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WO2025024688A1 - Inhibiteurs d'ire1alpha et leurs utilisations - Google Patents

Inhibiteurs d'ire1alpha et leurs utilisations Download PDF

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Publication number
WO2025024688A1
WO2025024688A1 PCT/US2024/039590 US2024039590W WO2025024688A1 WO 2025024688 A1 WO2025024688 A1 WO 2025024688A1 US 2024039590 W US2024039590 W US 2024039590W WO 2025024688 A1 WO2025024688 A1 WO 2025024688A1
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substituted
unsubstituted
compound
membered
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Feroz R. PAPA
Bradley J. Backes
Dustin J. MALY
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University of Washington
University of California Berkeley
University of California San Diego UCSD
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University of Washington
University of California Berkeley
University of California San Diego UCSD
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • ER protein-folding capacity During mammalian cell growth and differentiation, the unfolded protein response (UPR) homeostatically adjusts endoplasmic reticulum (ER) protein-folding capacity to match changing cellular secretory demands.
  • ER endoplasmic reticulum
  • RNase ER transmembrane kinase/endoribonuclease
  • IRE1 ⁇ kinase auto- phosphorylation operates as a rheostat to control downstream RNase-induced outputs that either sustain adaptive ER protein-folding or cause apoptosis.
  • the IRE1 ⁇ RNase can be controlled allosterically by kinase inhibitors that at maximal occupancy either fully inactivate or activate the RNAse.
  • kinase inhibitors that at maximal occupancy either fully inactivate or activate the RNAse.
  • Overwhelming of protein folding and structural maturation in the early secretory pathway leads to accumulation of misfolded and immature secretory proteins in the endoplasmic reticulum (ER) (PMIDs: 22116877).
  • ER endoplasmic reticulum
  • Eukaryotic cells evolved intracellular signaling pathways to respond to such “ER stress”. These “Unfolded Protein Response” (UPR) pathways maintain cellular secretory function and physiological health in the face of remediable ER stress (PMIDs: 29107536).
  • UTR Unfolded Protein Response
  • UPR pathways promote homeostatic/adaptive outputs through transcriptional upregulation of ER protein-folding and quality-control factors that extract terminally misfolded proteins back to the cytosol for degradation.
  • PCD programmed cell death
  • PMIDs 29107536
  • Multi-cellular organisms may benefit from culling irreversibly ER-stressed cells because the protein cargo that surviving cells continue to secrete is more likely to be pristine.
  • IRE1 ⁇ ER transmembrane multi-domain sensor protein
  • IRE1 ⁇ is activated upon ER stress elevation, causing this sensor to self-associate in the ER membrane.
  • This event causes IRE1 ⁇ ’s cytosolic Ser/Thr kinase to trans auto-phosphorylate, which results in subsequent activation of its C-terminal endoribonuclease (RNase) catalytic domain.
  • RNase C-terminal endoribonuclease
  • the range of available IRE1 ⁇ RNase activation states runs a gamut from the inactive, the active, to the hyperactive, with the level of activity controlled rheostatically by the upstream kinase module. From its inactive monomeric state, low-level kinase/RNase activation (caused by dimerization) initiates (adaptive) XBP1 mRNA transcription factor frame-shift splicing, while high-level kinase/RNase hyperactivation (due to homo-oligomerization) expands the RNase substrate repertoire to myriad ER-localized mRNAs that become endonucleolytically cleaved (in a process termed RIDD), (PMCIDs: 2762408, 4244221), thus initiating apoptosis.
  • RIDD RIDD
  • the “sweet spot” for IRE1 ⁇ RNase activation may lie at a level wherein XBP1 mRNA splicing remains permissible, but without the initiation of RIDD.
  • the cellular effects of such a meta-stable activation state have even been demonstrated with IRE1 ⁇ mutants (some found naturally as somatic mutations in cancers that act as RNase hypomorphs) and chemical-genetic (“bumped inhibitor/holed kinase”) systems (PMIDs: 25018104 and 19665977).
  • L 1 is a bond, -O-, -S-, -S(O)-, -S(O)2-, -NR 10 -, -C(O)-, -C(O)NR 10 -, -NR 10 C(O)-, -C(O)O-, -OC(O)-, -NR 10 S(O)-, -S(O)NR 10 -, -NR 10 S(O)2-, -S(O)2NR 10 -, -NR 10 C(O)O-, -OC(O)NR 10 -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene
  • L 2 is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, or substituted or unsubstituted heteroarylene.
  • R 1 is hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO 3 H, -SO 2 NH 2 , ⁇ NHNH 2 , ⁇ ONH 2 , ⁇ NHC(O)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I, -OCHCl
  • R 2 is –N(R 2A )(R 2B ) or a substituted or unsubstituted nitrogen-containing heterocycloalkyl.
  • R 2A and R 2B are independently hydrogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH2F, substituted or unsubstituted al
  • Each R 3 and R 4 is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -OCH 2 Cl, -OCH 2 Br, -OCH2F, -OCH2I, -OCHCl2,
  • R 10 is hydrogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubsti
  • a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a method of treating a cancer, neurodegenerative disorder, inflammatory disease, fibrosing disorder, demyelinating disorder, dermatologic disorder, rheumatic disease, autoimmune disease, metabolic disorder, or eye disease in a subject in need thereof the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a method of treating a disease associated with IRE1 ⁇ activity in a subject in need thereof including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • a method of decreasing the level of IRE1 ⁇ protein activity in a subject in need thereof the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • the alkyl may include a designated number of carbons (e.g., C1-C10 means one to ten carbons). In embodiments, the alkyl is fully saturated. In embodiments, the alkyl is monounsaturated. In embodiments, the alkyl is polyunsaturated. Alkyl is an uncyclized chain.
  • saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.
  • An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-).
  • An alkyl moiety may be an alkenyl moiety.
  • An alkyl moiety may be an alkynyl moiety.
  • An alkenyl includes one or more double bonds.
  • An alkynyl includes one or more triple bonds.
  • alkylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyl, as exemplified, but not limited by, -CH 2 CH 2 CH 2 CH 2 -.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred herein.
  • a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • alkenylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene.
  • alkynylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyne.
  • the alkylene is fully saturated.
  • the alkylene is monounsaturated.
  • the alkylene is polyunsaturated.
  • An alkenylene includes one or more double bonds.
  • An alkynylene includes one or more triple bonds.
  • heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom (e.g., O, N, P, Si, and S), and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) e.g., N, S, Si, or P
  • Heteroalkyl is an uncyclized chain.
  • a heteroalkyl moiety may include one heteroatom (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include two optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include three optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include four optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include five optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • a heteroalkyl moiety may include up to 8 optionally different heteroatoms (e.g., O, N, S, Si, or P).
  • the term “heteroalkenyl,” by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one double bond.
  • a heteroalkenyl may optionally include more than one double bond and/or one or more triple bonds in additional to the one or more double bonds.
  • heteroalkynyl by itself or in combination with another term, means, unless otherwise stated, a heteroalkyl including at least one triple bond.
  • a heteroalkynyl may optionally include more than one triple bond and/or one or more double bonds in additional to the one or more triple bonds.
  • the heteroalkyl is fully saturated.
  • the heteroalkyl is monounsaturated.
  • the heteroalkyl is polyunsaturated.
  • the term “heteroalkylene,” by itself or as part of another substituent means, unless otherwise stated, a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH2-CH2-S-CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-.
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula - C(O) 2 R'- represents both -C(O) 2 R'- and -R'C(O) 2 -.
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R'', -OR', -SR', and/or -SO 2 R'.
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R'' or the like, it will be understood that the terms heteroalkyl and -NR'R'' are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity.
  • heteroalkyl should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like.
  • heteroalkenylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkene.
  • heteroalkynylene by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkyne.
  • the heteroalkylene is fully saturated.
  • the heteroalkylene is monounsaturated.
  • the heteroalkylene is polyunsaturated.
  • a heteroalkenylene includes one or more double bonds.
  • a heteroalkynylene includes one or more triple bonds.
  • cycloalkyl examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocycloalkyl examples include, but are not limited to, 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3- morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl, 2-piperazinyl, and the like.
  • the cycloalkyl is fully saturated.
  • the cycloalkyl is monounsaturated.
  • the cycloalkyl is polyunsaturated.
  • the heterocycloalkyl is fully saturated.
  • the heterocycloalkyl is monounsaturated.
  • the heterocycloalkyl is polyunsaturated.
  • cycloalkyl means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system.
  • monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic.
  • cycloalkyl groups are fully saturated.
  • a bicyclic or multicyclic cycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a cycloalkyl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within a cycloalkyl ring of the multiple rings.
  • a cycloalkyl is a cycloalkenyl.
  • the term “cycloalkenyl” is used in accordance with its plain ordinary meaning.
  • a cycloalkenyl is a monocyclic, bicyclic, or a multicyclic cycloalkenyl ring system.
  • a bicyclic or multicyclic cycloalkenyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a cycloalkenyl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within a cycloalkenyl ring of the multiple rings.
  • heterocycloalkyl means a monocyclic, bicyclic, or a multicyclic heterocycloalkyl ring system.
  • heterocycloalkyl groups are fully saturated.
  • a bicyclic or multicyclic heterocycloalkyl ring system refers to multiple rings fused together wherein at least one of the fused rings is a heterocycloalkyl ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heterocycloalkyl ring of the multiple rings.
  • halo or “halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl” are meant to include monohaloalkyl and polyhaloalkyl.
  • halo(C1-C4)alkyl includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • acyl means, unless otherwise stated, -C(O)R where R is a substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • aryl means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent, which can be a single ring or multiple rings (preferably from 1 to 3 rings) that are fused together (i.e., a fused ring aryl) or linked covalently.
  • a fused ring aryl refers to multiple rings fused together wherein at least one of the fused rings is an aryl ring and wherein the multiple rings are attached to the parent molecular moiety through any carbon atom contained within an aryl ring of the multiple rings.
  • heteroaryl refers to aryl groups (or rings) that contain at least one heteroatom such as N, O, or S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized.
  • heteroaryl includes fused ring heteroaryl groups (i.e., multiple rings fused together wherein at least one of the fused rings is a heteroaromatic ring and wherein the multiple rings are attached to the parent molecular moiety through any atom contained within a heteroaromatic ring of the multiple rings).
  • a 5,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 5 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,6-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 6 members, and wherein at least one ring is a heteroaryl ring.
  • a 6,5-fused ring heteroarylene refers to two rings fused together, wherein one ring has 6 members and the other ring has 5 members, and wherein at least one ring is a heteroaryl ring.
  • a heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom.
  • Non-limiting examples of aryl and heteroaryl groups include phenyl, naphthyl, pyrrolyl, pyrazolyl, pyridazinyl, triazinyl, pyrimidinyl, imidazolyl, pyrazinyl, purinyl, oxazolyl, isoxazolyl, thiazolyl, furyl, thienyl, pyridyl, pyrimidyl, benzothiazolyl, benzoxazoyl benzimidazolyl, benzofuran, isobenzofuranyl, indolyl, isoindolyl, benzothiophenyl, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2- pyrrolyl, 3-pyrrolyl, 3-pyrazolyl, 2-imidazolyl, 4-imid
  • arylene and heteroarylene are selected from the group of acceptable substituents described below.
  • a heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen.
  • Spirocyclic rings are two or more rings wherein adjacent rings are attached through a single atom. The individual rings within spirocyclic rings may be identical or different.
  • Individual rings in spirocyclic rings may be substituted or unsubstituted and may have different substituents from other individual rings within a set of spirocyclic rings. Possible substituents for individual rings within spirocyclic rings are the possible substituents for the same ring when not part of spirocyclic rings (e.g., substituents for cycloalkyl or heterocycloalkyl rings).
  • Spirocylic rings may be substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heterocycloalkylene and individual rings within a spirocyclic ring group may be any of the immediately previous list, including having all rings of one type (e.g., all rings being substituted heterocycloalkylene wherein each ring may be the same or different substituted heterocycloalkylene).
  • heterocyclic spirocyclic rings means a spirocyclic rings wherein at least one ring is a heterocyclic ring and wherein each ring may be a different ring.
  • substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different.
  • alkylarylene as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker).
  • alkylarylene group has the formula: .
  • the alkylene moiety or the arylene linker (e.g., at carbons 2, 3, 4, or 6) with halogen, oxo, -N 3 , -CF3, -CCl3, -CBr3, -CI3, -CN, -CHO, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO2CH3, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, substituted or unsubstituted C1-C5 alkyl or substituted or unsubstituted 2 to 5 membered heteroalkyl).
  • the alkylarylene is unsubstituted.
  • Each of the above terms e.g., “alkyl,” “heteroalkyl,” “cycloalkyl,” “heterocycloalkyl,” “aryl,” and “heteroaryl” includes both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.
  • R, R', R'', R'', and R''' each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted heteroaryl, substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.
  • aryl e.g., aryl substituted with 1-3 halogens
  • substituted or unsubstituted heteroaryl substituted or unsubstituted alkyl, alkoxy, or thioalkoxy groups, or arylalkyl groups.
  • each of the R groups is independently selected as are each R', R'', R''', and R''' group when more than one of these groups is present.
  • R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7- membered ring.
  • -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4- morpholinyl.
  • alkyl is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF 3 and -CH 2 CF 3 ) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like).
  • haloalkyl e.g., -CF 3 and -CH 2 CF 3
  • acyl e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like.
  • each of the R groups is independently selected as are each R', R'', R'', and R''' groups when more than one of these groups is present.
  • Substituents for rings e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene
  • substituents on the ring may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent).
  • the substituent may be attached to any of the ring atoms (obeying the rules of chemical valency) and in the case of fused rings or spirocyclic rings, a substituent depicted as associated with one member of the fused rings or spirocyclic rings (a floating substituent on a single ring), may be a substituent on any of the fused rings or spirocyclic rings (a floating substituent on multiple rings).
  • the multiple substituents may be on the same atom, same ring, different atoms, different fused rings, different spirocyclic rings, and each substituent may optionally be different.
  • a point of attachment of a ring to the remainder of a molecule is not limited to a single atom (a floating substituent)
  • the attachment point may be any atom of the ring and in the case of a fused ring or spirocyclic ring, any atom of any of the fused rings or spirocyclic rings while obeying the rules of chemical valency.
  • a ring, fused rings, or spirocyclic rings contain one or more ring heteroatoms and the ring, fused rings, or spirocyclic rings are shown with one more floating substituents (including, but not limited to, points of attachment to the remainder of the molecule), the floating substituents may be bonded to the heteroatoms.
  • the ring heteroatoms are shown bound to one or more hydrogens (e.g., a ring nitrogen with two bonds to ring atoms and a third bond to a hydrogen) in the structure or formula with the floating substituent, when the heteroatom is bonded to the floating substituent, the substituent will be understood to replace the hydrogen, while obeying the rules of chemical valency.
  • Two or more substituents may optionally be joined to form aryl, heteroaryl, cycloalkyl, or heterocycloalkyl groups.
  • Such so-called ring-forming substituents are typically, though not necessarily, found attached to a cyclic base structure.
  • the ring-forming substituents are attached to adjacent members of the base structure.
  • two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure.
  • the ring-forming substituents are attached to a single member of the base structure.
  • two ring- forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure.
  • the ring-forming substituents are attached to non-adjacent members of the base structure.
  • Two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally form a ring of the formula -T-C(O)-(CRR') q -U-, wherein T and U are independently -NR-, -O-, -CRR'-, or a single bond, and q is an integer of from 0 to 3.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH 2 ) r -B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O) 2 -, -S(O) 2 NR'-, or a single bond, and r is an integer of from 1 to 4.
  • One of the single bonds of the new ring so formed may optionally be replaced with a double bond.
  • two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -(CRR') s -X'- (C''R''R'') d -, where s and d are independently integers of from 0 to 3, and X' is -O-, -NR'-, -S-, -S(O)-, -S(O) 2 -, or -S(O) 2 NR'-.
  • R, R', R'', and R''' are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
  • heteroatom or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), selenium (Se), and silicon (Si).
  • heteroatom or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si).
  • a “substituent group,” as used herein, means a group selected from the following moieties: (A) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -
  • a “size-limited substituent” or “size-limited substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 20 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3-C8 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl, and each substituted or unsubstituted heteroaryl
  • a “lower substituent” or “lower substituent group,” as used herein, means a group selected from all of the substituents described above for a “substituent group,” wherein each substituted or unsubstituted alkyl is a substituted or unsubstituted C1-C8 alkyl, each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C3- C 7 cycloalkyl, each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl, each substituted or unsubstituted aryl is a substituted or unsubstituted phenyl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstitute
  • each substituted group described in the compounds herein is substituted with at least one substituent group. More specifically, in some embodiments, each substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene described in the compounds herein are substituted with at least one substituent group. In other embodiments, at least one or all of these groups are substituted with at least one size-limited substituent group.
  • each substituted or unsubstituted alkyl may be a substituted or unsubstituted C 1 -C 20 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 20 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 8 cycloalkyl
  • each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 8 membered heterocycloalkyl
  • each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 - C10 aryl
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted or unsubstituted
  • each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C20 alkylene
  • each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 20 membered heteroalkylene
  • each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C 3 -C 8 cycloalkylene
  • each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 8 membered heterocycloalkylene
  • each substituted or unsubstituted arylene is a substituted or unsubstituted C6-C10 arylene
  • each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene.
  • each substituted or unsubstituted alkyl is a substituted or unsubstituted C 1 -C 8 alkyl
  • each substituted or unsubstituted heteroalkyl is a substituted or unsubstituted 2 to 8 membered heteroalkyl
  • each substituted or unsubstituted cycloalkyl is a substituted or unsubstituted C 3 -C 7 cycloalkyl
  • each substituted or unsubstituted heterocycloalkyl is a substituted or unsubstituted 3 to 7 membered heterocycloalkyl
  • each substituted or unsubstituted aryl is a substituted or unsubstituted C 6 -C 10 aryl
  • each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl.
  • each substituted or unsubstituted alkylene is a substituted or unsubstituted C1-C8 alkylene
  • each substituted or unsubstituted heteroalkylene is a substituted or unsubstituted 2 to 8 membered heteroalkylene
  • each substituted or unsubstituted cycloalkylene is a substituted or unsubstituted C3-C7 cycloalkylene
  • each substituted or unsubstituted heterocycloalkylene is a substituted or unsubstituted 3 to 7 membered heterocycloalkylene
  • each substituted or unsubstituted arylene is a substituted or unsubstituted C 6 -C 10 arylene
  • each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene.
  • the compound is a chemical species set forth in the Examples section, figures, or tables below.
  • a substituted or unsubstituted moiety e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is unsubstituted (e.g., is an unsubstituted alkyl, unsubstituted cycloalkyl, substituted
  • a substituted or unsubstituted moiety e.g., substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene, and/or substituted or unsubstituted heteroarylene) is substituted (e.g., is a substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alky
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • is substituted with at least one substituent group wherein if the substituted moiety is substituted with a plurality of substituent groups, each substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of substituent groups, each substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • is substituted with at least one size-limited substituent group wherein if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group may optionally be different.
  • each size-limited substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • each lower substituent group is different.
  • a substituted moiety e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, substituted heteroaryl, substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • each substituent group, size-limited substituent group, and/or lower substituent group is different.
  • each R substituent or L linker that is described as being “substituted” without reference as to the identity of any chemical moiety that composes the “substituted” group also referred to herein as an “open substitution” on an R substituent or L linker or an “openly substituted” R substituent or L linker
  • the recited R substituent or L linker may, in embodiments, be substituted with one or more first substituent groups as defined below.
  • the first substituent group is denoted with a corresponding first decimal point numbering system such that, for example, R 1 may be substituted with one or more first substituent groups denoted by R 1.1 , R 2 may be substituted with one or more first substituent groups denoted by R 2.1 , R 3 may be substituted with one or more first substituent groups denoted by R 3.1 , R 4 may be substituted with one or more first substituent groups denoted by R 4.1 , R 5 may be substituted with one or more first substituent groups denoted by R 5.1 , and the like up to or exceeding an R 100 that may be substituted with one or more first substituent groups denoted by R 100.1 .
  • R 1A may be substituted with one or more first substituent groups denoted by R 1A.1
  • R 2A may be substituted with one or more first substituent groups denoted by R 2A.1
  • R 3A may be substituted with one or more first substituent groups denoted by R 3A.1
  • R 4A may be substituted with one or more first substituent groups denoted by R 4A.1
  • R 5A may be substituted with one or more first substituent groups denoted by R 5A.1 and the like up to or exceeding an R 100A may be substituted with one or more first substituent groups denoted by R 100A.1 .
  • L 1 may be substituted with one or more first substituent groups
  • L 2 may be substituted with one or more first substituent groups denoted by be substituted with one or more first substituent groups denoted by R L3.1
  • L 4 may be substituted with one or more first substituent groups denoted by R L4.1
  • L 5 may be substituted with one or more first substituent groups denoted by R L5.1 and the like up to or exceeding an L 100 which may be substituted with one or more first substituent groups denoted by R L100.1 .
  • each numbered R group or L group (alternatively referred to herein as R WW or L WW wherein “WW” represents the stated superscript number of the subject R group or L group) described herein may be substituted with one or more first substituent groups referred to herein generally as R WW.1 or R LWW.1 , respectively.
  • each first substituent group (e.g., R 1.1 , R 2.1 , R 3.1 , R 4.1 , R 1A.1 , R 2A.1 , R 3A.1 , R 4A.1 , R 5A.1 ... R 100A.1 ; R L1.1 , R L2.1 , R L3.1 , R L4.1 , R L5.1 ... R L100.1 ) may be R 5.2 ... R 100.2 ; R 1A.2 , R 2A.2 , R 3A.2 , R 4A.2 , R 5A.2 ... R 100A.2 ; R L1.2 , R L2.2 , R L3.2 , R L4.2 , R L5.2 ... represented herein as R WW.1 as described above, may be further substituted with one or more second substituent groups, which may alternatively be represented herein as R WW.2 .
  • each second substituent group (e.g., R 1.2 , R 2.2 , R 3.2 , R 4.2 , R 5.2 ... R 100.2 ; R 1A.2 , R 2A.2 , R 3A.2 , R 4A.2 , R 5A.2 ... R 100A.2 ; R L1.2 , R L2.2 , R L3.2 , R L4.2 , R L5.2 ... R L100.2 ) may be further R 1A.3 , R 2A.3 , R 3A.3 , R 4A.3 , R 5A.3 ... R 100A.3 ; R L1.3 , R L2.3 , R L3.3 , R L4.3 , R L5.3 ... R L100.3 ; represented herein as R WW.2 as described above, may be further substituted with one or more third substituent groups, which may alternatively be represented herein as R WW.3 .
  • R WW represents a substituent recited in a claim or chemical formula description herein which is openly substituted.
  • WW represents the stated superscript number of the subject R group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.).
  • L WW is a linker recited in a claim or chemical formula description herein which is openly substituted.
  • WW represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.).
  • each R WW may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as R WW.1 ; each first substituent group, R WW.1 , may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as R WW.2 ; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as R WW.3 .
  • each L WW linker may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as R LWW.1 ; each first substituent group, R LWW.1 , may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as R LWW.2 ; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as R LWW.3 .
  • Each first substituent group is optionally different.
  • Each second substituent group is optionally different.
  • Each third substituent group is optionally different.
  • R WW is phenyl
  • the said phenyl group is optionally substituted by one or more R WW.1 groups as defined herein below, e.g., when R WW.1 is R WW.2 -substituted or unsubstituted alkyl, examples of groups so formed include but are not limited to itself optionally substituted by 1 or more R WW.2 , which R WW.2 is optionally substituted by one or more R WW.3 .
  • the R WW group is phenyl substituted by R WW.1 , which is methyl
  • the methyl group may be further substituted to form groups including but not limited to: .
  • R WW.1 is independently oxo, halogen, -CX WW.1 3 , -CHX WW.1 2 , -CH 2 X WW.1 , -OCX WW.1 3, -OCH2X WW.1 , -OCHX WW.1 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , ⁇ NHNH 2 , ⁇ ONH 2 , ⁇ NHC(O)NHNH 2 , ⁇ NHC(O)NH 2 , –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, R WW.2 -substituted or or unsubstituted 3 membered, or 4 to 5 membered), R WW.2 -substituted or un
  • R WW.1 is independently oxo, halogen, -CX WW.1 3, -CHX WW.1 2, -CH 2 X WW.1 , -OCX WW.1 3 , -OCH 2 X WW.1 , -OCHX WW.1 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), unsubstituted
  • X WW.1 is independently –F, -Cl, -Br, or –I.
  • R WW.2 is independently oxo, halogen, -CX WW.2 3 , -CHX WW.2 2 , -CH 2 X WW.2 , -OCX WW.2 3, -OCH2X WW.2 , -OCHX WW.2 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , ⁇ NHNH 2 , ⁇ ONH 2 , ⁇ NHC(O)NHNH 2 , ⁇ NHC(O)NH 2 , –NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , R WW.3 -substituted or unsubstit
  • R WW.2 is independently oxo, halogen, -CX WW.2 3 , -CHX WW.2 2 , -CH2X WW.2 , -OCX WW.2 3, -OCH2X WW.2 , -OCHX WW.2 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , ⁇ NHNH 2 , ⁇ ONH 2 , ⁇ NHC(O)NHNH 2 , ⁇ NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e
  • X WW.2 is independently –F, -Cl, -Br, or –I.
  • R WW.3 is independently oxo, halogen, -CX WW.3 3, -CHX WW.3 2, -CH2X WW.3 , -OCX WW.3 3 , -OCH 2 X WW.3 , -OCHX WW.3 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , unsubstituted alkyl (e.g., C1-C8,
  • X WW.3 is independently –F, -Cl, -Br, or –I.
  • the openly substituted ring may be independently substituted with one or more first substituent groups, referred to herein as R WW.1 ; each first substituent group, R WW.1 , may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as R WW.2 ; and each second substituent group, R WW.2 , may be unsubstituted or independently substituted with one or more third substituent groups, to herein as R WW.3 ; and each third substituent group, R WW.3 , is unsubstituted.
  • Each first substituent group is optionally different.
  • Each second substituent group is optionally different.
  • Each third substituent group is optionally different.
  • the “WW” symbol in the R WW.1 , R WW.2 and R WW.3 refers to the designated number of one of the two different R WW substituents.
  • R WW.1 is R 100A.1
  • R WW.2 is R 100A.2
  • R WW.3 is R 100A.3 .
  • R WW.1 is R 100B.1
  • R WW.2 is R 100B.2
  • R WW.3 is R 100B.3 .
  • R WW.1 , R WW.2 and R WW.3 in this paragraph are as defined in the preceding paragraphs.
  • R LWW.1 is independently oxo, halogen, -CX LWW.1 3, -CHX LWW.1 2, -CH2X LWW.1 , -OCX LWW.1 3 , -OCH 2 X LWW.1 , -OCHX LWW.1 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , R LWW.2 -substituted or unsubstituted alkyl (e.g., C1-
  • R LWW.1 is independently oxo, halogen, -CX LWW.1 3 , -CHX LWW.1 2, -CH2X LWW.1 , -OCX LWW.1 3, -OCH2X LWW.1 , -OCHX LWW.1 2, -CN, -OH, -NH2, -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , ⁇ NHNH 2 , ⁇ ONH 2 , ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-
  • X LWW.1 is independently –F, -Cl, -Br, or –I.
  • R LWW.2 is independently oxo, halogen, -CX LWW.2 3, -CHX LWW.2 2, -CH2X LWW.2 , -OCX LWW.2 3 , -OCH 2 X LWW.2 , -OCHX LWW.2 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, R LWW.3 -
  • R LWW.2 is independently oxo, halogen, -CX LWW.2 3, -CHX LWW.2 2 , -CH 2 X LWW.2 , -OCX LWW.2 3 , -OCH 2 X LWW.2 , -OCHX LWW.2 2 , -CN, -OH, -NH 2 , -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NHNH 2 , ⁇ NHC(O)NH 2 , –NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6
  • X LWW.2 is independently –F, -Cl, -Br, or –I.
  • R LWW.3 is independently oxo, halogen, -CX LWW.3 3 , -CHX LWW.3 2 , -CH 2 X LWW.3 , -OCX LWW.3 3, -OCH2X LWW.3 , -OCHX LWW.3 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g.,
  • X LWW.3 is independently –F, -Cl, -Br, or –I.
  • R group R WW group
  • R group is hereby defined as independently oxo, halogen, -CX WW 3 , -CHX WW 2 , -CH 2 X WW , -OCX WW 3 , -OCH 2 X WW , -OCHX WW 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NH2, ⁇ ONH2, ⁇ NHC(O)NHNH2, ⁇ NHC(O)NH2, –NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H,
  • X WW is independently –F, -Cl, -Br, or –I.
  • WW represents the stated superscript number of the subject R group (e.g., 1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.).
  • R WW.1 , R WW.2 , and R WW.3 are as defined above.
  • L group is herein defined as independently a bond, –O-, -NH-, -C(O)-, -C(O)NH-, -NHC(O)-, -NHC(O)NH-, —NHC(NH)NH-, -C(O)O-, -OC(O)-, -S-, -SO2-, -SO2NH-, R LWW.1 - substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), R LWW.1 -substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membere
  • R LWW.1 represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.).
  • R LWW.1 as well as R LWW.2 and R LWW.3 are as defined above.
  • Certain compounds of the present disclosure possess asymmetric carbon atoms (optical or chiral centers) or double bonds; the enantiomers, racemates, diastereomers, tautomers, geometric isomers, stereoisometric forms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)- or, as (D)- or (L)- for amino acids, and individual isomers are encompassed within the scope of the present disclosure.
  • the compounds of the present disclosure do not include those that are known in art to be too unstable to synthesize and/or isolate.
  • the present disclosure is meant to include compounds in racemic and optically pure forms.
  • Optically active (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.
  • the compounds described herein contain olefinic bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.
  • the term “isomers” refers to compounds having the same number and kind of atoms, and hence the same molecular weight, but differing in respect to the structural arrangement or configuration of the atoms.
  • the term “tautomer,” as used herein, refers to one of two or more structural isomers which exist in equilibrium and which are readily converted from one isomeric form to another. [0070] It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure.
  • structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure.
  • structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by 13 C- or 14 C-enriched carbon are within the scope of this disclosure.
  • the compounds of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • radioactive isotopes such as for example tritium ( 3 H), iodine-125 ( 125 I), or carbon-14 ( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure.
  • bioconjugate and “bioconjugate linker” refer to the resulting association between atoms or molecules of bioconjugate reactive groups or bioconjugate reactive moieties. The association can be direct or indirect.
  • a conjugate between a first bioconjugate reactive group e.g., –NH2, –COOH, –N- hydroxysuccinimide, or –maleimide
  • a second bioconjugate reactive group e.g., sulfhydryl, sulfur-containing amino acid, amine, amine sidechain containing amino acid, or carboxylate
  • covalent bond or linker e.g., a first linker of second linker
  • indirect e.g., by non-covalent bond (e.g., electrostatic interactions (e.g., ionic bond, hydrogen bond, halogen bond), van der Waals interactions (e.g., dipole-dipole, dipole-induced dipole, London dispersion), ring stacking (pi effects), hydrophobic interactions and the like).
  • bioconjugates or bioconjugate linkers are formed using bioconjugate chemistry (i.e., the association of two bioconjugate reactive groups) including, but are not limited to nucleophilic substitutions (e.g., reactions of amines and alcohols with acyl halides, active esters), electrophilic substitutions (e.g., enamine reactions) and additions to carbon-carbon and carbon-heteroatom multiple bonds (e.g., Michael reaction, Diels-Alder addition).
  • bioconjugate chemistry i.e., the association of two bioconjugate reactive groups
  • nucleophilic substitutions e.g., reactions of amines and alcohols with acyl halides, active esters
  • electrophilic substitutions e.g., enamine reactions
  • additions to carbon-carbon and carbon-heteroatom multiple bonds e.g., Michael reaction, Diels-Alder addition.
  • the first bioconjugate reactive group e.g., maleimide moiety
  • the second bioconjugate reactive group e.g., a sulfhydryl
  • the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl).
  • the first bioconjugate reactive group (e.g., pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl).
  • the first bioconjugate reactive group e.g., –N- hydroxysuccinimide moiety
  • is covalently attached to the second bioconjugate reactive group (e.g., an amine).
  • the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl).
  • the first bioconjugate reactive group (e.g., –sulfo–N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine).
  • bioconjugate reactive moieties used for bioconjugate chemistries herein include, for example: (a) carboxyl groups and various derivatives thereof including, but not limited to, N-hydroxysuccinimide esters, N-hydroxybenztriazole esters, acid halides, acyl imidazoles, thioesters, p-nitrophenyl esters, alkyl, alkenyl, alkynyl and aromatic esters; (b) hydroxyl groups which can be converted to esters, ethers, aldehydes, etc.; (c) haloalkyl groups wherein the halide can be later displaced with a nucleophilic group such as, for example, an amine, a carboxylate anion, thiol anion, carbanion, or an alkoxide ion, thereby resulting in the covalent attachment of a new group at the site of the halogen atom; (d) dienophile groups which are capable of participating in Die
  • bioconjugate reactive groups can be chosen such that they do not participate in, or interfere with, the chemical stability of the conjugate described herein.
  • a reactive functional group can be protected from participating in the crosslinking reaction by the presence of a protecting group.
  • the bioconjugate comprises a molecular entity derived from the reaction of an unsaturated bond, such as a maleimide, and a sulfhydryl group.
  • an analog is used in accordance with its plain ordinary meaning within Chemistry and Biology and refers to a chemical compound that is structurally similar to another compound (i.e., a so-called “reference” compound) but differs in composition, e.g., in the replacement of one atom by an atom of a different element, or in the presence of a particular functional group, or the replacement of one functional group by another functional group, or the absolute stereochemistry of one or more chiral centers of the reference compound. Accordingly, an analog is a compound that is similar or comparable in function and appearance but not in structure or origin to a reference compound.
  • the terms “a” or “an”, as used in herein means one or more.
  • substituted with a[n] means the specified group may be substituted with one or more of any or all of the named substituents.
  • a group such as an alkyl or heteroaryl group
  • the group may contain one or more unsubstituted C 1 -C 20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls.
  • R-substituted where a moiety is substituted with an R substituent, the group may be referred to as “R-substituted.” Where a moiety is R-substituted, the moiety is substituted with at least one R substituent and each R substituent is optionally different. Where a particular R group is present in the description of a chemical genus (such as Formula (I)), a Roman alphabetic symbol may be used to distinguish each appearance of that particular R group. For example, where multiple R 13 substituents are present, each R 13 substituent may be distinguished as R 13.A , R 13.B , R 13.C , R 13.D , etc., wherein each of R 13.A , R 13.B , R 13.C , R 13.D , etc.
  • a group may be substituted by one or more of a number of substituents
  • substitutions are selected so as to comply with principles of chemical bonding and to give compounds which are not inherently unstable and/or would be known to one of ordinary skill in the art as likely to be unstable under ambient conditions, such as aqueous, neutral, and several known physiological conditions.
  • a heterocycloalkyl or heteroaryl is attached to the remainder of the molecule via a ring heteroatom in compliance with principles of chemical bonding known to those skilled in the art thereby avoiding inherently unstable compounds.
  • salts are meant to include salts of the active compounds that are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p- tolylsulfonic, citric, tartaric, oxalic, methanesulfonic, and the like.
  • inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic,
  • salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge et al., “Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66, 1-19).
  • Certain specific compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.
  • the compounds of the present disclosure may exist as salts, such as with pharmaceutically acceptable acids.
  • the present disclosure includes such salts.
  • Non-limiting examples of such salts include hydrochlorides, hydrobromides, phosphates, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, proprionates, tartrates (e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof including racemic mixtures), succinates, benzoates, and salts with amino acids such as glutamic acid, and quaternary ammonium salts (e.g., methyl iodide, ethyl iodide, and the like). These salts may be prepared by methods known to those skilled in the art.
  • the neutral forms of the compounds are preferably regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound may differ from the various salt forms in certain physical properties, such as solubility in polar solvents.
  • the present disclosure provides compounds, which are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present disclosure.
  • Prodrugs of the compounds described herein may be converted in vivo after administration.
  • prodrugs can be converted to the compounds of the present disclosure by chemical or biochemical methods in an ex vivo environment, such as, for example, when contacted with a suitable enzyme or chemical reagent.
  • Certain compounds of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are encompassed within the scope of the present disclosure. Certain compounds of the present disclosure may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present disclosure and are intended to be within the scope of the present disclosure. [0087] A polypeptide, or a cell is “recombinant” when it is artificial or engineered, or derived from or contains an artificial or engineered protein or nucleic acid (e.g., non-natural or not wild type).
  • a polynucleotide that is inserted into a vector or any other heterologous location, e.g., in a genome of a recombinant organism, such that it is not associated with nucleotide sequences that normally flank the polynucleotide as it is found in nature is a recombinant polynucleotide.
  • a protein expressed in vitro or in vivo from a recombinant polynucleotide is an example of a recombinant polypeptide.
  • a polynucleotide sequence that does not appear in nature for example a variant of a naturally occurring gene, is recombinant.
  • compositions described herein are administered at the same time, just prior to, or just after the administration of one or more additional therapies.
  • the compounds of the invention can be administered alone or can be co-administered to the patient.
  • Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound).
  • the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation).
  • a “cell” as used herein, refers to a cell carrying out metabolic or other function sufficient to preserve or replicate its genomic DNA.
  • a cell can be identified by well-known methods in the art including, for example, presence of an intact membrane, staining by a particular dye, ability to produce progeny or, in the case of a gamete, ability to combine with a second gamete to produce a viable offspring.
  • Cells may include prokaryotic and eukaroytic cells.
  • Prokaryotic cells include but are not limited to bacteria.
  • Eukaryotic cells include but are not limited to yeast cells and cells derived from plants and animals, for example mammalian, insect (e.g., spodoptera) and human cells. Cells may be useful when they are naturally nonadherent or have been treated not to adhere to surfaces, for example by trypsinization.
  • treating refers to any indicia of success in the treatment or amelioration of an injury, disease, pathology or condition, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient; slowing in the rate of degeneration or decline; making the final point of degeneration less debilitating; improving a patient’s physical or mental well-being.
  • the treatment or amelioration of symptoms can be based on objective or subjective parameters; including the results of a physical examination, neuropsychiatric exams, and/or a psychiatric evaluation.
  • the term “treating” and conjugations thereof, include prevention of an injury, pathology, condition, or disease.
  • treating is preventing. In embodiments, treating does not include preventing. In embodiments, the treating or treatment is not prophylactic treatment.
  • An “effective amount” is an amount sufficient for a compound to accomplish a stated purpose relative to the absence of the compound (e.g., achieve the effect for which it is administered, treat a disease, reduce enzyme activity, increase enzyme activity, reduce signaling pathway, reduce one or more symptoms of a disease or condition.
  • An example of an “effective amount” is an amount sufficient to contribute to the treatment, prevention, or reduction of a symptom or symptoms of a disease, which could also be referred to as a “therapeutically effective amount” when referred to in this context.
  • a “reduction” of a symptom or symptoms means decreasing of the severity or frequency of the symptom(s), or elimination of the symptom(s).
  • a “prophylactically effective amount” of a drug is an amount of a drug that, when administered to a subject, will have the intended prophylactic effect, e.g., preventing or delaying the onset (or reoccurrence) of an injury, disease, pathology or condition, or reducing the likelihood of the onset (or reoccurrence) of an injury, disease, pathology, or condition, or their symptoms.
  • the full prophylactic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses.
  • a prophylactically effective amount may be administered in one or more administrations.
  • An “activity decreasing amount,” as used herein, refers to an amount of antagonist required to decrease the activity of an enzyme relative to the absence of the antagonist.
  • a “function disrupting amount,” as used herein, refers to the amount of antagonist required to disrupt the function of an enzyme or protein relative to the absence of the antagonist.
  • An “activity increasing amount,” as used herein, refers to an amount of agonist required to increase the activity of an enzyme relative to the absence of the agonist.
  • a “function increasing amount,” as used herein, refers to the amount of agonist required to increase the function of an enzyme or protein relative to the absence of the agonist.
  • Control or “control experiment” is used in accordance with its plain ordinary meaning and refers to an experiment in which the subjects or reagents of the experiment are treated as in a parallel experiment except for omission of a procedure, reagent, or variable of the experiment.
  • control is used as a standard of comparison in evaluating experimental effects.
  • a control is the measurement of the activity (e.g., signaling pathway) of a protein in the absence of a compound as described herein (including embodiments, examples, figures, or Tables).
  • Contacting is used in accordance with its plain ordinary meaning and refers to the process of allowing at least two distinct species (e.g., chemical compounds including biomolecules, or cells) to become sufficiently proximal to react, interact or physically touch. It should be appreciated; however, the resulting reaction product can be produced directly from a reaction between the added reagents or from an intermediate from one or more of the added reagents which can be produced in the reaction mixture.
  • the term “contacting” may include allowing two species to react, interact, or physically touch, wherein the two species may be a compound as described herein and a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, virus, lipid droplet, vesicle, small molecule, protein complex, protein aggregate, or macromolecule).
  • a cellular component e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, virus, lipid droplet, vesicle, small molecule, protein complex, protein aggregate, or macromolecule.
  • contacting includes allowing a compound described herein to interact with a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, virus, lipid droplet, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule) that is involved in a signaling pathway.
  • a cellular component e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, virus, lipid droplet, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule
  • the terms “agonist,” “activator,” “upregulator,” etc. refer to a substance capable of detectably increasing the expression or activity of a given gene or protein.
  • the agonist can increase expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the agonist.
  • expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or higher than the expression or activity in the absence of the agonist.
  • the term “inhibition,” “inhibit,” “inhibiting” and the like in reference to a cellular component-inhibitor interaction means negatively affecting (e.g., decreasing) the activity or function of the cellular component (e.g., decreasing the signaling pathway stimulated by a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)), relative to the activity or function of the cellular component in the absence of the inhibitor.
  • a cellular component e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule
  • inhibition means negatively affecting (e.g., decreasing) the concentration or levels of the cellular component relative to the concentration or level of the cellular component in the absence of the inhibitor.
  • inhibition refers to reduction of a disease or symptoms of disease.
  • inhibition refers to a reduction in the activity of a signal transduction pathway or signaling pathway (e.g., reduction of a pathway involving the cellular component).
  • inhibition includes, at least in part, partially or totally blocking stimulation, decreasing, preventing, or delaying activation, or inactivating, desensitizing, or down-regulating the signaling pathway or enzymatic activity or the amount of a cellular component.
  • inhibitor refers to a substance capable of detectably decreasing the expression or activity of a given gene or protein.
  • the antagonist can decrease expression or activity by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, or 99% in comparison to a control in the absence of the antagonist.
  • expression or activity is 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 10-fold or lower than the expression or activity in the absence of the antagonist.
  • modulator refers to a composition that increases or decreases the level of a target molecule or the function of a target molecule or the physical state of the target of the molecule (e.g., a target may be a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)) relative to the absence of the composition.
  • a target may be a cellular component (e.g., protein, ion, lipid, virus, lipid droplet, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule)) relative to the absence of the composition.
  • a target may be a cellular component (e.g., protein, ion
  • the term “expression” includes any step involved in the production of the polypeptide including, but not limited to, transcription, post-transcriptional modification, translation, post-translational modification, and secretion. Expression can be detected using conventional techniques for detecting protein (e.g., ELISA, Western blotting, flow cytometry, immunofluorescence, immunohistochemistry, etc.).
  • modulate is used in accordance with its plain ordinary meaning and refers to the act of changing or varying one or more properties. “Modulation” refers to the process of changing or varying one or more properties.
  • to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule.
  • “Patient”, “patient in need thereof”, “subject”, or “subject in need thereof” refers to a living organism suffering from or prone to a disease or condition that can be treated by administration of a pharmaceutical composition as provided herein.
  • Non-limiting examples include humans, other mammals, bovines, rats, mice, dogs, monkeys, goat, sheep, cows, deer, and other non-mammalian animals.
  • a patient is human.
  • a patient in need thereof is human.
  • a subject is human.
  • a subject in need thereof is human.
  • Disease or “condition” refer to a state of being or health status of a patient or subject capable of being treated with the compounds or methods provided herein.
  • the disease is a disease related to (e.g., caused by) a cellular component (e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule).
  • a cellular component e.g., protein, ion, lipid, nucleic acid, nucleotide, amino acid, protein, particle, organelle, cellular compartment, microorganism, vesicle, small molecule, protein complex, protein aggregate, or macromolecule.
  • the disease is a cancer (e.g., breast cancer, ovarian cancer, colon adenocarcinoma, lung adenocarcinoma, lung small cell carcinoma, pancreatic adenocarcinoma, pancreatic neuroendocrine tumors, glioblastoma, prostate cancer, hepatocellular carcinoma, myeloma, leukemia, or lymphoma).
  • the disease is a neurodegenerative disorder.
  • the disease is an inflammatory disease (e.g., gastrointestinal disease or chronic inflammatory lung disease).
  • the disease is a fibrosing disorder (e.g., pulmonary fibrosis).
  • the disease is a demyelinating disorder.
  • the disease is a dermatologic disorder.
  • the disease is a rheumatic disease.
  • the disease is an autoimmune disease (e.g., peripheral neuropathy).
  • the disease is a metabolic disorder (e.g., diabetes mellitus).
  • the disease is an eye disease.
  • cancer refers to all types of cancer, neoplasm or malignant tumors found in mammals (e.g., humans), including leukemia, lymphoma, carcinomas and sarcomas.
  • Exemplary cancers that may be treated with a compound or method provided herein include cancer of the thyroid, endocrine system, brain, breast, cervix, colon, head and neck, liver, kidney, lung, non-small cell lung, melanoma, mesothelioma, ovary, sarcoma, stomach, uterus medulloblastoma, colorectal cancer, or pancreatic cancer.
  • Additional examples include Hodgkin’s Disease, Non-Hodgkin’s Lymphoma, multiple myeloma, neuroblastoma, glioma, glioblastoma multiforme, ovarian cancer, rhabdomyosarcoma, primary thrombocytosis, primary macroglobulinemia, primary brain tumors, malignant pancreatic insulanoma, malignant carcinoid, urinary bladder cancer, premalignant skin lesions, testicular cancer, lymphomas, thyroid cancer, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, endometrial cancer, adrenal cortical cancer, neoplasms of the endocrine or exocrine pancreas, medullary thyroid cancer, medullary thyroid carcinoma, melanoma, colorectal cancer, papillary thyroid cancer, hepatocellular carcinoma, or prostate cancer.
  • leukemia refers broadly to progressive, malignant diseases of the blood- forming organs and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia is generally clinically classified on the basis of (1) the duration and character of the disease-acute or chronic; (2) the type of cell involved; myeloid (myelogenous), lymphoid (lymphogenous), or monocytic; and (3) the increase or non-increase in the number abnormal cells in the blood- leukemic or aleukemic (subleukemic).
  • Exemplary leukemias that may be treated with a compound or method provided herein include, for example, acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophylic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia,
  • lymphoma refers to a group of cancers affecting hematopoietic and lymphoid tissues. It begins in lymphocytes, the blood cells that are found primarily in lymph nodes, spleen, thymus, and bone marrow. Two main types of lymphoma are non-Hodgkin lymphoma and Hodgkin’s disease. Hodgkin’s disease represents approximately 15% of all diagnosed lymphomas. This is a cancer associated with Reed- Sternberg malignant B lymphocytes. Non-Hodgkin’s lymphomas (NHL) can be classified based on the rate at which cancer grows and the type of cells involved.
  • B-cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, small lymphocytic lymphoma, Mantle cell lymphoma, follicular lymphoma, marginal zone lymphoma, extranodal (MALT) lymphoma, nodal (monocytoid B-cell) lymphoma, splenic lymphoma, diffuse large cell B-lymphoma, Burkitt’s lymphoma, lymphoblastic lymphoma, immunoblastic large cell lymphoma, or precursor B-lymphoblastic lymphoma.
  • Exemplary T- cell lymphomas that may be treated with a compound or method provided herein include, but are not limited to, cutaneous T-cell lymphoma, peripheral T-cell lymphoma, anaplastic large cell lymphoma, mycosis fungoides, and precursor T-lymphoblastic lymphoma.
  • the term "sarcoma” generally refers to a tumor which is made up of a substance like the embryonic connective tissue and is generally composed of closely packed cells embedded in a fibrillar or homogeneous substance.
  • Sarcomas that may be treated with a compound or method provided herein include a chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, Abemethy's sarcoma, adipose sarcoma, liposarcoma, alveolar soft part sarcoma, ameloblastic sarcoma, botryoid sarcoma, chloroma sarcoma, chorio carcinoma, embryonal sarcoma, Wilms' tumor sarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma, giant cell sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multiple pigmented hemo
  • melanoma is taken to mean a tumor arising from the melanocytic system of the skin and other organs.
  • Melanomas that may be treated with a compound or method provided herein include, for example, acral-lentiginous melanoma, amelanotic melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, Harding-Passey melanoma, juvenile melanoma, lentigo maligna melanoma, malignant melanoma, nodular melanoma, subungal melanoma, or superficial spreading melanoma.
  • carcinoma refers to a malignant new growth made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases.
  • exemplary carcinomas that may be treated with a compound or method provided herein include, for example, medullary thyroid carcinoma, familial medullary thyroid carcinoma, acinar carcinoma, acinous carcinoma, adenocystic carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, carcinoma of adrenal cortex, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma, carcinoma basocellulare, basaloid carcinoma, basosquamous cell carcinoma, bronchioalveolar carcinoma, bronchiolar carcinoma, bronchogenic carcinoma, cerebriform carcinoma, cholangiocellular carcinoma, chorionic carcinoma, colloid carcinoma, comedo carcinoma, corpus carcinoma, cribriform carcinoma, carcinoma en cuirasse, carcinoma cutaneum, cylindrical carcinoma, cylindrical cell carcinoma, duct carcinoma, carcinoma durum, embryonal carcinoma, encephaloid
  • the terms “metastasis,” “metastatic,” and “metastatic cancer” can be used interchangeably and refer to the spread of a proliferative disease or disorder, e.g., cancer, from one organ or another non-adjacent organ or body part. “Metastatic cancer” is also called “Stage IV cancer.” Cancer occurs at an originating site, e.g., breast, which site is referred to as a primary tumor, e.g., primary breast cancer. Some cancer cells in the primary tumor or originating site acquire the ability to penetrate and infiltrate surrounding normal tissue in the local area and/or the ability to penetrate the walls of the lymphatic system or vascular system circulating through the system to other sites and tissues in the body.
  • a second clinically detectable tumor formed from cancer cells of a primary tumor is referred to as a metastatic or secondary tumor.
  • the metastatic tumor and its cells are presumed to be similar to those of the original tumor.
  • the secondary tumor at the site of the breast consists of abnormal lung cells and not abnormal breast cells.
  • the secondary tumor in the breast is referred to a metastatic lung cancer.
  • metastatic cancer refers to a disease in which a subject has or had a primary tumor and has one or more secondary tumors.
  • non- metastatic cancer or subjects with cancer that is not metastatic refers to diseases in which subjects have a primary tumor but not one or more secondary tumors.
  • metastatic lung cancer refers to a disease in a subject with or with a history of a primary lung tumor and with one or more secondary tumors at a second location or multiple locations, e.g., in the breast.
  • the terms “cutaneous metastasis” or “skin metastasis” refer to secondary malignant cell growths in the skin, wherein the malignant cells originate from a primary cancer site (e.g., breast).
  • a primary cancer site e.g., breast
  • cancerous cells from a primary cancer site may migrate to the skin where they divide and cause lesions. Cutaneous metastasis may result from the migration of cancer cells from breast cancer tumors to the skin.
  • visceral metastasis refers to secondary malignant cell growths in the interal organs (e.g., heart, lungs, liver, pancreas, intestines) or body cavities (e.g., pleura, peritoneum), wherein the malignant cells originate from a primary cancer site (e.g., head and neck, liver, breast).
  • a primary cancer site e.g., head and neck, liver, breast.
  • a primary cancer site e.g., head and neck, liver, breast
  • Visceral metastasis may result from the migration of cancer cells from liver cancer tumors or head and neck tumors to internal organs.
  • neurodegenerative disorder or “neurodegenerative disease” refers to a disease or condition in which the function of a subject’s nervous system becomes impaired.
  • neurodegenerative diseases include Alexander’s disease, Alper’s disease, Alzheimer’s disease, Amyotrophic lateral sclerosis, Ataxia telangiectasia, Batten disease (also known as Spielmeyer-Vogt-Sjogren-Batten disease), Bovine spongiform encephalopathy (BSE), Canavan disease, chronic fatigue syndrome, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-St syndromesler-Scheinker syndrome, Huntington’s disease, HIV-associated dementia, Kennedy’s disease, Krabbe’s disease, kuru, Lewy body dementia, Machado-Joseph disease (Spino
  • posterior eye indication refers to eye conditions caused by changes in the anterior hyaloid membrane of the eye and the optical structures behind it.
  • posterior eye indication is retinal degeneration represented by retinitis pigmentosa, Stargardt’s disease, wet AMD, and dry AMD.
  • anterior eye indication is glaucoma and Fuch’s dystrophy.
  • inflammatory disease refers to a disease or condition characterized by aberrant inflammation (e.g., an increased level of inflammation compared to a control such as a healthy person not suffering from a disease).
  • inflammatory diseases include autoimmune diseases, arthritis, rheumatoid arthritis, psoriatic arthritis, juvenile idiopathic arthritis, multiple sclerosis, systemic lupus erythematosus (SLE), myasthenia gravis, juvenile onset diabetes, diabetes mellitus type 1, Guillain-Barre syndrome, Hashimoto’s encephalitis, Hashimoto’s thyroiditis, ankylosing spondylitis, psoriasis, Sjogren’s syndrome,vasculitis, glomerulonephritis, auto-immune thyroiditis, Behcet’s disease, Crohn’s disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, ichthyosis, Graves ophthalmopathy, inflammatory bowel disease, Addison’s disease, Vitiligo,asthma, allergic asthma, acne vulgaris, celiac disease, chronic prostatitis, inflammatory bowel disease, pelvi
  • chronic inflammatory lung disease is used in accordance with its plain ordinary meaning and refers to chronic inflammation of lung tissue.
  • exemplary disorders include, but are not limited to, bronchial asthma, chronic obstructive pulmonary disease (COPD), and bronchiectasis or cystic fibrosis (CF).
  • COPD chronic obstructive pulmonary disease
  • CF cystic fibrosis
  • fibrosing disorder refers to a condition characterizied by lesions of circumscribed fibrotic areas involving different levels of the dermis, subcutis, and sometimes, underlying soft tissue and bone.
  • the fibrosing disorder is idiopathic pulmonary fibrosis (IPF), familial pulmonary fibrosis (FPF), scleroderma (systemic sclerosis), renal finrosis, and hepatic fibrosis.
  • IPF idiopathic pulmonary fibrosis
  • FPF familial pulmonary fibrosis
  • scleroderma systemic sclerosis
  • renal finrosis renal finrosis
  • hepatic fibrosis idiopathic pulmonary fibrosis
  • the term “demyelinating disorder” refers to a disorder of the nervous system in which the myelin sheath of neurons is damaged.
  • the demyelinating disorder is multiple sclerosis (MS), Guillan-Barre syndrome, adrenoleukodystrophy, adrenomyeloneuropathy, optic neuritis, and transverse myelitis.
  • the term “dermatologic disorder” refers to a disease or condition that affects the integumentary system, i.e., the organ system that encloses the bosy and includes skin, nails, and related myscle and glands.
  • dermatologic disorders include, but are not limited to, acne, alopecia areata, atopic dermatitis, psoriasis, Raynaud’s phenomenon, rosacea, skin cancer, vitiligo, actinic prurigo, argyria, chromhidrosis, epidermolysis bullosa, harlequin ichthyosis, lamellar ichthyosis, and necrobiosis lipoidica.
  • rheumatic disease refers to a disease or condition that affects joints, tendons, muscle, ligaments, bones, and muscles.
  • dermatologic disorders include, but are not limited to, rheumatoid arthritis, palindromic rheumatism, juvenile arthritis, systemic lupus erythematosus, Sjögren syndrome, scleroderma, polymyositis, dermatomyositis, Behçet’s disease, relapsing polychondritis, ankylosing spondylitis, reactive arthritis, psoriatic arthritis, osteoarthritis, gout, neoplasms, neurovascular disorders, bone and cartilage disorders, bursitis, tendinitis, and capsulitis.
  • autoimmune disease refers to a disease or condition in which a subject’s immune system has an aberrant immune response against a substance that does not normally elicit an immune response in a healthy subject.
  • autoimmune diseases include Acute Disseminated Encephalomyelitis (ADEM), Acute necrotizing hemorrhagic leukoencephalitis, Addison’s disease, Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti-GBM/Anti-TBM nephritis, Antiphospholipid syndrome (APS), Autoimmune angioedema, Autoimmune aplastic anemia, Autoimmune dysautonomia, Autoimmune hepatitis, Autoimmune hyperlipidemia, Autoimmune immunodeficiency, Autoimmune inner ear disease (AIED), Autoimmune myo
  • Acute Disseminated Encephalomyelitis Acute necrotizing hemorrhagic le
  • the autoimmune disease is rheumamtoid arthritis, Grave’s disease, Hashimoto disease, Addison’s disease, lupus, ankylosing spondylitis, and sarcoidosis.
  • peripheral neuropathy refers to a damaged neuron, a condition caused by trauma, injury, local compression, prolonged pressure, or inflammation of a nerve or group of nerves. Peripheral neuropathy can be primary, such as Charcot-Marie Tooth (CMT), or secondary, caused by diabetes mellitus.
  • CMT Charcot-Marie Tooth
  • metabolic disorder refers to a disorder characterized by one or more abnormal metabolic processes in a subject.
  • a metabolic disorder may be associated with, related to, or may be diabetes (e.g., type 1 diabetes or type 2 diabetes), insulin resistance, metabolic syndrome, obesity, hyperlipidemia, hyperglycemia, high serum triglycerides, and/or high blood pressure.
  • a metabolic disorder may be associated with, related to, or may be a diabetes associated disease selected from nephropathy, retinopathy, neuropathy, cardiovascular disease, or inflammation.
  • a metabolic disorder may be associated with, related to, or may be nephropathy, retinopathy, neuropathy, cardiovascular disease, or inflammation.
  • diabetes mellitus refers to a group of metabolic discorders characterized by high blood sugar levels over a prolonged period of time.
  • diabetes mellitus is represented by type 1 diabetes, type 2 diabetes, monogenic (MODY) syndrome, and recessive genetic disorders (Wolcott Rallisson syndrome and Wolfram syndrome).
  • eye disease refers to a disease or condition characterized by eye problems (e.g., an increased level of eye problems compared to a control such as a healthy person not suffering from a disease).
  • eye diseases include, but are not limited to, cataract (e.g., congenital cataract), optic nerve disorders (e.g., glaucoma), retinal disorders, macular degeneration, diabetic eye problems, and conjunctivitis.
  • cataract e.g., congenital cataract
  • optic nerve disorders e.g., glaucoma
  • retinal disorders macular degeneration
  • diabetic eye problems e.g., diabetic eye problems
  • conjunctivitis e.g., cataract, congenital cataract
  • optic nerve disorders e.g., glaucoma
  • retinal disorders e.g., macular degeneration
  • diabetic eye problems e.g., diabetic eye problems
  • conjunctivitis e.g., cataract, congenital cataract
  • retinal disorders e.g., macular degeneration
  • diabetic eye problems e.g., diabetic eye problems
  • conjunctivitis e.g., cataract, congenital cataract
  • a “detectable agent,” “detectable compound,” “detectable label,” or “detectable moiety” is a substance (e.g., element), molecule, or composition detectable by spectroscopic, photochemical, biochemical, immunochemical, chemical, magnetic resonance imaging, or other physical means.
  • detectable agents include 18 F, 32 P, 33 P, 45 Ti, 47 Sc, 52 Fe, 59 Fe, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 77 As, 86 Y, 90 Y, 89 Sr, 89 Zr, 94 Tc, 94 Tc, 99m Tc, 99 Mo, 105 Pd, 105 Rh, 111 Ag, 111 In, 123 I, 124 I, 125 I, 131 I, 142 Pr, 143 Pr, 149 Pm, 153 Sm, 154-1581 Gd, 161 Tb, 166 Dy, 166 Ho, Tm, Yb, Lu, 32 P, fluorophore (e.g., fluorescent dyes), modified oligonucleotides (e.g., moieties described in PCT/US2015/022063, which is incorporated herein by reference), electron-dense reagents, enzymes (e.g., as commonly used in an ELISA), biotin,
  • Radioactive substances e.g., radioisotopes
  • Radioactive substances include, but are not limited to, 18 F, 32 P, 33 P, 45 Ti, 47 Sc, 52 Fe, 59 Fe, 62 Cu, 64 Cu, 67 Cu, 67 Ga, 68 Ga, 77 As, 86 Y, 90 Y, 89 Sr, 89 Zr, 94 Tc, 94 Tc, 99m Tc, 99 Mo, 105 Pd, 105 Rh, 111 Ag, 111 In, 123 I, 124 I, 125 I, 131 I, 142 Pr, 143 Pr, 149 Pm, 153 Sm, 154-158 Gd, 161 Tb, 166 Dy, 166 Ho, 169 Er, 175 Lu, 177 Lu, 186 Re, 188 Re, 189 Re, 194 Ir, 198 Au, 199 Au, 211 At, 211 Pb, 212 Bi, 212
  • Paramagnetic ions that may be used as additional imaging agents in accordance with the embodiments of the disclosure include, but are not limited to, ions of transition and lanthanide metals (e.g., metals having atomic numbers of 21-29, 42, 43, 44, or 57-71). These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu.
  • transition and lanthanide metals e.g., metals having atomic numbers of 21-29, 42, 43, 44, or 57-71.
  • These metals include ions of Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, and Lu.
  • “Pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to a substance that aids the administration of an active agent to and absorption by a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect on the patient.
  • Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors, salt solutions (such as Ringer’s solution), alcohols, oils, gelatins, carbohydrates such as lactose, amylose or starch, fatty acid esters, hydroxymethycellulose, polyvinyl pyrrolidine, and colors, and the like.
  • preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, coloring, and/or aromatic substances and the like that do not deleteriously react with the compounds of the invention.
  • auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents,
  • Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.
  • the term “about” means a range of values including the specified value, which a person of ordinary skill in the art would consider reasonably similar to the specified value. In embodiments, about means within a standard deviation using measurements generally acceptable in the art. In embodiments, about means a range extending to +/- 10% of the specified value. In embodiments, about includes the specified value.
  • administering is used in accordance with its plain and ordinary meaning and includes oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intrathecal, intranasal or subcutaneous administration, or the implantation of a slow-release device, e.g., a mini- osmotic pump, to a subject.
  • Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal).
  • Parenteral administration includes, e.g., intravenous, intramuscular, intra- arteriole, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial.
  • Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, etc.
  • co-administer it is meant that a composition described herein is administered at the same time, just prior to, or just after the administration of one or more additional therapies.
  • the compounds of the invention can be administered alone or can be co-administered to the patient.
  • Co-administration is meant to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound).
  • compositions of the present invention can be delivered by transdermally, by a topical route, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.
  • the compounds described herein can be used in combination with one another, with other active agents known to be useful in treating a disease associated with cells expressing a disease associated cellular component, or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.
  • co-administration includes administering one active agent within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent.
  • Co- administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order.
  • co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents.
  • the active agents can be formulated separately.
  • the active and/or adjunctive agents may be linked or conjugated to one another.
  • compound utilized in the pharmaceutical compositions of the present invention may be administered at the initial dosage of about 0.001 mg/kg to about 1000 mg/kg daily.
  • the dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound or drug being employed.
  • dosages can be empirically determined considering the type and stage of disease (e.g., a cancer, neurodegenerative disorder, inflammatory disease, fibrosing disorder, demyelinating disorder, dermatologic disorder, rheumatic disease, autoimmune disease, metabolic disorder, or eye disease) diagnosed in a particular patient.
  • the dose administered to a patient should be sufficient to affect a beneficial therapeutic response in the patient over time.
  • the size of the dose will also be determined by the existence, nature, and extent of any adverse side effects that accompany the administration of a compound in a particular patient. Determination of the proper dosage for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound.
  • the term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease means that the disease (e.g., a cancer, neurodegenerative disorder, inflammatory disease, fibrosing disorder, demyelinating disorder, dermatologic disorder, rheumatic disease, autoimmune disease, metabolic disorder, or eye disease) is caused by (in whole or in part), or a symptom of the disease is caused by (in whole or in part) the substance or substance activity or function or the disease or a symptom of the disease may be treated by modulating (e.g., inhibiting or activating) the substance (e.g., cellular component).
  • the disease e.g., a cancer, neurodegenerative disorder, inflammatory disease, fibrosing disorder, demyelinating disorder, dermatologic disorder, rheumatic disease, autoimmune disease, metabolic disorder, or eye disease
  • modulating e.g., inhibiting or activating
  • aberrant refers to different from normal. When used to describe enzymatic activity, aberrant refers to activity that is greater or less than a normal control or the average of normal non-diseased control samples. Aberrant activity may refer to an amount of activity that results in a disease, wherein returning the aberrant activity to a normal or non-disease-associated amount (e.g., by administering a compound or using a method as described herein), results in reduction of the disease or one or more disease symptoms.
  • electrophilic refers to a chemical group that is capable of accepting electron density.
  • An “electrophilic substituent,” “electrophilic chemical moiety,” or “electrophilic moiety” refers to an electron-poor chemical group, substituent, or moiety (monovalent chemical group), which may react with an electron-donating group, such as a nucleophile, by accepting an electron pair or electron density to form a bond.
  • “Nucleophilic” as used herein refers to a chemical group that is capable of donating electron density.
  • nucleic acid or protein when applied to a nucleic acid or protein, denotes that the nucleic acid or protein is essentially free of other cellular components with which it is associated in the natural state. It can be, for example, in a homogeneous state and may be in either a dry or aqueous solution. Purity and homogeneity are typically determined using analytical chemistry techniques such as polyacrylamide gel electrophoresis or high performance liquid chromatography. A protein that is the predominant species present in a preparation is substantially purified.
  • amino acid refers to naturally occurring and synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids.
  • Naturally occurring amino acids are those encoded by the genetic code, as well as those amino acids that are later modified, e.g., hydroxyproline, ⁇ - carboxyglutamate, and O-phosphoserine.
  • Amino acid analogs refers to compounds that have the same basic chemical structure as a naturally occurring amino acid, i.e., an ⁇ carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, e.g., homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium.
  • Such analogs have modified R groups (e.g., norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid.
  • Amino acid mimetics refers to chemical compounds that have a structure that is different from the general chemical structure of an amino acid, but that functions in a manner similar to a naturally occurring amino acid.
  • the terms “non-naturally occurring amino acid” and “unnatural amino acid” refer to amino acid analogs, synthetic amino acids, and amino acid mimetics which are not found in nature.
  • Amino acids may be referred to herein by either their commonly known three letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Nucleotides, likewise, may be referred to by their commonly accepted single-letter codes.
  • polypeptide “peptide,” and “protein” are used interchangeably herein to refer to a polymer of amino acid residues, wherein the polymer may in embodiments be conjugated to a moiety that does not consist of amino acids.
  • the terms apply to amino acid polymers in which one or more amino acid residue is an artificial chemical mimetic of a corresponding naturally occurring amino acid, as well as to naturally occurring amino acid polymers and non-naturally occurring amino acid polymers.
  • An amino acid or nucleotide base “position” is denoted by a number that sequentially identifies each amino acid (or nucleotide base) in the reference sequence based on its position relative to the N-terminus (or 5'-end).
  • the amino acid residue number in a test sequence determined by simply counting from the N-terminus will not necessarily be the same as the number of its corresponding position in the reference sequence.
  • the amino acid residue number in a test sequence determined by simply counting from the N-terminus will not necessarily be the same as the number of its corresponding position in the reference sequence.
  • that insertion will not correspond to a numbered amino acid position in the reference sequence.
  • protein complex is used in accordance with its plain ordinary meaning and refers to a protein which is associated with an additional substance (e.g., another protein, protein subunit, or a compound). Protein complexes typically have defined quaternary structure.
  • the association between the protein and the additional substance may be a covalent bond.
  • the association between the protein and the additional substance is via non-covalent interactions.
  • a protein complex refers to a group of two or more polypeptide chains. Proteins in a protein complex are linked by non-covalent protein–protein interactions. A non-limiting example of a protein complex is the proteasome.
  • the term “protein aggregate” is used in accordance with its plain ordinary meaning and refers to an aberrant collection or accumulation of proteins (e.g., misfolded proteins). Protein aggregates are often associated with diseases (e.g., amyloidosis).
  • the unfolded/misfolded protein may aggregate.
  • protein aggregates There are three main types of protein aggregates that may form: amorphous aggregates, oligomers, and amyloid fibrils. In embodiments, protein aggregates are termed aggresomes.
  • IRE1 or “IRE1 ⁇ ” or “ERN1” or “inositol-requiring enzyme 1 ⁇ ” refers to a serine/threonine protein kinase and endoribonuclease.
  • IRE1 ⁇ includes any recombinant or naturally-occurring form of IRE1 ⁇ , including variants thereof that maintain IRE1 ⁇ function or activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% function or activity compared to wildtype).
  • IRE1 ⁇ is encoded by the ERN1 gene.
  • IRE1 ⁇ has the amino acid sequence set forth in or corresponding to Entrez 2081, UniProt O75460, or RefSeq (protein) NP_001424.3.
  • arylene e.g., C 6 -C 10 or phenylene
  • substituted or unsubstituted heteroarylene e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered.
  • L 1 is a bond, -O-, -S-, -S(O)-, -S(O) 2 -, -NR 10 -, -C(O)-, -C(O)NR 10 -, -NR 10 C(O)-, -C(O)O-, -OC(O)-, -NR 10 S(O)-, -S(O)NR 10 -, -NR 10 S(O)2-, -S(O)2NR 10 -, -NR 10 C(O)O-, -OC(O)NR 10 -, substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 -C 2 ), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered,
  • L 2 is a bond, substituted or unsubstituted alkylene (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C 1 - C2), substituted or unsubstituted heteroalkylene (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkylene (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), substituted or unsubstituted arylene (e.g., C6-C10 or phenylene), or substituted or unsubstituted
  • R 1 is hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl 3 , -OCBr 3 , -OCF 3 , -OCI 3 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 F, -OCH 2 I, -OCHCl 2
  • R 2 is –N(R 2A )(R 2B ) or a substituted or unsubstituted nitrogen-containing heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered).
  • a substituted or unsubstituted nitrogen-containing heterocycloalkyl e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered.
  • R 2A and R 2B are independently hydrogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH2F, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (e.g
  • Each R 3 and R 4 is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2,
  • R 10 is hydrogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C
  • the compound has the formula: .
  • L 1 , L 2 , R 1 , R 2 , R 3 , R 4 , and z4 are as described herein,
  • R 5 is independently halogen, -CX 5 3 , -CHX 5 2 , -CH 2 X 5 , -OCX 5 3 , -OCH 2 X 5 , -OCHX 5 2, -CN, -SOn5R 5D , -SOv5NR 5A R 5B , ⁇ NR 5C NR 5A R 5B , ⁇ ONR 5A R 5B , -NR 5C C(O)NR 5A R 5B , -N(O) m5 , -NR 5A R 5B , -C(O)R 5C , -C(O)OR 5C , -OC(O)R 5C , -OC(O)OR 5C , -C(O)NR 5A , -C(O
  • R 5A , R 5B , R 5C , and R 5D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH 2 Br, -OCH 2 I, -OCH 2 F, substituted or unsubstituted alkyl (e.g., C 1 -C 8 , C 1 -C 6 , C 1 -C 4 , or C1-C2), substituted or unsubstituted hetero
  • Each X 5 is independently –F, -Cl, -Br, or –I.
  • the symbol n5 is an integer from 0 to 4.
  • the symbols m5 and v5 are independently 1 or 2.
  • the symbol z5 is an integer from 0 to 6. [0167] In embodiments, the compound has the formula:
  • a substituted Ring A (e.g., substituted arylene and/or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted Ring A is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • Ring A when Ring A is substituted, it is substituted with at least one substituent group.
  • Ring A when Ring A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when Ring A is substituted, it is substituted with at least one lower substituent group. [0170] In embodiments, Ring A is a substituted or unsubstituted arylene. In embodiments, Ring A is a substituted or unsubstituted C6-C10 arylene. In embodiments, Ring A is a substituted or unsubstituted naphthylene. In embodiments, Ring A is a substituted or unsubstituted 1-naphthylene. In embodiments, Ring A is a substituted or unsubstituted 2- naphthylene.
  • Ring A is a substituted or unsubstituted heteroarylene. In embodiments, Ring A is a substituted or unsubstituted 5 to 10 membered heteroarylene. , a heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L 1 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • L 1 when L 1 is substituted, it is substituted with at least one substituent group. In embodiments, when L 1 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L 1 is substituted, it is substituted with at least one lower substituent group. [0173] In embodiments, L 1 is a bond. In embodiments, L 1 is -O-. In embodiments, L 1 is -S-. In embodiments, L 1 is -S(O)-. In embodiments, L 1 is -S(O)2-. In embodiments, L 1 is -NR 10 -. In embodiments, L 1 is -NH-. In embodiments, L 1 is -C(O)-.
  • L 1 is -C(O)NR 10 -. In embodiments, L 1 is -C(O)NH-. In embodiments, L 1 is -NR 10 C(O)-. In embodiments, L 1 is -NHC(O)-. In embodiments, L 1 is -C(O)O-. In embodiments, L 1 is -OC(O)-. In embodiments, L 1 is -NR 10 S(O)-. In embodiments, L 1 is -NHS(O)-. In embodiments, L 1 is -S(O)NR 10 -. In embodiments, L 1 is -S(O)NH-. In embodiments, L 1 is -NR 10 S(O)2-.
  • L 1 is -NHS(O)2-. In embodiments, L 1 is -S(O)2NR 10 -. In embodiments, L 1 is -S(O) 2 NH-. In embodiments, L 1 is -NR 10 C(O)O-. In embodiments, L 1 is -NHC(O)O-. In embodiments, L 1 is -OC(O)NR 10 -. In embodiments, L 1 is -OC(O)NH-. In embodiments, L 1 is unsubstituted C 1 -C 4 alkylene. In embodiments, L 1 is unsubstituted methylene. In embodiments, L 1 is unsubstituted ethylene.
  • L 1 is unsubstituted propylene. In embodiments, L 1 is unsubstituted n-propylene. In embodiments, L 1 is unsubstituted isopropylene. In embodiments, L 1 is unsubstituted butylene. In embodiments, L 1 is unsubstituted n-butylene. In embodiments, L 1 is unsubstituted isobutylene. In embodiments, L 1 is unsubstituted tert-butylene. In embodiments, L 1 is substituted or unsubstituted 2 to 6 membered heteroalkylene. In embodiments, L 1 is oxo- substituted 2 to 6 membered heteroalkylene.
  • L 1 is unsubstituted 2 to 6 membered heteroalkylene.
  • L 1 is -NR 10 S(O) 2 - or substituted or unsubstituted 2 to 8 membered heteroalkylene.
  • L 1 is -NR 10 S(O) 2 - or -NR 10 S(O) 2 -(unsubstituted C 1 -C 6 alkylene)-.
  • L 1 is 1 . In embodiments, L 1 is .
  • alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 10 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 10 when R 10 is substituted, it is substituted with at least one substituent group.
  • R 10 when R 10 is substituted, it is substituted with at least one size-limited substituent group.
  • R 10 when R 10 is substituted, it is substituted with at least one lower substituent group.
  • R 10 is hydrogen. In embodiments, R 10 is -CCl3. In embodiments, R 10 is -CBr 3 . In embodiments, R 10 is -CF 3 . In embodiments, R 10 is -CI 3 . In embodiments, R 10 is -CHCl2. In embodiments, R 10 is -CHBr2. In embodiments, R 10 is -CHF2. In embodiments, R 10 is -CHI 2 . In embodiments, R 10 is -CH 2 Cl. In embodiments, R 10 is -CH 2 Br. In embodiments, R 10 is -CH2F.
  • R 10 is -CH2I. In embodiments, R 10 is –CN. In embodiments, R 10 is —OH. In embodiments, R 10 is -NH 2 . In embodiments, R 10 is –COOH. In embodiments, R 10 is -CONH2. In embodiments, R 10 is -OCCl3. In embodiments, R 10 is -OCF 3 . In embodiments, R 10 is -OCBr 3 . In embodiments, R 10 is -OCI 3 . In embodiments, R 10 is -OCHCl2. In embodiments, R 10 is -OCHBr2. In embodiments, R 10 is -OCHI2. In embodiments, R 10 is -OCHF 2 .
  • R 10 is -OCH 2 Cl. In embodiments, R 10 is -OCH2Br. In embodiments, R 10 is -OCH2I. In embodiments, R 10 is -OCH2F. In embodiments, R 10 is unsubstituted C 1 -C 4 alkyl. In embodiments, R 10 is unsubstituted methyl. In embodiments, R 10 is unsubstituted ethyl. In embodiments, R 10 is unsubstituted propyl. In embodiments, R 10 is unsubstituted n-propyl. In embodiments, R 10 is unsubstituted isopropyl. In embodiments, R 10 is unsubstituted butyl.
  • R 10 is unsubstituted n-butyl. In embodiments, R 10 is unsubstituted isobutyl. In embodiments, R 10 is unsubstituted tert-butyl. [0178] In embodiments, R 10 is hydrogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr 2 , -OCHI 2 , -OCHF 2 , -OCH 2 Cl, -OCH 2 Br, -OCH 2 I, -OC
  • R 10 is hydrogen or unsubstituted C 1 -C 4 alkyl.
  • a substituted R 1 e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 1 is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 1 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 1 when R 1 is substituted, it is substituted with at least one substituent group. In embodiments, when R 1 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1 is substituted, it is substituted with at least one lower substituent group.
  • R 1 is hydrogen. In embodiments, R 1 is halogen. In embodiments, R 1 is –F. In embodiments, R 1 is –Cl. In embodiments, R 1 is –Br. In embodiments, R 1 is –I. In embodiments, R 1 is -CCl3. In embodiments, R 1 is -CBr3. In embodiments, R 1 is -CF3. In embodiments, R 1 is -CI 3 .
  • R 1 is -CH 2 Cl. In embodiments, R 1 is -CH 2 Br. In embodiments, R 1 is -CH2F. In embodiments, R 1 is -CH2I. In embodiments, R 1 is -CHCl2. In embodiments, R 1 is -CHBr 2 . In embodiments, R 1 is -CHF 2 . In embodiments, R 1 is -CHI 2 . In embodiments, R 1 is –CN. In embodiments, R 1 is –OH. In embodiments, R 1 is -NH2. In embodiments, R 1 is –COOH. In embodiments, R 1 is -CONH 2 . In embodiments, R 1 is -NO 2 . In embodiments, R 1 is –SH.
  • R 1 is -SO 3 H. In embodiments, R 1 is -OSO 3 H. In embodiments, R 1 is -SO2NH2. In embodiments, R 1 is ⁇ NHNH2. In embodiments, R 1 is ⁇ ONH2. In embodiments, R 1 is ⁇ NHC(O)NH2. In embodiments, R 1 is -NHSO2H. In embodiments, R 1 is -NHC(O)H. In embodiments, R 1 is -NHC(O)OH. In embodiments, R 1 is –NHOH. In embodiments, R 1 is -OCCl3. In embodiments, R 1 is -OCBr3. In embodiments, R 1 is -OCF3. In embodiments, R 1 is -OCI3.
  • R 1 is -OCH2Cl. In embodiments, R 1 is -OCH2Br. In embodiments, R 1 is -OCH2F. In embodiments, R 1 is -OCH2I. In embodiments, R 1 is -OCHCl2. In embodiments, R 1 is -OCHBr2. In embodiments, R 1 is -OCHF2. In embodiments, R 1 is -OCHI2. In embodiments, R 1 is -SF5. In embodiments, R 1 is -N 3 . In embodiments, R 1 is unsubstituted C 1 -C 4 alkyl. In embodiments, R 1 is unsubstituted methyl. In embodiments, R 1 is unsubstituted ethyl.
  • R 1 is unsubstituted propyl. In embodiments, R 1 is unsubstituted n-propyl. In embodiments, R 1 is unsubstituted isopropyl. In embodiments, R 1 is unsubstituted butyl. In embodiments, R 1 is unsubstituted n-butyl. In embodiments, R 1 is unsubstituted isobutyl. In embodiments, R 1 is unsubstituted tert-butyl. In embodiments, R 1 is substituted or unsubstituted C 3 -C 6 cycloalkyl. In embodiments, R 1 is substituted or unsubstituted cyclopropyl.
  • R 1 is substituted or unsubstituted cyclobutyl. In embodiments, R 1 is substituted or unsubstituted cyclopentyl. In embodiments, R 1 is substituted or unsubstituted cyclohexyl. In embodiments, R 1 is substituted or unsubstituted phenyl. [0181] In embodiments, R 1 is –CF3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, or substituted or unsubstituted phenyl.
  • R 1 is –CF3, unsubstituted methyl, unsubstituted ethyl, unsubstituted isopropyl, unsubstituted tert- butyl, unsubstituted cyclopropyl, unsubstituted cyclobutyl, unsubstituted cyclopentyl, unsubstituted , .
  • R 1 is .
  • R 1 In is [0182]
  • -L 1 -R 1 is , , embodiments, -L 1 -R 1 is .
  • -L 1 -R 1 In embodiments, -L 1 -R 1 .
  • -L 1 -R 1 In embodiments, -L 1 -R 1 . In embodiments, -L 1 -R 1 . In embodiments, -L 1 -R 1 In embodiments, -L 1 -R 1 . In embodiments, -L 1 -R 1 In embodiments, -L 1 -R 1 . In embodiments, -L 1 -R 1 In embodiments, -L 1 -R 1 . In embodiments, -L 1 -R 1 In embodiments, -L 1 -R 1 . In embodiments, -L 1 -R 1 In embodiments, -L 1 -R 1 is . In embodiments, -L 1 -R 1 In embodiments, -L 1 -R 1 .
  • L 2 e.g., substituted alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene
  • L 2 is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L 2 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • L 2 when L 2 is substituted, it is substituted with at least one substituent group. In embodiments, when L 2 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L 2 is substituted, it is substituted with at least one lower substituent group.
  • L 2 is a bond. In embodiments, L 2 is unsubstituted C1-C4 alkylene. In embodiments, L 2 is unsubstituted methylene. In embodiments, L 2 is unsubstituted ethylene. In embodiments, L 2 is unsubstituted propylene. In embodiments, L 2 is unsubstituted n-propylene.
  • L 2 is unsubstituted isopropylene. In embodiments, L 2 is unsubstituted butylene. In embodiments, L 2 is unsubstituted n-butylene. In embodiments, L 2 is unsubstituted isobutylene. In embodiments, L 2 is unsubstituted tert- butylene.
  • a substituted R 2 (e.g., substituted nitrogen-containing heterocycloalkyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 2 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 2 when R 2 is substituted, it is substituted with at least one substituent group.
  • R 2 when R 2 is substituted, it is substituted with at least one size-limited substituent group.
  • R 2 when R 2 is substituted, it is substituted with at least one lower substituent group.
  • R 2 is a substituted or unsubstituted nitrogen-containing heterocycloalkyl. In embodiments, R 2 is a substituted or unsubstituted nitrogen-containing 3 to 8 membered heterocycloalkyl. In embodiments, R 2 is a substituted or unsubstituted piperidinyl. In embodiments, R 2 is an unsubstituted piperidinyl. In embodiments, R 2 is a piperidinyl substituted with a halogen. In embodiments, R 2 is a piperidinyl substituted with -F. In embodiments, R 2 is a piperidinyl substituted with -Cl.
  • R 2 is a piperidinyl substituted with -Br. In embodiments, R 2 is a piperidinyl substituted with -I. In . In . [0187] In is –N(R 2A )(R 2B ); herein, including in embodiments.
  • a substituted R 2A (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 2A is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 2A is substituted, it is substituted with at least one substituent group.
  • R 2A when R 2A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 2A is substituted, it is substituted with at least one lower substituent group.
  • R 2A is hydrogen. In embodiments, R 2A is -CCl 3 . In embodiments, R 2A is -CBr3. In embodiments, R 2A is -CF3. In embodiments, R 2A is -CI3. In embodiments, R 2A is -CHCl 2 . In embodiments, R 2A is -CHBr 2 . In embodiments, R 2A is -CHF 2 . In embodiments, R 2A is -CHI2.
  • R 2A is -CH2Cl. In embodiments, R 2A is -CH 2 Br. In embodiments, R 2A is -CH 2 F. In embodiments, R 2A is -CH 2 I. In embodiments, R 2A is –CN. In embodiments, R 2A is –OH. In embodiments, R 2A is -NH2. In embodiments, R 2A is –COOH. In embodiments, R 2A is -CONH 2 . In embodiments, R 2A is -OCCl 3 . In embodiments, R 2A is -OCF3. In embodiments, R 2A is -OCBr3. In embodiments, R 2A is -OCI3.
  • R 2A is -OCHCl 2 . In embodiments, R 2A is -OCHBr 2 . In embodiments, R 2A is -OCHI2. In embodiments, R 2A is -OCHF2. In embodiments, R 2A is -OCH2Cl. In embodiments, R 2A is -OCH 2 Br. In embodiments, R 2A is -OCH 2 I. In embodiments, R 2A is -OCH2F. In embodiments, R 2A is substituted or unsubstituted C1-C4 alkyl. In embodiments, R 2A is unsubstituted methyl. In embodiments, R 2A is unsubstituted ethyl.
  • R 2A is unsubstituted propyl. In embodiments, R 2A is unsubstituted n-propyl. In embodiments, R 2A is unsubstituted isopropyl. In embodiments, R 2A is unsubstituted butyl. In embodiments, R 2A is unsubstituted n-butyl. In embodiments, R 2A is unsubstituted isobutyl. In embodiments, R 2A is unsubstituted tert-butyl. In embodiments, R 2A is substituted or unsubstituted 2 to 6 membered heteroalkyl.
  • R 2A is substituted or unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 2A is substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 2A is substituted or unsubstituted phenyl. In embodiments, R 2A is substituted or unsubstituted 5 to 6 membered heteroaryl.
  • a substituted R 2B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 2B is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 2B is substituted, it is substituted with at least one substituent group.
  • R 2B when R 2B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 2B is substituted, it is substituted with at least one lower substituent group.
  • R 2B is hydrogen. In embodiments, R 2B is -CCl 3 . In embodiments, R 2B is -CBr3. In embodiments, R 2B is -CF3. In embodiments, R 2B is -CI3. In embodiments, R 2B is -CHCl 2 . In embodiments, R 2B is -CHBr 2 . In embodiments, R 2B is -CHF 2 . In embodiments, R 2B is -CHI2.
  • R 2B is -CH2Cl. In embodiments, R 2B is -CH 2 Br. In embodiments, R 2B is -CH 2 F. In embodiments, R 2B is -CH 2 I. In embodiments, R 2B is –CN. In embodiments, R 2B is —OH. In embodiments, R 2B is -NH2. In embodiments, R 2B is –COOH. In embodiments, R 2B is -CONH 2 . In embodiments, R 2B is -OCCl 3 . In embodiments, R 2B is -OCF3. In embodiments, R 2B is -OCBr3. In embodiments, R 2B is -OCI3.
  • R 2B is -OCHCl 2 . In embodiments, R 2B is -OCHBr 2 . In embodiments, R 2B is -OCHI2. In embodiments, R 2B is -OCHF2. In embodiments, R 2B is -OCH2Cl. In embodiments, R 2B is -OCH 2 Br. In embodiments, R 2B is -OCH 2 I. In embodiments, R 2B is -OCH2F. In embodiments, R 2B is substituted or unsubstituted C1-C4 alkyl. In embodiments, R 2B is unsubstituted methyl. In embodiments, R 2B is unsubstituted ethyl.
  • R 2B is unsubstituted propyl. In embodiments, R 2B is unsubstituted n-propyl. In embodiments, R 2B is unsubstituted isopropyl. In embodiments, R 2B is unsubstituted butyl. In embodiments, R 2B is unsubstituted n-butyl. In embodiments, R 2B is unsubstituted isobutyl. In embodiments, R 2B is unsubstituted tert-butyl. In embodiments, R 2B is substituted or unsubstituted 2 to 6 membered heteroalkyl.
  • R 2B is substituted or unsubstituted C 3 -C 8 cycloalkyl. In embodiments, R 2B is substituted or unsubstituted 3 to 8 membered heterocycloalkyl. In embodiments, R 2B is substituted or unsubstituted phenyl. In embodiments, R 2B is substituted or unsubstituted 5 to 6 membered heteroaryl.
  • a substituted R 3 (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 3 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 3 is substituted, it is substituted with at least one substituent group.
  • R 3 when R 3 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 3 is substituted, it is substituted with at least one lower substituent group.
  • R 3 is independently halogen. In embodiments, R 3 is independently –F. In embodiments, R 3 is independently –Cl. In embodiments, R 3 is independently –Br. In embodiments, R 3 is independently –I. In embodiments, R 3 is independently -CCl 3 . In embodiments, R 3 is independently -CBr3. In embodiments, R 3 is independently -CF3. In embodiments, R 3 is independently -CI 3 . In embodiments, R 3 is independently -CH 2 Cl.
  • R 3 is independently -CH2Br. In embodiments, R 3 is independently -CH2F. In embodiments, R 3 is independently -CH 2 I. In embodiments, R 3 is independently -CHCl 2 . In embodiments, R 3 is independently -CHBr2. In embodiments, R 3 is independently -CHF2. In embodiments, R 3 is independently -CHI 2 . In embodiments, R 3 is independently –CN. In embodiments, R 3 is independently –OH. In embodiments, R 3 is independently -NH2. In embodiments, R 3 is independently –COOH. In embodiments, R 3 is independently -CONH 2 . In embodiments, R 3 is independently -NO2. In embodiments, R 3 is independently –SH.
  • R 3 is independently -SO 3 H. In embodiments, R 3 is independently -OSO 3 H. In embodiments, R 3 is independently -SO 2 NH 2 . In embodiments, R 3 is independently ⁇ NHNH 2 . In embodiments, R 3 is independently ⁇ ONH 2 . In embodiments, R 3 is independently ⁇ NHC(O)NH2. In embodiments, R 3 is independently -NHSO2H. In embodiments, R 3 is independently -NHC(O)H. In embodiments, R 3 is independently -NHC(O)OH. In embodiments, R 3 is independently –NHOH. In embodiments, R 3 is independently -OCCl 3 . In embodiments, R 3 is independently -OCBr3.
  • R 3 is independently -OCF3. In embodiments, R 3 is independently -OCI 3 . In embodiments, R 3 is independently -OCH 2 Cl. In embodiments, R 3 is independently -OCH2Br. In embodiments, R 3 is independently -OCH 2 F. In embodiments, R 3 is independently -OCH 2 I. In embodiments, R 3 is independently -OCHCl2. In embodiments, R 3 is independently -OCHBr2. In embodiments, R 3 is independently -OCHF 2 . In embodiments, R 3 is independently -OCHI 2 . In embodiments, R 3 is independently -SF5. In embodiments, R 3 is independently -N3.
  • R 3 is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 3 is independently unsubstituted methyl. In embodiments, R 3 is independently unsubstituted ethyl. In embodiments, R 3 is independently unsubstituted propyl. In embodiments, R 3 is independently unsubstituted n-propyl. In embodiments, R 3 is independently unsubstituted isopropyl. In embodiments, R 3 is independently unsubstituted butyl. In embodiments, R 3 is independently unsubstituted n-butyl. In embodiments, R 3 is independently unsubstituted isobutyl.
  • R 3 is independently unsubstituted tert-butyl.
  • z3 is 0. In embodiments, z3 is 1. In embodiments, z3 is 2.
  • a substituted R 4 e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 4 when R 4 is substituted, it is substituted with at least one substituent group. In embodiments, when R 4 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 4 is substituted, it is substituted with at least one lower substituent group. [0196] In embodiments, R 4 is independently halogen. In embodiments, R 4 is independently –F. In embodiments, R 4 is independently –Cl. In embodiments, R 4 is independently –Br. In embodiments, R 4 is independently –I. In embodiments, R 4 is independently –CCl3. In embodiments, R 4 is independently –CBr 3 . In embodiments, R 4 is independently –CF 3 .
  • R 4 is independently –CI3. In embodiments, R 4 is independently -CH2Cl. In embodiments, R 4 is independently -CH 2 Br. In embodiments, R 4 is independently -CH 2 F. In embodiments, R 4 is independently -CH2I. In embodiments, R 4 is independently -CHCl2. In embodiments, R 4 is independently -CHBr 2 . In embodiments, R 4 is independently -CHF 2 . In embodiments, R 4 is independently -CHI2. In embodiments, R 4 is independently –CN. In embodiments, R 4 is independently –OH. In embodiments, R 4 is independently -NH 2 . In embodiments, R 4 is independently –COOH. In embodiments, R 4 is independently -CONH2.
  • R 4 is independently -NO 2 . In embodiments, R 4 is independently –SH. In embodiments, R 4 is independently –SO 3 H. In embodiments, R 4 is independently –OSO 3 H. In embodiments, R 4 is independently -SO 2 NH 2 . In embodiments, R 4 is independently ⁇ NHNH 2 . In embodiments, R 4 is independently ⁇ ONH 2 . In embodiments, R 4 is independently ⁇ NHC(O)NH 2 . In embodiments, R 4 is independently -NHSO 2 H. In embodiments, R 4 is independently -NHC(O)H. In embodiments, R 4 is independently -NHC(O)OH. In embodiments, R 4 is independently –NHOH.
  • R 4 is independently –OCCl3. In embodiments, R 4 is independently –OCBr3. In embodiments, R 4 is independently –OCF3. In embodiments, R 4 is independently –OCI3. In embodiments, R 4 is independently -OCH2Cl. In embodiments, R 4 is independently -OCH2Br. In embodiments, R 4 is independently -OCH2F. In embodiments, R 4 is independently -OCH2I. In embodiments, R 4 is independently -OCHCl2. In embodiments, R 4 is independently -OCHBr2. In embodiments, R 4 is independently -OCHF 2 . In embodiments, R 4 is independently -OCHI 2 . In embodiments, R 4 is independently -SF5.
  • R 4 is independently –N3. In embodiments, R 4 is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 4 is independently unsubstituted methyl. In embodiments, R 4 is independently unsubstituted ethyl. In embodiments, R 4 is independently unsubstituted propyl. In embodiments, R 4 is independently unsubstituted n-propyl. In embodiments, R 4 is independently unsubstituted isopropyl. In embodiments, R 4 is independently unsubstituted butyl. In embodiments, R 4 is independently unsubstituted n-butyl. In embodiments, R 4 is independently unsubstituted isobutyl.
  • R 4 is independently unsubstituted tert-butyl. In embodiments, R 4 is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R 4 is independently unsubstituted methoxy. In embodiments, R 4 is independently unsubstituted ethoxy. In embodiments, R 4 is independently unsubstituted propoxy. In embodiments, R 4 is independently unsubstituted n-propoxy. In embodiments, R 4 is independently unsubstituted isopropoxy. In embodiments, R 4 is independently unsubstituted butoxy. [0197] In embodiments, z4 is 0. In embodiments, z4 is 1. In embodiments, z4 is 2.
  • z4 is 3.
  • a substituted R 5 e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 5 is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 5 is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 5 when R 5 is substituted, it is substituted with at least one substituent group.
  • R 5 when R 5 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 5 is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 5A e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 5A is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 5A is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 5A when R 5A is substituted, it is substituted with at least one substituent group. In embodiments, when R 5A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 5A is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 5B (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 5B is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 5B is substituted, it is substituted with at least one substituent group.
  • R 5B when R 5B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 5B is substituted, it is substituted with at least one lower substituent group.
  • a substituted ring formed when R 5A and R 5B substituents bonded to the same nitrogen atom are joined e.g., substituted heterocycloalkyl and/or substituted heteroaryl
  • R 5A and R 5B substituents bonded to the same nitrogen atom are joined e.g., substituted heterocycloalkyl and/or substituted heteroaryl
  • the substituted ring formed when R 5A and R 5B substituents bonded to the same nitrogen atom are joined is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • when the substituted ring formed when R 5A and R 5B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one substituent group. In embodiments, when the substituted ring formed when R 5A and R 5B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when the substituted ring formed when R 5A and R 5B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 5C (e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 5C is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different. In embodiments, when R 5C is substituted, it is substituted with at least one substituent group.
  • R 5C when R 5C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 5C is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 5D e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 5D is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 5D is substituted with a plurality of groups selected from substituent groups, size-limited substituent groups, and lower substituent groups; each substituent group, size-limited substituent group, and/or lower substituent group may optionally be different.
  • R 5D when R 5D is substituted, it is substituted with at least one substituent group. In embodiments, when R 5D is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 5D is substituted, it is substituted with at least one lower substituent group.
  • R 5A is independently hydrogen. In embodiments, R 5A is independently unsubstituted C1-C4 alkyl. In embodiments, R 5A is independently unsubstituted methyl. In embodiments, R 5A is independently unsubstituted ethyl. In embodiments, R 5A is independently unsubstituted propyl.
  • R 5A is independently unsubstituted n-propyl. In embodiments, R 5A is independently unsubstituted isopropyl. In embodiments, R 5A is independently unsubstituted butyl. In embodiments, R 5A is independently unsubstituted n-butyl. In embodiments, R 5A is independently unsubstituted isobutyl. In embodiments, R 5A is independently unsubstituted tert-butyl. [0205] In embodiments, R 5B is independently hydrogen. In embodiments, R 5B is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 5B is independently unsubstituted methyl.
  • R 5B is independently unsubstituted ethyl. In embodiments, R 5B is independently unsubstituted propyl. In embodiments, R 5B is independently unsubstituted n-propyl. In embodiments, R 5B is independently unsubstituted isopropyl. In embodiments, R 5B is independently unsubstituted butyl. In embodiments, R 5B is independently unsubstituted n-butyl. In embodiments, R 5B is independently unsubstituted isobutyl. In embodiments, R 5B is independently unsubstituted tert-butyl. [0206] In embodiments, R 5C is independently hydrogen.
  • R 5C is independently unsubstituted C1-C4 alkyl. In embodiments, R 5C is independently unsubstituted methyl. In embodiments, R 5C is independently unsubstituted ethyl. In embodiments, R 5C is independently unsubstituted propyl. In embodiments, R 5C is independently unsubstituted n-propyl. In embodiments, R 5C is independently unsubstituted isopropyl. In embodiments, R 5C is independently unsubstituted butyl. In embodiments, R 5C is independently unsubstituted n-butyl. In embodiments, R 5C is independently unsubstituted isobutyl.
  • R 5C is independently unsubstituted tert-butyl.
  • R 5D is independently hydrogen. In embodiments, R 5D is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 5D is independently unsubstituted methyl. In embodiments, R 5D is independently unsubstituted ethyl. In embodiments, R 5D is independently unsubstituted propyl. In embodiments, R 5D is independently unsubstituted n-propyl. In embodiments, R 5D is independently unsubstituted isopropyl. In embodiments, R 5D is independently unsubstituted butyl.
  • R 5D is independently unsubstituted n-butyl. In embodiments, R 5D is independently unsubstituted isobutyl. In embodiments, R 5D is independently unsubstituted tert-butyl.
  • R 5 is independently halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH 2 F, -OCH 2 I, -OCHCl 2 , -OCHBr 2 ,
  • R 5 is independently halogen. In embodiments, R 5 is independently –F. In embodiments, R 5 is independently –Cl. In embodiments, R 5 is independently –Br. In embodiments, R 5 is independently –I. In embodiments, R 5 is independently –CCl3. In embodiments, R 5 is independently –CBr 3 . In embodiments, R 5 is independently –CF 3 . In embodiments, R 5 is independently –CI3. In embodiments, R 5 is independently -CH2Cl. In embodiments, R 5 is independently -CH 2 Br. In embodiments, R 5 is independently -CH 2 F. In embodiments, R 5 is independently -CH2I. In embodiments, R 5 is independently -CHCl2.
  • R 5 is independently -CHBr 2 . In embodiments, R 5 is independently -CHF 2 . In embodiments, R 5 is independently -CHI 2 . In embodiments, R 5 is independently –CN. In embodiments, R 5 is independently –OH. In embodiments, R 5 is independently -NH2. In embodiments, R 5 is independently –COOH. In embodiments, R 5 is independently -CONH 2 . In embodiments, R 5 is independently -NO2. In embodiments, R 5 is independently –SH. In embodiments, R 5 is independently –SO 3 H. In embodiments, R 5 is independently –OSO 3 H. In embodiments, R 5 is independently -SO2NH2. In embodiments, R 5 is independently ⁇ NHNH2.
  • R 5 is independently ⁇ ONH2. In embodiments, R 5 is independently ⁇ NHC(O)NH2. In embodiments, R 5 is independently -NHSO2H. In embodiments, R 5 is independently -NHC(O)H. In embodiments, R 5 is independently -NHC(O)OH. In embodiments, R 5 is independently –NHOH. In embodiments, R 5 is independently –OCCl3. In embodiments, R 5 is independently –OCBr3. In embodiments, R 5 is independently –OCF 3 . In embodiments, R 5 is independently –OCI 3 . In embodiments, R 5 is independently -OCH2Cl. In embodiments, R 5 is independently -OCH2Br.
  • R 5 is independently -OCH 2 F. In embodiments, R 5 is independently -OCH 2 I. In embodiments, R 5 is independently -OCHCl2. In embodiments, R 5 is independently -OCHBr2. In embodiments, R 5 is independently -OCHF 2 . In embodiments, R 5 is independently -OCHI 2 . In embodiments, R 5 is independently -SF5. In embodiments, R 5 is independently –N3. In embodiments, R 5 is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 5 is independently unsubstituted methyl. In embodiments, R 5 is independently unsubstituted ethyl. In embodiments, R 5 is independently unsubstituted propyl.
  • R 5 is independently unsubstituted n-propyl. In embodiments, R 5 is independently unsubstituted isopropyl. In embodiments, R 5 is independently unsubstituted butyl. In embodiments, R 5 is independently unsubstituted n-butyl. In embodiments, R 5 is independently unsubstituted isobutyl. In embodiments, R 5 is independently unsubstituted tert-butyl. In embodiments, R 5 is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R 5 is independently unsubstituted methoxy. In embodiments, R 5 is independently unsubstituted ethoxy.
  • R 5 is independently unsubstituted propoxy. In embodiments, R 5 is independently unsubstituted n-propoxy. In embodiments, R 5 is independently unsubstituted isopropoxy. In embodiments, R 5 is independently unsubstituted butoxy. [0210] In embodiments, R 5 is independently halogen or unsubstituted C1-C4 alkyl. In embodiments, R 5 is independently –F or unsubstituted methyl. [0211] In embodiments, z5 is 0. In embodiments, z5 is 1. In embodiments, z5 is 2. In embodiments, z5 is 3. In embodiments, z5 is 4. In embodiments, z5 is 5. In embodiments, z5 is 6.
  • Ring A when Ring A is substituted, Ring A is substituted with one or more first substituent groups denoted by R A.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R A.1 substituent group when an R A.1 substituent group is substituted, the R A.1 substituent group is substituted with one or more second substituent groups denoted by R A.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R A.2 substituent group when an R A.2 substituent group is substituted, the R A.2 substituent group is substituted with one or more third substituent groups denoted by R A.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R A , R A.1 , R A.2 , and R A.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R A , R A.1 , R A.2 , and R A.3 , respectively.
  • R 1 when R 1 is substituted, R 1 is substituted with one or more first substituent groups denoted by R 1.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1.1 substituent group when an R 1.1 substituent group is substituted, the R 1.1 substituent group is substituted with one or more second substituent groups denoted by R 1.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1.2 substituent group when an R 1.2 substituent group is substituted, the R 1.2 substituent group is substituted with one or more third substituent groups denoted by R 1.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1 , R 1.1 , R 1.2 , and R 1.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 1 , R 1.1 , R 1.2 , and R 1.3 , respectively.
  • R 2 when R 2 is substituted, R 2 is substituted with one or more first substituent groups denoted by R 2.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2.1 substituent group when an R 2.1 substituent group is substituted, the R 2.1 substituent group is substituted with one or more second substituent groups denoted by R 2.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2.2 substituent group when an R 2.2 substituent group is substituted, the R 2.2 substituent group is substituted with one or more third substituent groups denoted by R 2.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2 , R 2.1 , R 2.2 , and R 2.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 2 , R 2.1 , R 2.2 , and R 2.3 , respectively.
  • R 2A when R 2A is substituted, R 2A is substituted with one or more first substituent groups denoted by R 2A.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2A.1 substituent group when an R 2A.1 substituent group is substituted, the R 2A.1 substituent group is substituted with one or more second substituent groups denoted by R 2A.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2A.2 substituent group when an R 2A.2 substituent group is substituted, the R 2A.2 substituent group is substituted with one or more third substituent groups denoted by R 2A.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2A , R 2A.1 , R 2A.2 , and R 2A.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 2A , R 2A.1 , R 2A.2 , and R 2A.3 , respectively.
  • R 2B when R 2B is substituted, R 2B is substituted with one or more first substituent groups denoted by R 2B.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2B.1 substituent group when an R 2B.1 substituent group is substituted, the R 2B.1 substituent group is substituted with one or more second substituent groups denoted by R 2B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2B.2 substituent group when an R 2B.2 substituent group is substituted, the R 2B.2 substituent group is substituted with one or more third substituent groups denoted by R 2B.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 2B , R 2B.1 , R 2B.2 , and R 2B.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 2B , R 2B.1 , R 2B.2 , and R 2B.3 , respectively.
  • R 3 when R 3 is substituted, R 3 is substituted with one or more first substituent groups denoted by R 3.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 3.1 substituent group when an R 3.1 substituent group is substituted, the R 3.1 substituent group is substituted with one or more second substituent groups denoted by R 3.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 3.2 substituent group when an R 3.2 substituent group is substituted, the R 3.2 substituent group is substituted with one or more third substituent groups denoted by R 3.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 3 , R 3.1 , R 3.2 , and R 3.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 3 , R 3.1 , R 3.2 , and R 3.3 , respectively.
  • R 4 when R 4 is substituted, R 4 is substituted with one or more first substituent groups denoted by R 4.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4.1 substituent group when an R 4.1 substituent group is substituted, the R 4.1 substituent group is substituted with one or more second substituent groups denoted by R 4.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4.2 substituent group when an R 4.2 substituent group is substituted, the R 4.2 substituent group is substituted with one or more third substituent groups denoted by R 4.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 4 , R 4.1 , R 4.2 , and R 4.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 4 , R 4.1 , R 4.2 , and R 4.3 , respectively.
  • R 5 when R 5 is substituted, R 5 is substituted with one or more first substituent groups denoted by R 5.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 5.1 substituent group when an R 5.1 substituent group is substituted, the R 5.1 substituent group is substituted with one or more second substituent groups denoted by R 5.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R 5.2 substituent group is substituted, the R 5.2 substituent group is substituted with one or more third substituent groups denoted by R 5.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 5 , R 5.1 , R 5.2 , and R 5.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 5 , R 5.1 , R 5.2 , and R 5.3 , respectively.
  • R 5A when R 5A is substituted, R 5A is substituted with one or more first substituent groups denoted by R 5A.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 5A.1 substituent group when an R 5A.1 substituent group is substituted, the R 5A.1 substituent group is substituted with one or more second substituent groups denoted by R 5A.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 5A.2 substituent group when an R 5A.2 substituent group is substituted, the R 5A.2 substituent group is substituted with one or more third substituent groups denoted by R 5A.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 5A , R 5A.1 , R 5A.2 , and R 5A.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 5A , R 5A.1 , R 5A.2 , and R 5A.3 , respectively.
  • R 5B when R 5B is substituted, R 5B is substituted with one or more first substituent groups denoted by R 5B.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 5B.1 substituent group when an R 5B.1 substituent group is substituted, the R 5B.1 substituent group is substituted with one or more second substituent groups denoted by R 5B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 5B.2 substituent group when an R 5B.2 substituent group is substituted, the R 5B.2 substituent group is substituted with one or more third substituent groups denoted by R 5B.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 5B , R 5B.1 , R 5B.2 , and R 5B.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 5B , R 5B.1 , R 5B.2 , and R 5B.3 , respectively.
  • R 5A and R 5B substituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R 5A.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 5A.1 when an R 5A.1 substituent group is substituted, the R 5A.1 substituent group is substituted with one or more second substituent groups denoted by R 5A.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 5A.2 substituent group when an R 5A.2 substituent group is substituted, the R 5A.2 substituent group is substituted with one or more third substituent groups denoted by R 5A.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 5A.1 , R 5A.2 , and R 5A.3 have values corresponding to the values of R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW.1 , R WW.2 , and R WW.3 correspond to R 5A.1 , R 5A.2 , and R 5A.3 , respectively.
  • R 5A and R 5B substituents bonded to the same nitrogen atom are optionally joined to form a moiety that is substituted (e.g., a substituted heterocycloalkyl or substituted heteroaryl), the moiety is substituted with one or more first substituent groups denoted by R 5B.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 5B.1 when an R 5B.1 substituent group is substituted, the R 5B.1 substituent group is substituted with one or more second substituent groups denoted by R 5B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 5B.2 substituent group when an R 5B.2 substituent group is substituted, the R 5B.2 substituent group is substituted with one or more third substituent groups denoted by R 5B.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 5B.1 , R 5B.2 , and R 5B.3 have values corresponding to the values of R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the group(s)”, wherein R WW.1 , R WW.2 , and R WW.3 correspond to R 5B.1 , R 5B.2 , and R 5B.3 , respectively.
  • R 5C when R 5C is substituted, R 5C is substituted with one or more first substituent groups denoted by R 5C.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 5C.1 when an R 5C.1 substituent group is substituted, the R 5C.1 substituent group is substituted with one or more second substituent groups denoted by R 5C.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 5C.2 substituent group when an R 5C.2 substituent group is substituted, the R 5C.2 substituent group is substituted with one or more third substituent groups denoted by R 5C.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 5C , R 5C.1 , R 5C.2 , and R 5C.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 5C , R 5C.1 , R 5C.2 , and R 5C.3 , respectively.
  • R 5D when R 5D is substituted, R 5D is substituted with one or more first substituent groups denoted by R 5D.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 5D.1 when an R 5D.1 substituent group is substituted, the R 5D.1 substituent group is substituted with one or more second substituent groups denoted by R 5D.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 5D.2 substituent group when an R 5D.2 substituent group is substituted, the R 5D.2 substituent group is substituted with one or more third substituent groups denoted by R 5D.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 5D , R 5D.1 , R 5D.2 , and R 5D.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 5D , R 5D.1 , R 5D.2 , and R 5D.3 , respectively.
  • R 10 when R 10 is substituted, R 10 is substituted with one or more first substituent groups denoted by R 10.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 10.1 substituent group when an R 10.1 substituent group is substituted, the R 10.1 substituent group is substituted with one or more second substituent groups denoted by R 10.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 10.2 substituent group when an R 10.2 substituent group is substituted, the R 10.2 substituent group is substituted with one or more third substituent groups denoted by R 10.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 10 , R 10.1 , R 10.2 , and R 10.3 have values corresponding to the values of R WW , R WW.1 , R WW.2 , and R WW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to R 10 , R 10.1 , R 10.2 , and R 10.3 , respectively.
  • L 1 when L 1 is substituted, L 1 is substituted with one or more first substituent groups denoted by R L1.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R L1.1 substituent group when an R L1.1 substituent group is substituted, the R L1.1 substituent group is substituted with one or more second substituent groups denoted by R L1.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R L1.2 substituent group when an R L1.2 substituent group is substituted, the R L1.2 substituent group is substituted with one or more third substituent groups denoted by R L1.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • L 1 , R L1.1 , R L1.2 , and R L1.3 have values corresponding to the values of L WW , R LWW.1 , R LWW.2 , and R LWW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein L WW , R LWW.1 , R LWW.2 , and R LWW.3 are L 1 , R L1.1 , R L1.2 , and R L1.3 , respectively.
  • L 2 when L 2 is substituted, L 2 is substituted with one or more first substituent groups denoted by R L2.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R L2.1 substituent group when an R L2.1 substituent group is substituted, the R L2.1 substituent group is substituted with one or more second substituent groups denoted by R L2.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R L2.2 substituent group when an R L2.2 substituent group is substituted, the R L2.2 substituent group is substituted with one or more third substituent groups denoted by R L2.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • L 2 , R L2.1 , R L2.2 , and R L2.3 have values corresponding to the values of L WW , R LWW.1 , R LWW.2 , and R LWW.3 , respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein L WW , R LWW.1 , R LWW.2 , and R LWW.3 are L 2 , R L2.1 , R L2.2 , and R L2.3 , respectively.
  • the compound has the formul In embodiments, the compound has the . In embodiments, the
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  • the compound has the formu . odiments, the compound is useful as a comparator . embodiments, the comparator compound can be used to assess the activity of a test compound as set forth in an assay described herein (e.g., in the examples section, figures, or tables).
  • the compound is a compound as described herein, including in embodiments. In embodiments the compound is a compound described herein (e.g., in the examples section, figures, tables, or claims).
  • Pharmaceutical compositions [0233] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition includes an effective amount of the compound. In embodiments, the pharmaceutical composition includes a therapeutically effective amount of the compound.
  • the compound is a compound of formula (I), (II), (III), (IV), (V), or (VI), including all embodiments thereof. IV. Methods of use [0236] In an aspect is provided a method of treating a cancer, neurodegenerative disorder, inflammatory disease, fibrosing disorder, demyelinating disorder, dermatologic disorder, rheumatic disease, autoimmune disease, metabolic disorder, or eye disease in a subject in need thereof, the method including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • the cancer is breast cancer, ovarian cancer, colon adenocarcinoma, lung adenocarcinoma, lung small cell carcinoma, pancreatic adenocarcinoma, pancreatic neuroendocrine tumors, glioblastoma, prostate cancer, hepatocellular carcinoma, myeloma, leukemia, or lymphoma.
  • the cancer is a solid cancer or a hematologic cancer.
  • the cancer is an ovarian cancer, a colon carcinoma, a bladder cancer, hepatocellular carcinoma, a breast cancer, a pancreatic adenocarcinoma, a prostate cancer, a gliobastoma, or a lung cancer.
  • the cancer is a leukemia, lymphoma, or multiple myeloma. In embodiments, the cancer is multiple myeloma. In embodiments, the cancer is a cancer of the breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma (NSCLC), small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma and biliary passages, kidney carcinoma, pancreatic, myeloid disorders, lymphoma, hairy cells, buccal cavity, na
  • the cancer is squamous cell cancer, small-cell lung cancer, non-small cell lung cancer (NSCLC), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, stomach cancer, gastrointestinal cancer, esophageal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, penile carcinoma, or head and neck cancer.
  • NSCLC non-small cell lung cancer
  • the cancer is a hematological malignancy selected from the group consisting of lymphomas, lymphocytic leukemia, myeloma, acute and chronic myelogenous leukemia, myelodysplastic syndrome and myeloproliferative disease.
  • the compound is administered to the subject intravenously.
  • the compound is administered to the subject orally.
  • the inflammatory disease is a gastrointestinal disease or chronic inflammatory lung disease.
  • the gastrointestinal disease is an inflammatory bowel disease, Crohn’s disease, or colitis.
  • the chronic inflammatory lung disease is bronchial asthma, chronic obstructive pulmonary disease, bronchiectasis, or cystic fibrosis.
  • the fibrosing disorder is pulmonary fibrosis.
  • the autoimmune disease is a peripheral neuropathy.
  • the metabolic disorder is a diabetes mellitus.
  • the disease is a neurodegenerative disease (ND) (e.g., amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Alzheimer’s disease, prion disorders (e.g., BSE), frontotemporal dementia), posterior eye indication (e.g., retinal degeneration (e.g., a subset of ND), retinitis pigmentosa (ADRP), Stargardt’s disease, wet AMD (choroidal neovascularization-CNV), dry AMD), Anterior eye indication (e.g., glaucoma, Fuch’s dystrophy), Diabetes mellitus (e.g., type 1 (autoimmune), type 2 (e.g., obesity- induced/insulin-resistant), monogenic (e.g., MODY syndromes, for example pro-insulin mutations), recessive genetic disorders in which diabetes mellitus is a prominent component (e.g., Wolcott Rallisson syndrome (e.g., associated with Pera neurodegenerative disease (ND
  • the disease is Type 1 Diabetes Melllitus, Type 2 Diabetes Mellitus, Mature Onset diabetes of the Young (MODY), Mutant INS-gene-induced Diabetes of the young (MIDY), Immune Checkpoint-induced Diabetes Mellitus, Wolfram’s Syndrome, Wolcott- Rallison Syndrome, Idiopathic Pulmonary fibrosis (IPF), Familial Pulmonary Fibrosis (FPF), Asthma, Alzheimer’s disease, Amyotrophic lateral sclerosis, Charcot–Marie–Tooth disease, Chronic traumatic encephalopathy, Cystic fibrosis, cytochrome c oxidase deficiency, degenerative Leigh syndrome, Ehlers–Danlos syndrome, Fibrodysplasia ossificans progressiva, Friedreich's ataxia, Frontotemporal dementia, cardiovascular diseases, coronary artery disease, aortic stenosis, Huntington's disease, Infantile neuroaxonal dystrophy, Keratoconus
  • the disease is a neurodegenerative disease (ND) (e.g., amyotrophic lateral sclerosis (ALS), Parkinson’s disease, Alzheimer’s disease, prion disorders (e.g., BSE), frontotemporal dementia).
  • ND neurodegenerative disease
  • the disease is a posterior eye indication (e.g., retinal degeneration (e.g., a subset of ND), retinitis pigmentosa (ADRP), Stargardt’s disease, wet AMD (choroidal neovascularization-CNV), dry AMD).
  • the disease is an anterior eye indication (e.g., glaucoma, Fuch’s dystrophy).
  • the disease is diabetes mellitus (e.g., type 1 (autoimmune), type 2 (e.g., obesity-induced/insulin-resistant), monogenic (e.g. MODY syndromes, for example pro-insulin mutations), recessive genetic disorders in which diabetes mellitus is a prominent component (e.g., Wolcott Rallisson syndrome (e.g., associated with Perk genetic deficiency), Wolfram syndrome (WFS1 or WFS2 deficiency)).
  • type 1 autoimmune
  • type 2 e.g., obesity-induced/insulin-resistant
  • monogenic e.g. MODY syndromes, for example pro-insulin mutations
  • recessive genetic disorders in which diabetes mellitus is a prominent component e.g., Wolcott Rallisson syndrome (e.g., associated with Perk genetic deficiency), Wolfram syndrome (WFS1 or WFS2 deficiency)
  • WFS1 or WFS2 deficiency e.g., a prominent
  • the disease is a fibrosing disorder or fibrosis (e.g., idiopathic pulmonary fibrosis (IPF), familial pulmonary fibrosis (FPF), scleroderma (systemic sclerosis), renal fibrosis, hepatic fibrosis).
  • the disease is a demyelinating disorder (e.g., multiple sclerosis (MS), Guillan-Barre, adrenoleukodystrophy, adrenomyeloneuropathy, optic neuritis, transverse myelitis).
  • the disease is a peripheral neuropathy (e.g., primary such as Charcot-Marie Tooth (CMT) or secondary from diabetes mellitus).
  • CMT Charcot-Marie Tooth
  • the disease is a dermatologic disease (e.g., psoriasis). In embodiments, the disease is a rheumatologic disease. In embodiments, the disease is an autoimmune disease (e.g., rheumatoid arthritis, Grave’s disease, Hashimoto’s Disease, Addison’s disease, Lupus, ankylosing spondylitis, sarcoidosis). In embodiments, the compound treats an autoimmune disease associated with checkpoint inhibitor treatment (e.g., cancer treatment). In embodiments, the compound treats a disease (e.g., diabetes mellitus) associated with checkpoint inhibitor treatment (e.g., cancer treatment).
  • a disease e.g., diabetes mellitus
  • the compound is a compound of formula (I), (II), (III), (IV), (V), or (VI), including all embodiments thereof.
  • a method of decreasing the level of IRE1 ⁇ protein activity in a subject in need thereof including administering to the subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof.
  • the activity is kinase activity.
  • the activity is RNase activity.
  • the level of IRE1 ⁇ protein activity is decreased by about 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IRE1 ⁇ protein activity is decreased by about 1.5-fold relative to a control (e.g., absence of the compound).
  • the level of IRE1 ⁇ protein activity is decreased by about 2-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IRE1 ⁇ protein activity is decreased by about 5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IRE1 ⁇ protein activity is decreased by about 10-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IRE1 ⁇ protein activity is decreased by about 25-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IRE1 ⁇ protein activity is decreased by about 50-fold relative to a control (e.g., absence of the compound).
  • the level of IRE1 ⁇ protein activity is decreased by about 100-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IRE1 ⁇ protein activity is decreased by about 250-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IRE1 ⁇ protein activity is decreased by about 500-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IRE1 ⁇ protein activity is decreased by about 1000-fold relative to a control (e.g., absence of the compound).
  • the level of IRE1 ⁇ protein activity is decreased by at least 1.5-, 2-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 15-, 20-, 25-, 30-, 35-, 40-, 45-, 50-, 60-, 70-, 80-, 90-, 100-, 150-, 200-, 250-, 300-, 350-, 400-, 450-, 500-, 600-, 700-, 800-, 900-, or 1000-fold relative to a control (e.g., absence of the compound).
  • the level of IRE1 ⁇ protein activity is decreased by at least 1.5-fold relative to a control (e.g., absence of the compound).
  • the level of IRE1 ⁇ protein activity is decreased by at least 2-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IRE1 ⁇ protein activity is decreased by at least 5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IRE1 ⁇ protein activity is decreased by at least 10-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IRE1 ⁇ protein activity is decreased by at least 25-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IRE1 ⁇ protein activity is decreased by at least 50-fold relative to a control (e.g., absence of the compound).
  • the level of IRE1 ⁇ protein activity is decreased by at least 100-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IRE1 ⁇ protein activity is decreased by at least 250-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IRE1 ⁇ protein activity is decreased by at least 500-fold relative to a control (e.g., absence of the compound). In embodiments, the level of IRE1 ⁇ protein activity is decreased by at least 1000-fold relative to a control (e.g., absence of the compound). V. Embodiments [0246] Embodiment P1. A compound, or a pharmaceutically acceptable salt thereof, having the formula:
  • Ring A is substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene;
  • L 1 is a bond, -O-, -S-, -S(O)-, -S(O) 2 -, -NR 10 -, -C(O)-, -C(O)NR 10 -, -NR 10 C(O)-, -C(O)O-, -OC(O)-, -NR 10 S(O)-, -S(O)NR 10 -, -NR 10 S(O)2-, -S(O)2NR 10 -, -NR 10 C(O)O-, -OC(O)NR 10 -, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted ary
  • Embodiment P2 The compound of embodiment P1, having the formula: ; wherein -CHX 5 2, -CH2X 5 , -OCX 5 3, -OCH2X 5 , -OCHX 5 2, -CN, -SO n5 R 5D , -SO v5 NR 5A R 5B , ⁇ NR 5C NR 5A R 5B , ⁇ ONR 5A R 5B , -NR 5C C(O)NR 5A R 5B , -N(O) m5 , -NR 5A R 5B , -C(O)R 5C , -C(O)OR 5C , -OC(O)R 5C , -OC(O)OR 5C , -C(O)NR 5A R 5B , -OC(O)NR 5A R 5B , -OR 5D , -SR 5D , -NR 5A SO2R 5D , -NR 5D ,
  • Embodiment P3 The compound of embodiment P2, having the formula: [0250] Embodiment P5.
  • Embodiment P4 The compound of one of embodiments P1 to P4, wherein L 1 is -NR 10 S(O)2- or substituted or unsubstituted 2 to 8 membered heteroalkylene.
  • Embodiment P6 The compound of one of embodiments P1 to P4, wherein L 1 is -NR 10 S(O) 2 - or -NR 10 S(O) 2 -(unsubstituted C 1 -C 6 alkylene)-.
  • Embodiment P7 Embodiment P7.
  • R 10 is hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH 2 I, -CN, -OH, -NH 2 , -COOH, -CONH 2 , -OCCl 3 , -OCF 3 , -OCBr 3 , -OCI 3 , -OCHCl 2 , -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, or substituted or unsubstituted heteroalkyl.
  • Embodiment P8 The compound of one of embodiments P1 to P6, wherein R 10 is hydrogen or unsubstituted C1-C4 alkyl.
  • Embodiment P9. The compound of one of embodiments P1 to P4, wherein L 1 . R 1 is –CF3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted phenyl.
  • Embodiment P11 is preferably, phenyl.
  • Embodiment P15 The compound of one of embodiments P1 to P13, wherein R 2 is a substituted or unsubstituted piperidinyl.
  • Embodiment P16 The compound of one of embodiments P1 to P13, wherein R 2 is an unsubstituted piperidinyl.
  • Embodiment P17 The compound of one of embodiments P1 to P13, wherein R 2 is a piperidinyl substituted with a halogen.
  • Embodiment P18 Embodiment P18.
  • Embodiment P19 The compound of one of embodiments P1 to P13, wherein R 2 is a piperidinyl substituted with -F.
  • Embodiment P20 The compound of one of embodiments P1 to P13, wherein R 2 is [0265] Embodiment P20.
  • Embodiment P21 The compound of one of embodiments P1 to P20, wherein z4 is 0.
  • Embodiment P22 The compound of one of embodiments P2 to P21, wherein R 5 is independently halogen or unsubstituted C1-C4 alkyl.
  • Embodiment P23 The compound of one of embodiments P2 to P21, wherein R 5 is independently halogen or unsubstituted C1-C4 alkyl.
  • Embodiment P24 The compound of one of embodiments P2 to P23, wherein z5 is 1 or 2.
  • Embodiment P25 The compound of embodiment P1, is . a compound of one of embodiments P1 to P25, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Embodiment P27 is a compound of one of embodiments P1 to P25, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a method of treating a cancer, neurodegenerative disorder, inflammatory disease, fibrosing disorder, demyelinating disorder, dermatologic disorder, rheumatic disease, autoimmune disease, metabolic disorder, or eye disease in a subject in need thereof comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of embodiments P1 to P25, or a pharmaceutically acceptable salt thereof.
  • Embodiment P27 wherein the cancer is breast cancer, ovarian cancer, colon adenocarcinoma, lung adenocarcinoma, lung small cell carcinoma, pancreatic adenocarcinoma, pancreatic neuroendocrine tumors, glioblastoma, prostate cancer, hepatocellular carcinoma, myeloma, leukemia, or lymphoma.
  • Embodiment P29 The method of embodiment P27, wherein the inflammatory disease is a gastrointestinal disease or chronic inflammatory lung disease.
  • Embodiment P30 The method of embodiment P29, wherein the gastrointestinal disease is an inflammatory bowel disease, Crohn’s disease, or colitis.
  • Embodiment P31 Embodiment P31.
  • Embodiment P29 wherein the chronic inflammatory lung disease is bronchial asthma, chronic obstructive pulmonary disease, bronchiectasis, or cystic fibrosis.
  • Embodiment P32 The method of embodiment P27, wherein the fibrosing disorder is pulmonary fibrosis.
  • Embodiment P33 The method of embodiment P27, wherein the autoimmune disease is a peripheral neuropathy.
  • Embodiment P34 The method of embodiment P27, wherein the metabolic disorder is a diabetes mellitus.
  • Atomic level resolution co-crystal structures show that these small molecule kinase inhibitors — which we named ‘PAIR’s for (Partial Antagonists of IRE1 ⁇ RNase) — bind ATP-competitively in the kinase to partially displace the IRE1 ⁇ ⁇ kinase helix ⁇ C, leading to stabilization of dimeric IRE1 ⁇ ⁇ species.
  • PAIRs permit adaptive XBP1 mRNA splicing, while quelling destructive/terminal outputs from extra-XBP1 mRNA endonucleolytic decay, thus preventing apoptosis.
  • RNAse-inhibitory “sweet spot”, achieved by PAIR- bound IRE1 ⁇ ⁇ may capture a structural conformation naturally available to IRE1 ⁇ ⁇ that could represent a desirable therapeutic state for drugging this master UPR sensor/effector.
  • PAIRs Partial Antagonists of IRE1 ⁇ RNase

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne, entre autres, des composés pour inhiber IRE1α et leurs utilisations.
PCT/US2024/039590 2023-07-25 2024-07-25 Inhibiteurs d'ire1alpha et leurs utilisations Pending WO2025024688A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100160280A1 (en) * 2008-12-17 2010-06-24 Amgen Inc. Aminopyridine and carboxypyridine compounds as phosphodiesterase 10 inhibitors
US20150011575A1 (en) * 2008-09-15 2015-01-08 The Regents Of The University Of California Methods and compositions for modulating ire1, src, and abl activity

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150011575A1 (en) * 2008-09-15 2015-01-08 The Regents Of The University Of California Methods and compositions for modulating ire1, src, and abl activity
US20100160280A1 (en) * 2008-12-17 2010-06-24 Amgen Inc. Aminopyridine and carboxypyridine compounds as phosphodiesterase 10 inhibitors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE PubChem 12 February 2015 (2015-02-12), "232071171", XP093269077, Database accession no. 232071171 *

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