-6 alkyl.
  • R A is methyl.
  • l is 1.
  • R B is meta to the point of attachment of the amide linker,
  • l is 2.
  • the two R B groups are meta to the point of attachment of the amide linker.
  • l is 2; one R B group is meta to the point of attachment of the amide linker; and the second R B group is para to the point of attachment of the amide linker.
  • one R B group is substituted or unsubstituted C 1-6 alkyl.
  • one R B group is C 1-6 alkyl substituted with one —CN group.
  • one R B group is
  • one R B group is
  • a compound of Formula (A4) is a compound of Formula (A4-a), (A4-b), or (A4-c):
  • Compounds of Formula (V) include an aryl group for Ring A′ optionally substituted with one or more R A ′ groups.
  • Ring A′ is phenyl
  • the invention provides compounds of Formula (V-d):
  • Compounds of Formula (V) include an heteroaryl group for Ring A′ optionally substituted with one or more R A ′ groups.
  • Ring A′ is furo[2,3-c]pyridin-7-amine
  • the invention provides compounds of Formula (V-e C ):
  • Ring C′, Cy, Q′, U′, X′, Y′, Z′, R A ′, R B ′, R X ′, k′, and l′ are as defined herein.
  • R D3 ′ is selected from the group consisting of hydrogen, halogen, optionally substituted acyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted heteroaryl, —CN, —NO 2 , —OR D3a ′, —N(R D3a ′) 2 , —SR D3a ′, —CH 2 OR D3a ′, —CH 2 N(R D3a ′) 2 , —CH 2 SR D3a ′—C( ⁇ O)R D3a ′, —C( ⁇ O)OR D3a ′—C( ⁇ O)SR D3a ′, —C( ⁇ O)N(R D3a ′) 2 , —C( ⁇ S)R D3a ′, —C( ⁇ S)OR D3a ′
  • Compounds of Formula (II) include an aryl group for Ring A′ optionally substituted with one or more R A ′ groups.
  • Ring A′ is naphthyl
  • the invention provides compounds of Formula (II-b):
  • Compounds of Formula (II) include an aryl group for Ring A′ optionally substituted with one or more R A ′ groups.
  • Ring A′ is phenyl
  • the invention provides compounds of Formula (II-c):
  • Ring C′, Cy, Q′, U′, X′, Y′, Z′, R A ′, R B ′, R D ′, R X ′, k′, and l′, and m′ are as defined herein.
  • Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more R A ′ groups.
  • Ring A′ is pyrrolopyrimidine
  • the invention provides compounds of Formula (II-e):
  • Ring C′, Cy, Q′, U′, X′, Y′, Z′, R A ′, R B ′, R D ′, R X ′, k′, and l′, and m′ are as defined herein.
  • Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more R A ′ groups.
  • Ring A′ is pyrimidine
  • the invention provides compounds of Formula (II-e A ):
  • Ring C′, Cy, Q′, U′, X′, Y′, Z′, R A ′, R B ′, R D ′, R X ′, k′, and l′, and m′ are as defined herein.
  • Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more R A ′ groups.
  • Ring A′ is a furo[2,3-c]pyridin-7-amine
  • the invention provides compounds of Formula (II-e C ):
  • Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more R A ′ groups.
  • Ring A′ is quinazoline
  • the invention provides compounds of Formula (II-e D ):
  • Ring C′, Cy, Q′, U′, X′, Y′, Z′, R A ′, R B ′, R X ′, k′, and l′ are as defined herein.
  • Compounds of Formula (II) include an heteroaryl group for Ring A′ optionally substituted with one or more R A ′ groups.
  • Ring A′ is phenyl, and at least one R A ′ group links to Cy forming an optional 5 to 8 membered ring, the invention provides copounds of Formula (II-f):
  • R D ′ is a substituent on Ring A′, Ring C′, or Cy.
  • R D ′ comprises a Michael acceptor moiety. This Michael aceptor moiety may reach with a cysteine or other nucleophilic residue to allow covalent attachment of the compound to the target.
  • the covalent attachment is irreversible. In other embodiments, the covalent attachment is reversible.
  • R D ′ is of Formula (i-1). In certain embodiments, R D ′ is of Formula (i-2). In certain embodiments, R D ′ is of Formula (i-3). In certain embodiments, R D ′ is of Formula (I-4). In certain embodiments, R D ′ is of Formula (i-5).
  • R D ′ is of Formula (i-6). In certain embodiments, R D ′ is of Fomrula (i-7). In certain embodiments, R D ′ is of Formula (i-8). In certain embodiments, R D ′ is of Formula (i-9). In certain embodiments, R D ′ is of Formula (i-10). In certain embodiments, R D ′ is of Formula (i-11). In certain embodiments, R D ′ is of Formula (i-12). In certain embodiments, R D ′ is of Formula (i-13). In certain embodiments, R D ′ is of Formula (i-14). In certain embodiments, R D ′ is of Formula (i-15). In certain embodiments, R D ′ is of Formula (i-16). In certain embodiments, R D ′ is of Formula (i-17).
  • R D1 is unsubstituted alkyl.
  • R D1 ′ is C 1-6 alkyl.
  • R D1 ′ is methyl.
  • R D1 ′ is ethyl.
  • R D1 ′ is propyl.
  • R D1 ′ is butyl.
  • R D1 ′ is substituted alkenyl.
  • R D1 ′ is unsubstituted alkenyl.
  • R D1 ′ is substituted alkynyl.
  • R D1 ′ is unsubstituted alkynyl.
  • R D1′ is substituted carbocyclyl. In certain embodiments, R D1 ′ is unsubstituted carbocyclyl. In certain embodiments, R D1 ′ is substituted heterocyclyl. In certain embodiments, R D1 ′ is unsubstituted heterocyclyl. In certain embodiments, R D1 ′ is substituted aryl. In certain embodiments, R D1 ′ is unsubstituted aryl. In certain embodiments, R D1 ′ is substituted phenyl. In certain embodiments, R D1 ′ is unsubstituted phenyl. In certain embodiments, R D1 ′ is substituted heteroaryl.
  • At least one R D1a ′ is H. In certain embodiments, at least one R D1a ′ is substituted acyl. In certain embodiments, at least one R D1a ′ is unsubstituted acyl. In certain embodiments, at least one R D1a ′ is acetyl. In certain embodiments, at least one R D1a ′, is substituted alkyl. In certain embodiments, at least one R D1a ′ is unsubstituted alkyl. In certain embodiments, at least one R D1a ′ is C 1-6 alkyl. In certain embodiments, at least one R D1a ′ is methyl. In certain embodiments, at least one R D1a ′ is ethyl.
  • At least one R D1a ′ is substituted pyridyl. In certain embodiments, at least one R D1a ′ is unsubstituted pyridyl. In certain embodiments, at least one R D1a ′ is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R D1a ′ is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R D1a ′ is an oxygen protecting group when attached to an oxygen atom.
  • R D1a ′ is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom.
  • R D1a ′ is a sulfur protecting group when attached to a sulfur atom.
  • R D1a ′ is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom.
  • two R D1a ′ groups are joined to form a substituted heterocyclic ring.
  • two R D1a ′ groups are joined to form an unsubstituted heterocyclic ring.
  • R D2a ′ is unsubstituted alkyl. In certain embodiments, R D2a ′ is C 1-6 alkyl. In certain embodiments, R D2a ′ is methyl. In certain embodiments, R D2a ′ is ethyl. In certain embodiments, R D2a ′ is propyl. In certain embodiments, R D2a ′ is butyl. In certain embodiments, R D2a ′ is substituted alkenyl. In certain embodiments, R D2a ′ is unsubstituted alkenyl. In certain embodiments, R D2a ′ is substituted alkynyl. In certain embodiments, R D2a ′ is unsubstituted alkynyl.
  • R D2a ′ is substituted carbocyclyl. In certain embodiments, R D2a ′ is unsubstituted carbocyclyl. In certain embodiments, R D2a ′ is substituted heterocyclyl. In certain embodiments, R D2a ′ is unsubstituted heterocyclyl. In certain embodiments, R D2a ′ is substituted aryl. In certain embodiments, R D2a ′ is unsubstituted aryl. In certain embodiments, R D2a ′ is substituted phenyl. In certain embodiments, R D2a ′ is unsubstituted phenyl. In certain embodiments,R D2a ′ is substituted heteroaryl.
  • R D2a ′ is —CH 2 OR D2a ′. In certain embodiments, R D2a ′ is —CH 2 N(R D2a ′) 2 . In certain embodiments, R D2a ′ is —CH 2 SR D2a ′.
  • At least one R D2a ′ is H. In certain embodiments, at least one R D2a ′ is substituted acyl. In certain embodiments, at least one R D2a ′ is unsubstituted acyl. In certain embodiments, at least one R D2a ′ is acetyl. In certain embodiments, at least one R D2a ′ is substituted alkyl. In certain embodiments, at least one R D2a ′ is unsubstituted alkyl. In certain embodiments, at least one R D2a ′ is C 1-6 alkyl. In certain embodiments, at least one R D2a ′ is methyl. In certain embodiments, at least one R D2a ′ is ethyl.
  • At least one R D2a ′ is propyl. In certain embodiments, at least one R D2a ′ is butyl. In certain embodiments, at least one R D2a ′ is substituted alkenyl. In certain embodiments, at least one R D2a ′ is unsubstituted alkenyl. In certain embodiments, at least one R D2a ′ is substituted alkynyl. In certain embodiments, at least one R D2a ′ is unsubstituted alkynyl. In certain embodiments, at least one R D2a ′ is substituted carbocyclyl. In certain embodiments, at least one R D2a ′ is unsubstituted carbocyclyl.
  • At least one R D2a ′ is substituted heterocyclyl. In certain embodiments, at least one R D2a ′ is unsubstituted heterocyclyl. In certain embodiments, at least one R D2a ′ is substituted aryl. In certain embodiments, at least one R D2a ′ is unsubstituted aryl. In certain embodiments, at least one R D2a ′ is substituted phenyl. In certain embodiments, at least one R D2a ′ is unsubstituted phenyl. In certain embodiments, at least one R D2a ′ is substituted heteroaryl. In certain embodiments, at least one R D2a ′ is unsubstituted heteroaryl.
  • At least one R D2a ′ is substituted pyridyl. In certain embodiments, at least one R D2a ′ is unsubstituted pyridyl. In certain embodiments, at least one R D2a ′ is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R D2a ′ is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R D2a ′ is an oxygen protecting group when attached to an oxygen atom.
  • R D2a ′ is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom.
  • R D2a ′ is a sulfur protecting group when attached to a sulfur atom.
  • R D2a ′ is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom.
  • two R D2a ′ groups are joined to form a substituted heterocyclic ring.
  • two R D2a ′ groups are joined to form an unsubstituted heterocyclic ring.
  • R D ′ may include a substituent R D3 ′.
  • R D3 ′ is H.
  • R D3 ′ is halogen.
  • R D3 ′ is F.
  • R D3 ′ is Cl.
  • R D3 ′ is Br.
  • R D3 ′ is I (iodine).
  • R D3 ′ is substituted acyl.
  • R D3 ′ is unsubstituted acyl.
  • R D3 ′ is acetyl.
  • R D3 ′ is substituted alkyl.
  • R D3 ′ is unsubstituted alkyl. In certain embodiments, R D3 ′ is C 1-6 alkyl. In certain embodiments, R D3 ′ is methyl. In certain embodiments, R D3 ′ is ethyl. In certain embodiments, R D3 ′ is propyl. In certain embodiments, R D3 ′ is butyl. In certain embodiments, R D3 ′ is substituted alkenyl. In certain embodiments, R D3 ′ is unsubstituted alkenyl. In certain embodiments, R D3 ′ is substituted alkynyl. In certain embodiments, R D3 ′ is unsubstituted alkynyl.
  • R D3 ′ is substituted carbocyclyl. In certain embodiments, R D3 ′ is unsubstituted carbocyclyl. In certain embodiments, R D3 ′ is substituted heterocyclyl. In certain embodiments, R D3 ′ is unsubstituted heterocyclyl. In certain embodiments, R D3a ′ is substituted aryl. In certain embodiments, R D3a ′ is unsubstituted aryl. In certain embodiments, R D3a ′ is substituted phenyl. In certain embodiments, R D3 ′ is unsubstituted phenyl. In certain embodiments, R D3 ′ is substituted heteroaryl.
  • R D3 ′ is unsubstituted heteroaryl. In certain embodiments, R D3 ′ is substituted pyridyl. In certain embodiments, R D3a ′ is unsubstituted pyridyl. In certain embodiments, R D3a ′ is —CN. In certain embodiments, R D3a ′ is —NO 2 . In certain embodiments, R D3 ′ is —OR D3a ′. In certain embodiments, R D3a ′ is —N(R D3a ′) 2 . In certain embodiments, R D3 ′ is —SR D3a ′. In certain embodinrents, R D3 ′ is —CH 2 OR D3a ′. In certain embodiments, R D3 ′ is —CH 2 N(R D3a ′) 2 . In certain embodiments, R D3 ′ is —CH 2 SR D3a ′.
  • At least one R D3a ′ is H. In certain embodiments, at least one R D3a ′ is substituted acyl. In certain embodiments, at least one R D3a ′ is unsubstituted acyl. In certain embodiments, at least one R D3a ′ is acetyl. In certain embodiments, at least one R D3a ′ is substituted alkyl. In certain embodiments, at least one R D3a ′ is unsubstituted alkyl. In certain embodiments, at least one R D3a ′ is C 1-6 alkyl. In certain embodiments, at least one R D3a ′ is methyl. In certain embodiments, at least one R D3a ′ is ethyl.
  • At least one R D3a ′ is propyl. In certain embodiments, at least one R D3a ′ is butyl. In certain embodiments, at least one R D3a ′ is substituted alkenyl. In certain embodiments, at least one R D3a ′ is unsubstituted alkenyl. In certain embodiments, at least one R D3a ′ is substituted alkynyl. In certain embodiments, at least one R D3a ′ is unsubstituted alkynyl. In certain embodiments, at least one R D3a ′ is substituted carbocyclyl. In certain embodiments, at least one R D3a ′ is unsubstituted carbocyclyl.
  • At least one R D3a ′ is substituted heterocyclyl. In certain embodiments, at least one R D3a ′ is unsubstituted heterocyclyl. In certain embodiments, at least one R D3a ′ is substituted aryl. In certain embodiments, at least one R D3a ′ is unsubstituted aryl. In certain embodiments, at least one R D3a ′ is substituted phenyl. In certain embodiments, at least one R D3a ′ is unsubstituted phenyl. In certain embodiments, at least one R D3a ′, is substituted heteroaryl. In certain embodiments, at least one R D3a ′ is unsubstituted heteroaryl.
  • At least one R D3a ′ is substituted pyridyl. In certain embodiments, at least one R D3a ′ is unsubstituted pyridyl. In certain embodiments, at least one R D3a ′ is a nitrogen protecting group when attached to a nitrogen atom. In certain embodiments, at least one R D3a ′ is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts when attached to a nitrogen atom. In certain embodiments, R D3a ′ is an oxygen protecting group when attached to an oxygen atom.
  • R D3a ′ is silyl, TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl, pivaloyl, or benzoyl when attached to an oxygen atom.
  • R D3a ′ is a sulfur protecting group when attached to a sulfur atom.
  • R D3a ′ is acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl when attached to a sulfur atom.
  • two R D3a ′ groups are joined to form a substituted heterocyclic ring.
  • two R D3a ′ groups are joined to form an unsubstituted heterocyclic ring.
  • R D ′ may include a substituent R D4 ′.
  • R D4 ′ is a leaving group.
  • R D4 ′ is halogen.
  • R D4 ′ is F.
  • R D4 ′ is Cl.
  • R D4 ′ is Br.
  • R D4 ′ is I (iodine).
  • R D4 ′ is —OS( ⁇ O) w′ R D4a ′.
  • w′ is 1.
  • w′ is 2.
  • R D4 ′ is —OMs.
  • R D4 ′ is —OTf. In certain embodiments, R D4 ′ is —OTs. In certain embodiments, R D4 ′ is —OBs. In certain embodiments, R D4 ′ is 2-nitrobenzene-sulfonyloxy. In certain embodiments, R D4 ′ is —OR D4a ′. In certain embodiments, R D4 ′ is —OMe. In certain embodiments, R D4 ′ is —OCF 3 . In certain embodiments, R D4 ′ is —OPh. In certain embodimentsR D4 ′ is —OC( ⁇ O)R D4a ′. In certain embodiments, R D4 ′ is —OC( ⁇ O)Me.
  • R D4 ′ is —OC( ⁇ O)CF 3 . In certain embodiments, R D4 ′ is —OC( ⁇ O)Ph. In certain embodiments, R D4 ′ is —OC( ⁇ O)Cl. In certain embodiments, R D4 ′ is —OC( ⁇ O)OR D4a ′. In certain embodiments, R D4 ′ is —OC( ⁇ O)OMe. In certain embodiments, R D4 ′ is —OC( ⁇ O)O(t-Bu).
  • R D4a ′ is substituted alkynyl. In certain embodiments, R D4a ′ is unsubstituted alkynyl. In certain embodiments, R D4a ′ is ethynyl. In certain embodiments, R D4a ′ is substituted carbocyclyl. In certain embodiments, R D4a ′ is unsubstituted carbocyclyl. In certain embodiments, R D4a ′ is substituted heterocyclyl. In certain embodiments, R D4a ′ is unsubstituted heterocyclyl. In certain embodiments, R D4a ′ is substituted aryl. In certain embodiments, R D4a ′ is unsubstituted aryl.
  • R D4a ′ is substituted phenyl. In certain embodiments, R D4a ′ is unsubstituted phenyl. In certain embodiments, R D4a ′ is substituted heteroaryl. In certain embodiments, R D4a ′ is unsubstituted heteroaryl. In certain embodiments, R D4a ′ is substituted pyridyl. In certain embodiments, R D4a ′ is unsubstituted pyridyl.
  • R D ′ may include a substituent R D5 ′.
  • R D5 ′ is H.
  • R D5 ′ is substituted alkyl.
  • R D5 ′ is unsubstituted alkyl.
  • R D5 ′ is C 1-6 alkyl.
  • R D5 ′ is methyl.
  • R D5 ′ is ethyl.
  • R D5 ′ is propyl.
  • R D5 ′ is butyl.
  • R D5 ′ is a nitrogen protecting group.
  • R D5 ′ is Bn, BOC, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl, or Ts.
  • R D1 ′ and R D2 ′ are each hydrogen. In certain embodiments, R D1 ′ and R D3 ′ are each hydrogen. In certain embodiments, R D2 ′ and R D3 ′ are each hydrogen. In certain embodiments, R D1 ′, R D2′ , and R D3 ′ are each hydrogen. In certain embodiments, R D1 ′, R D2′ , and R D3′ , and R D5 ′ are each hydrogen.
  • A′ is 1. In certain embodiments, A′ is 2.
  • 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.
  • Y Z ′ is —O—. In certain embodiments, Y Z ′ is ⁇ O. In certain embodiments, Y Z ′ is —S—. In certain embodiments Y Z ′ is ⁇ S. In certain embodiments, Y Z ′ is 'NR D6 ′—, wherein R D6 ′ is hydrogen, C 1-6 alkyl, or a nitrogen protecting group. In certain embodiments, Y Z ′ is —NH—. In certain embodiments, Y Z ′ is —NCH 3 —. In certain embodiments, Y Z ′ is —N(BOC)—. In certain embodiments, Y Z ′ is —N(Fmoc)-.
  • Y Z ′ is —N(Cbz)-. In certain embodiments, Y Z ′ is —N(Bn)-. In certain embodiments, Y Z ′ is —NR D6 ′, wherein R D6 ′ is hydrogen, C 1-6 alkyl, or a nitrogen protecting group. In certain embodiments, Y Z ′ is ⁇ NH. In certain embodiments, Y Z ′ is ⁇ NCH 3 . In certain embodiments, Y Z ′ is —NTs. In certain embodiments, Y Z ′ is ⁇ NBn. In certain embodiments, Y Z ′ is ⁇ NCH(Ph) 2 .
  • R D ′ is of the formula:
  • R D ′ is of the formula:
  • R D ′ is of the formula:
  • R D ′ is of the formula:
  • R D ′ is of the formula:
  • R D ′ is of the formula:
  • R D ′ is of the formula:
  • R D ′ is of the formula:
  • Ring A′ is of the formula:
  • Ring A′ is of the formula:
  • Ring A′ is of the formula:
  • Ring A′ is of the formula:
  • Ring A′ is of the formula:
  • Ring A′ is of the formula:
  • Ring A′ is of the formula:
  • k′ is 4.
  • Ring A′ is of the formula:
  • Ring A′ is of the formula:
  • Compounds of Formula (II) or (V) include an aryl Ring A′ optionally substituted with one or more R A ′ groups.
  • X′, Y′, and Z′ are bonds, and Cy is hydrogen.
  • k′ is 0.
  • Ring A′ is of the formula:
  • k′ is 1.
  • Ring A′ is of the formula:
  • Ring A′ is of the formula:
  • Ring A′ is of the formula:
  • k′ is 2. In certain embodiments, Ring A′ is of the formula:
  • Ring A′ is of the formula:
  • Ring A′ is of the formula:
  • Ring A′ is of the formula:
  • Ring A′ is of the formula:
  • Ring A′ is of the formula:
  • Ring A′ is of the formula:
  • Ring A′ is of the formula:
  • Ring A′ may be substituted with one or more R A ′ groups.
  • at least one R A ′ is H.
  • at least two R A ′ groups are H.
  • at least three R A ′ groups are H.
  • at least four R A ′ groups are H.
  • at least one R A ′ is halogen.
  • at least one R A ′ is F.
  • at least one R A ′ is Cl.
  • at least one R A ′ is Br.
  • at least one R A ′ is I (iodine).
  • At least one R A ′ is substituted acyl. In certain embodiments, at least one R A ′ is —C( ⁇ O)N(R A1 ′) 2 . In certain embodiments, at least one R A ′ is —C( ⁇ O)NHR A1 ′. In certain embodiments, at least one R A ′ is —C( ⁇ O)NH(C 1-6 alkyl). In certain embodiments, at least one R A ′ is —C( ⁇ O)NHMe. In certain embodiments, at least one R A ′ is —C( ⁇ O)NH 2 . In certain embodiments, at least one R A ′ is unsubstituted acyl.
  • At least one R A ′ is acetyl. In certain embodiments, at least one R A ′ is substituted alkyl. In certain embodiments, at least one R A ′ is substituted methyl. In certain embodiments, at least one R A ′ is unsubstituted alkyl. In certain embodiments, at least one R A ′ is C 1-6 alkyl. In certain embodiments, at least one R A ′ is methyl. In certain embodiments, at least one R A ′ is ethyl. In certain embodiments, at least one R A ′ is propyl. In certain embodiments, at least one R A ′ is butyl. In certain embodiments, at least one R A ′ is substituted alkenyl.
  • At least one R A ′ is unsubstituted alkenyl. In certain embodiments, at least one R A ′ is substituted alkynyl. In certain embodiments, at least one R A ′ is unsubstituted alkynyl. In certain embodiments, at least one R A ′ is substituted carbocyclyl. In certain embodiments, at least one R A ′ is unsubstituted carbocyclyl. In certain embodiments, at least one R A ′ is substituted heterocyclyl. In certain embodiments, at least one R A ′ is unsubstituted heterocyclyl. In certain embodiments, at least one R A ′ is
  • At least one R A ′ is substituted aryl. In certain embodiments, at least one R A ′ is unsubstituted aryl. In certain embodiments, at least one R A ′ is substituted phenyl. In certain embodiments, at least one R A ′ is unsubstituted phenyl. In certain embodiments, at least one R A ′ is substituted heteroaryl. In certain embodiments, at least one R A ′ is unsubstituted heteroaryl. In certain embodiments, at least one R A ′ is substituted pyridyl. In certain embodiments, at least one R A ′ is unsubstituted pyridyl.
  • At least one R A ′ is —OR A1 ′. In certain embodiments, at least one R A ′ is —O(C 1-6 alkyl). In certain embodiments, at least one R A ′ is OMe. In certain embodiments, at least one R A ′ is —OH. In certain embodiments, at least one R A ′ is —N(R A1 ′) 2 . In certain embodiments, at least one R A ′ is —NH 2 . In certain embodiments, at least one R A ′ is —SR A1′ . In certain embodiments, at least one R A ′ is —SH.
  • At least one R A ′ is —NR A1 ′C( ⁇ O)N(R A1 ′) 2 . In certain embodiments, at least one R A ′ is —NHC( ⁇ O)N(R A1 ′) 2 . In certain embodiments, at least one one R A ′ is —NHC( ⁇ O)NHR A1 ′. In certain embodiments, at least one R A ′ is —NHC( ⁇ O)NH(C 1-6 alkyl). In certain embodiments, at least one one R A ′ is —NHC( ⁇ O)NHMe. In certain embodiments, at least one R A ′ is —NHC( ⁇ O)NH 2 .
  • At least one R A ′ is —NR A1 ′C( ⁇ O)NHR A1 ′. In certain embodiments, at least one R A ′ is —NR A1 ′C( ⁇ O)NH 2 . In certain embodiments, at least one one R A ′ is —NR A1 ′S( ⁇ O) 2 R A1 ′. In certain embodiments, at least one R A ′ is —NHS( ⁇ O) 2 R A1 ′. In certain embodiments, at least one R A ′ is —NHS( ⁇ O) 2 (C 1-6 alkyl). In certain embodiments, at least one R A ′ is —NHS( ⁇ O) 2 Me.
  • At least one R A ′ is —S( ⁇ O) 2 N(R A1 ′) 2 . In certain embodiments, at least one R A ′ is —S( ⁇ O) 2 N(R A1 ′) 2 . In certain embodiments, at least one R A ′ is —S( ⁇ O) 2 N(C 1-6 alkyl) 2 . In certain embodiments, at least one R A ′ is —S( ⁇ O) 2 NH(C 1-6 alkyl). In certain embodiments, at least one R A ′ is —S( ⁇ O) 2 NH(t-Bu). In certain embodiments, at least one R A ′ is —S( ⁇ O) 2 NH 2 .
  • Ring C′ may be substituted with one or more one R B ′ groups.
  • at least one R B ′ is H.
  • at least two R B ′ groups are H.
  • at least three R B ′ groups are H.
  • at least four R B ′ groups are H.
  • at least one R B ′ is halogen.
  • at least one R B ′ is F.
  • at least one R B ′ is Cl.
  • at least one R B ′ is Br.
  • at least one R B ′ is I (iodine).
  • At least one R B ′ is substituted alkenyl. In certain embodiments, at least one R B ′ is unsubstituted alkenyl. In certain embodiments, at least one R B ′ is substituted alkynyl. In certain embodiments, at least one R B ′ is unsubstituted alkynyl. In certain embodiments, at least one R B ′ is substituted carbocyclyl. In certain embodiments, at least one R B ′ is unsubstituted carbocyclyl. In certain embodiments, at least one R B ′ is substituted heterocyclyl. In certain embodiments, at least one R B ′ is unsubstituted heterocyclyl.
  • At least one R B ′ is substituted aryl. In certain embodiments, at least one R B ′ is unsubstituted aryl. In certain embodiments, at least one R B ′ is substituted phenyl. In certain embodiments, at least one R B ′ is unsubstituted phenyl. In certain embodiments, at least one R B ′ is substituted heteroaryl. In certain embodiments, at least one R B ′ is unsubstituted heteroaryl. In certain embodiments, at least one R B ′ is substituted pyridyl. In certain embodiments, at least one R B ′ is unsubstituted pyridyl.
  • At least one R B ′ is —O A1 . In certain embodiments, at least one R B ′ is —O(C 1-6 alkyl). In certain embodiments, at least one R B ′ is —OMe. In certain embodiments, at least one R B ′ is —OH. In certain embodiments, at least one R B ′ is —N(R A1 ′) 2 . In certain embodiments, at least one R B ′ is —NH 2 . In certain embodiments, at least one R B ′ is —SR A1 ′. In certain embodiments, at least one R B ′ is —SH.
  • At least one R B ′ is —NR A1 ′C( ⁇ O)N(R A1 ′) 2 . In certain embodiments, at least one R B ′ is —NHC( ⁇ O)N(R A1 ′) 2 . In certain embodiments, at least one R B ′ is —NHC( ⁇ O)NHR A1 ′. In certain embodiments, at least one R B ′ is —NHC( ⁇ O)NH(C 1-6 alkyl). In certain embodiments, at least one R B ′ is —NHC( ⁇ O)NHMe. In certain embodiments, at least one R B ′ is —NHC( ⁇ O)NH 2 .
  • At least one R B ′ is —NR A1 ′C( ⁇ O)NHR A1 ′. In certain embodiments, at least one R B ′ is —NR A1 ′C( ⁇ O)NH 2 . In certain embodiments, at least one R B ′ is —NR A1 ′S( ⁇ O) 2 R A1 ′. In certain embodiments, at least one R B ′ is —NHS( ⁇ O) 2 R A1 ′. In certain embodiments, at least one R B ′ is —NHS( ⁇ O) 2 (C 1-6 alkyl). In certain embodiments, at least one R B ′ is —NHS( ⁇ O) 2 Me.
  • At least one R B ′ is
  • At least one R B ′ is
  • At least one R B ′ is
  • At least one R B ′ is
  • At least one R B ′ is
  • At least one R B ′ is
  • X′, Y′, and Z′ together represent
  • X′, Y′, and Z′ together represent

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