WO2024129892A2 - Inhibitors of procaspase-6 activation and uses thereof - Google Patents

Inhibitors of procaspase-6 activation and uses thereof Download PDF

Info

Publication number
WO2024129892A2
WO2024129892A2 PCT/US2023/083886 US2023083886W WO2024129892A2 WO 2024129892 A2 WO2024129892 A2 WO 2024129892A2 US 2023083886 W US2023083886 W US 2023083886W WO 2024129892 A2 WO2024129892 A2 WO 2024129892A2
Authority
WO
WIPO (PCT)
Prior art keywords
substituted
unsubstituted
compound
membered
ring
Prior art date
Application number
PCT/US2023/083886
Other languages
French (fr)
Inventor
Adam R. Renslo
Xochina ELHILALI-POLLARD
Original Assignee
The Regents Of The University Of California
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Regents Of The University Of California filed Critical The Regents Of The University Of California
Publication of WO2024129892A2 publication Critical patent/WO2024129892A2/en

Links

Definitions

  • Caspase-6 is implicated in several neurodegenerative conditions, including Huntington’s and Alzheimer’s disease. Expressed as an inactive zymogen form, procaspase- 6, its conversion to proteolytically active caspase-6 is observed during all stages of AD. Additionally, the activation of Casp6 correlates with a lower cognitive score in normal aged individuals.
  • BRIEF SUMMARY [0004] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula: .
  • L 1 is a bond or substituted or unsubstituted C1-C3 alkylene.
  • R 1 is independently halogen, -CX 1 3, -CHX 1 2, -CH2X 1 , -OCX 1 3, -OCH2X 1 , -OCHX 1 2 , -CN, -SO n1 R 1D , -SO v1 NR 1A R 1B , ⁇ NR 1C NR 1A R 1B , ⁇ ONR 1A R 1B , -NR 1C C(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -C(O)OR 1C , -OC(O)R 1C , -OC(O)OR 1C , -C(O)NR 1A R 1B , -OC(O)NR 1A R 1B , -OR 1D , -SR 1D , -NR 1A SO2R 1D , -NR 1A C(O) C(
  • R 1A , R 1B , R 1C , and R 1D 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, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or
  • Each X 1 is independently –F, -Cl, -Br, or –I.
  • the symbol n1 is an integer from 0 to 4.
  • the symbols m1 and v1 are independently 1 or 2.
  • the symbol z1 is an integer from 0 to 5.
  • Provided Ring A is not a substituted or unsubstituted pyrimidinyl.
  • Ring B is a substituted or unsubstituted pyrimidinyl.
  • R 1.1 and R 1.5 are not –OH; or (ii) wherein if R 1.1 or R 1.5 is –OH, then Ring B is not substituted or unsubstituted 2- pyrimidinyl or unsubstituted 5-pyrimidinyl; or (iii) wherein if Ring B is 5-pyrimidinyl, then the Ring B 5-pyrimidinyl is substituted.
  • a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • a method of treating a neurodegenerative disease 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 treating a liver 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 fibrotic 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 coronavirus infection 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 reducing the level of activity of caspase-6 protein in a cell the method including contacting the cell with an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • a method of reducing the level of activation of procaspase-6 protein in a cell the method including contacting the cell with an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • FIG.1 Structure and bound conformation of compound 1, a molecular glue that binds the dimer interface of procaspase-6.
  • the pyrimidine ring of 1 stacks between tyrosine 198 A and 198 B from the respective halves of the C2 symmetric dimer (PDB: 4NBL).
  • FIG.2. Compounds 1-30 bearing diverse heteroaryl substitutions (Ring A). The grey sphere indicates the site of connection to the shared ligand scaffold present in progenitor ligand 1.
  • FIG.3. The aligned complex crystal structures of five-membered ring analogs 7, 8, 10, 11, 19, 20, and 21 bound to procaspase-6 are shown on the left.
  • FIG.4 Computed interaction energies (E int ) and experimental binding free energies ( ⁇ G; kcal/mol) for test compounds bearing heteroarene Ring A’s with either one or two heteroatoms. Data points are labelled with compound numbers from FIG.2. [0025] FIG.5. Computed interaction energies (Eint) and experimental binding free energies ( ⁇ G; kcal/mol) for test compounds bearing heteroarene Ring A’s with either three or four heteroatoms.
  • FIG.6 Dose ⁇ response curves (top) and IC 50 values for procaspase-6 binding as determined using homogeneous time-resolved QRET with europium-labeled probe 32. KD values determined by SPR are provided for reference. DETAILED DESCRIPTION I. Definitions [0027] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di-, and multivalent radicals.
  • the alkyl may include a designated number of carbons (e.g., C 1 -C 10 means one to ten carbons).
  • the alkyl is fully saturated. In embodiments, the alkyl is monounsaturated. In embodiments, the alkyl is polyunsaturated. Alkyl is an uncyclized chain. Examples of 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)2R'- represents both -C(O)2R'- 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 -SO2R'.
  • 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(C 1 -C 4 )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 may (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, -SO 3 H, -OSO 3 H, -SO 2 NH 2 , ⁇ NHNH 2 , ⁇ ONH 2 , ⁇ NHC(O)NHNH 2 , 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., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 , and the like).
  • haloalkyl e.g., -CF3 and -CH2CF3
  • acyl e.g., -C(O)CH 3 , -C(O)CF 3 , -C(O)CH 2 OCH 3 , 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)2NR'-, 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 C6-C10 aryl, and each substituted or unsubstituted heteroaryl is
  • 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 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 - C7 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 un
  • 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 C 6 -C 10 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 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-C7 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 denoted by R L1.1
  • L 2 may be substituted with one or more first substituent groups denoted by R L2.1
  • L 3 may 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 5.1 ... R 100.1 ; 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 further substituted with one or more second substituent groups (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 , respectively).
  • each first substituent group which may alternatively be 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 substituted with one or more third substituent groups e.g., R 1.3 , R 2.3 , R 3.3 , R 4.3 , R 5.3 ... R 100.3 ; R 1A.3 , R 2A.3 , R 3A.3 , R 4A.3 , R 5A.
  • 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 , -CH2X WW.1 , -OCX WW.1 3, -OCH2X WW.1 , -OCHX WW.1 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.1 is independently –F, -Cl, -Br, or –I.
  • R WW.2 is independently oxo, halogen, -CX WW.2 3, -CHX WW.2 2, -CH2X WW.2 , -OCX WW.2 3 , -OCH 2 X WW.2 , -OCHX WW.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)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , R WW.3 -substituted or unsubstituted alky
  • 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)NH 2 , –NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N 3 , unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted
  • 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 , -CH 2 X WW.3 , -OCX WW.3 3, -OCH2X WW.3 , -OCHX WW.3 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, unsubstituted alkyl (e.g., C 1 -
  • 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, referred 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 –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-C8, C1-C6, C1-C4, or C1-C2), R LWW.2 -substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R LWW.2 -substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C 5 -C 6 ), R LWW.2 -substit
  • 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, -CONH2, -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., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (
  • 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, or heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), R WW.3
  • R LWW.2 is independently oxo, halogen, -CX LWW.2 3 , -CHX LWW.2 2, -CH2X LWW.2 , -OCX LWW.2 3, -OCH2X LWW.2 , -OCHX LWW.2 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)NHNH 2 , ⁇ NHC(O)NH 2 , –NHC(NH)NH 2 , -NHSO 2 H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-
  • 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, -CH2X LWW.3 , -OCX LWW.3 3 , -OCH 2 X LWW.3 , -OCHX LWW.3 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -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 alky
  • 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 , -CH2X WW , -OCX WW 3, -OCH2X WW , -OCHX WW 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,
  • 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. [0079] 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 13A , R 13B , R 13C , R 13D , etc., wherein each of R 13A , R 13B , R 13C , R 13D , etc.
  • R 13 is defined within the scope of the definition of R 13 and optionally differently.
  • R moiety, group, or substituent as disclosed herein is attached through the representation of a single bond and the R moiety, group, or substituent is oxo
  • a person having ordinary skill in the art will immediately recognize that the oxo is attached through a double bond in accordance with the normal rules of chemical valency.
  • Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art.
  • 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.
  • 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 no 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).
  • the disease is a neurodegenerative disease.
  • the disease is a liver disease.
  • the disease is a fibrotic disease.
  • the disease is a coronavirus infection.
  • the term “neurodegenerative disease” refers to a disease or condition in which the function of a subject’s nervous system becomes impaired.
  • Examples of neurodegenerative diseases that may be treated with a compound, pharmaceutical composition, or method described herein 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, 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 (
  • tauopathy refers to a neurodegenerative disease characterized by tau deposits in the brain.
  • tauopathies include, but are not limited to, Alzheimer’s disease, primary age-related tauopathy, chronic traumatic encephalopathy, progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia, vacuolar tauopathy, Lytico-bodig disease, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Pantothenate kinase-associated neurodegeneration, and lipofuscinosis.
  • liver disease refers to a disease or condition characterized by liver problems (e.g., an increased level of liver problems compared to a control such as a healthy person not suffering from a disease).
  • liver diseases include, but are not limited to, Alagille syndrome, autoimmune hepatitis, biliary atresia, cirrhosis, endoscopic retrograde cholangiopancreatography (ERCP), hemochromatosis, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, viral hepatitis, liver cancer, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), porphyria, primary biliary cholangitis, primary sclerosing cholangitis (PSC), and Wilson disease.
  • NAFLD nonalcoholic fatty liver disease
  • NASH nonalcoholic steatohepatitis
  • PSC primary sclerosing cholang
  • Fibrosis or “fibrotic disease” is used in accordance with its plain ordinary meaning and refers to any disease or condition characterized by the formation of excess fibrous connective tissue. The formation of excess fibrous connective tissue may be in response to a reparative or reactive process. Fibrosis may be pulmonary fibrosis, liver fibrosis, myelofibrosis, skin fibrosis (e.g., nephrogenic systemic fibrosis and keloid fibrosis), mediastinal fibrosis, cardiac fibrosis, kidney fibrosis, stromal fibrosis, epidural fibrosis, epithelial fibrosis, or idiopathic fibrosis.
  • pulmonary fibrosis pulmonary fibrosis
  • liver fibrosis fibrosis
  • myelofibrosis myelofibrosis
  • skin fibrosis e.g., nephrogenic systemic fibrosis and keloid fibrosis
  • coronavirus is used in accordance with its plain ordinary meaning and refers to an RNA virus that in humans causes respiratory tract infections. Coronaviruses constitute the subfamily Orthocoronavirinae, in the family Coronaviridae, order Nidovirales, and realm Riboviria. In embodiments, the coronavirus is an enveloped viruses with a positive-sense single-stranded RNA genome.
  • severe acute respiratory syndrome coronavirus or “SARS-CoV” or “SARS-CoV-1” refers to the strain of coronavirus that causes severe acute respiratory syndrome (SARS).
  • SARS-CoV-1 is an enveloped, positive-sense, single- stranded RNA virus that infects the epithelial cells within the lungs.
  • the virus enters the host cell by binding to the angiotensin-converting enzyme 2 (ACE2) receptor.
  • ACE2 angiotensin-converting enzyme 2
  • SARS-CoV-2 refers to the strain of coronavirus that causes coronavirus disease 2019 (COVID-19).
  • SARS-CoV-2 is a positive-sense single-stranded RNA virus.
  • 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.
  • cutaneous T-cell lymphoma 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.
  • 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).
  • 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.
  • drug is used in accordance with its common meaning and refers to a substance which has a physiological effect (e.g., beneficial effect, is useful for treating a subject) when introduced into or to a subject (e.g., in or on the body of a subject or patient).
  • a drug moiety is a radical of a drug.
  • 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, 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, digoxigen
  • 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, 154-1581 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., neurodegenerative disease, liver disease, fibrotic disease, or coronavirus infection) 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. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached.
  • the total daily dosage may be divided and administered in portions during the day, if desired.
  • a disease e.g., a protein associated disease, disease associated with a cellular component
  • the disease e.g., neurodegenerative disease, liver disease, fibrotic disease, or coronavirus infection
  • 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).
  • 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.
  • a selected residue in a selected protein corresponds to Y198 A of procaspase-6 when the selected residue occupies the same essential spatial or other structural relationship as Y198 A of procaspase-6.
  • the position in the aligned selected protein aligning with Y198 A is said to correspond to Y198 A .
  • a three dimensional structural alignment can also be used, e.g., where the structure of the selected protein is aligned for maximum correspondence with the procaspase-6 protein and the overall structures compared.
  • 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. In embodiments, the association between the protein and the additional substance (e.g., compound) is via non-covalent interactions. In embodiments, 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.
  • 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). Typically, when a protein misfolds as a result of a change in the amino acid sequence or a change in the native environment which disrupts normal non-covalent interactions, and the misfolded protein is not corrected or degraded, the unfolded/misfolded protein may aggregate. There are three main types of protein aggregates that may form: amorphous aggregates, oligomers, and amyloid fibrils.
  • protein aggregates are termed aggresomes.
  • procaspase 6 or “procaspase-6” refers to an inactive precursor form of caspase 6. In embodiments, procaspase-6 exhibits a dimeric structure.
  • caspase 6 or “caspase-6” or “Casp6” refers to a protein (including homologs, isoforms, and functional fragments thereof) that is a member of the cysteine- aspartic acid protease (caspase) family.
  • Caspase-6 cleaves substrates (e.g., HTT in Huntington’s, APP in Alzheimer’s disease, tau in Alzheimer’s disease), which may result in protein aggregation of the fragments.
  • caspase-6 cleaves substrates that lead to inflammation (e.g., neuroinflammation), and to cell death.
  • inflammation e.g., neuroinflammation
  • cell death leads to cirrhosis and fibrosis (e.g., in liver or other organs).
  • caspase-6 is involved in axonal degradation.
  • caspase-6 is encoded by the CASP6 gene.
  • caspase-6 has the amino acid sequence set forth in or corresponding to Entrez 839, UniProt P55212, RefSeq (protein) NP_001217.2, or RefSeq (protein) NP_116787.1.
  • caspase-6 has the sequence: MSSASGLRRGHPAGGEENMTETDAFYKREMFDPAEKYKMDHRRRGIALIFNHERFF WHLTLPERRGTCADRDNLTRRFSDLGFEVKCFNDLKAEELLLKIHEVSTVSHADADC FVCVFLSHGEGNHIYAYDAKIEIQTLTGLFKGDKCHSLVGKPKIFIIQACRGNQHDVP VIPLDVVDNQTEKLDTNITEVDAASVYTLPAGADFLMCYSVAEGYYSHRETVNGSW YIQDLCEMLGKYGSSLEFTELLTLVNRKVSQRRVDFCKDPSAIGKKQVPCFASMLTK KLHFFPKSN (SEQ ID NO:1).
  • a compound, or a pharmaceutically acceptable salt thereof having the formula: . substituted or unsubstituted 5 to 6 membered heteroaryl or substituted or unsubstituted 8 to 10 membered fused ring heteroaryl.
  • L 1 is a bond or substituted or unsubstituted C 1 -C 3 alkylene.
  • R 1 is independently halogen, -CX 1 3 , -CHX 1 2 , -CH 2 X 1 , -OCX 1 3 , -OCH 2 X 1 , -OCHX 1 2, -CN, -SOn1R 1D , -SOv1NR 1A R 1B , ⁇ NR 1C NR 1A R 1B , ⁇ ONR 1A R 1B , -NR 1C C(O)NR 1A R 1B , -N(O) m1 , -NR 1A R 1B , -C(O)R 1C , -C(O)OR 1C , -OC(O)R 1C , -OC(O)OR 1C , -C(O)NR 1A R 1B , -OC(O)NR 1A R 1B , -OR 1D , -SR 1D , -NR 1A SO2R 1D , -NR 1A
  • R 1A , R 1B , R 1C , and R 1D 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 1 is independently –F, -Cl, -Br, or –I.
  • the symbol n1 is an integer from 0 to 4.
  • the symbols m1 and v1 are independently 1 or 2.
  • the symbol z1 is an integer from 0 to 5.
  • Ring A is not a substituted or unsubstituted pyrimidinyl.
  • a substituted Ring A (e.g., substituted 5 to 6 membered heteroaryl and/or substituted 8 to 10 membered fused ring heteroaryl) 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.
  • Ring A when Ring A is substituted, it is substituted with at least one lower substituent group.
  • Ring A is a substituted or unsubstituted nitrogen-containing 5 to 6 membered heteroaryl or substituted or unsubstituted nitrogen-containing 8 to 10 membered fused ring heteroaryl. In embodiments, Ring A is a substituted or unsubstituted nitrogen- containing 5 to 6 membered heteroaryl. In embodiments, Ring A is a substituted or unsubstituted nitrogen-containing 8 to 10 membered fused ring heteroaryl.
  • Ring A is substituted or unsubstituted pyridyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted imidazolyl, substituted
  • Ring A is substituted or unsubstituted pyridyl. In embodiments, Ring A is substituted or unsubstituted pyridazinyl. In embodiments, Ring A is substituted or unsubstituted pyrazinyl. In embodiments, Ring A is substituted or unsubstituted triazinyl. In embodiments, Ring A is substituted or unsubstituted imidazolyl. In embodiments, Ring A is substituted or unsubstituted pyrazolyl. In embodiments, Ring A is substituted or unsubstituted oxazolyl. In embodiments, Ring A is substituted or unsubstituted isoxazolyl.
  • Ring A is substituted or unsubstituted furanyl. In embodiments, Ring A is substituted or unsubstituted thienyl. In embodiments, Ring A is substituted or unsubstituted thiazolyl. In embodiments, Ring A is substituted or unsubstituted isothiazolyl. In embodiments, Ring A is substituted or unsubstituted triazolyl. In embodiments, Ring A is substituted or unsubstituted oxadiazolyl. In embodiments, Ring A is substituted or unsubstituted tetrazolyl. In embodiments, Ring A is substituted or unsubstituted imidazopyridinyl.
  • Ring A is substituted or unsubstituted benzothiazolyl. In embodiments, Ring A is substituted or unsubstituted benzoimidazolyl. [0167] In embodiments, Ring A is N N N , , -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, -OCH2F, -OCH 2 I, -OCHCl 2 , -OCHBr
  • a substituted R 2 e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • a substituted R 2 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. In embodiments, when R 2 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 2 is substituted, it is substituted with at least one lower substituent group.
  • R 2 is independently unsubstituted C1-C4 alkyl. In embodiments, R 2 is independently unsubstituted methyl. In embodiments, R 2 is independently unsubstituted ethyl. In embodiments, R 2 is independently unsubstituted propyl. In embodiments, R 2 is independently unsubstituted n-propyl.
  • R 2 is independently unsubstituted isopropyl. In embodiments, R 2 is independently unsubstituted butyl. In embodiments, R 2 is independently unsubstituted n-butyl. In embodiments, R 2 is independently unsubstituted isobutyl. In embodiments, R 2 is independently unsubstituted tert-butyl. In embodiments, R 2 is independently –NH 2 . [0172] In embodiments, z2 is 0. In embodiments, z2 is 1. In embodiments, z2 is 2. In embodiments, z2 is 3. In embodiments, z2 is 4. In embodiments, z2 is 5. [0173] In embodiments, Ring A .
  • Ring A is . In embodiments, Ring A is In embodiments, Ring A z2 . In embodiments, Ring A is NH embodiments, Ring A z2 . In embodiments, Ring A is embodiments, In embodiments, Ring A is embodiments, In embodiments, Ring A is O N is . In embodiments, Ring A . In embodiments, Ring A is . In embodiments, Ring A . In embodiments, Ring A is . In embodiments, Ring A . In embodiments, Ring A is . In embodiments, Ring A . In embodiments, Ring A is . In embodiments, Ring A . In embodiments, Ring A . In embodiments, Ring A . , . In embodiments, Ring A is . In embodiments, Ring A is . In embodiments, Ring A is . In embodiments, Ring A . In embodiments, Ring A In embodiments, Ring A . In embodiments, Ring A In embodiments, Ring A . In embodiments, Ring A In embodiments, Ring A . In embodiments, Ring A
  • Ring A In embodiments, Ring A In embodiments, Ring A . In embodiments, Ring A In embodiments, Ring A . In embodiments, Ring A In embodiments, Ring A . In embodiments, Ring A In embodiments, Ring A . In embodiments, Ring A In embodiments, Ring A . In embodiments, Ring A In embodiments, Ring A . In embodiments, Ring A In embodiments, Ring A in embodiments, Ring A in embodiments, Ring A in embodiments, Ring A . In embodiments, Ring A In embodiments, . [0175] In an or a pharmaceutically acceptable salt thereof, having the formula: described herein, including in embodiments. R 1.1 , R 1.2 , R 1.3 , hydrogen or any value of R 1 as described herein, including in embodiments. [0176] Ring B is a substituted or unsubstituted pyrimidinyl.
  • R 1.1 and R 1.5 are not –OH; or (ii) wherein if R 1.1 or R 1.5 is –OH, then Ring B is not substituted or unsubstituted 2- pyrimidinyl or unsubstituted 5-pyrimidinyl; or (iii) wherein if Ring B is 5-pyrimidinyl, then the Ring B 5-pyrimidinyl is substituted.
  • a substituted Ring B (e.g., substituted pyrimidinyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted Ring B 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 B when Ring B is substituted, it is substituted with at least one substituent group.
  • Ring B when Ring B is substituted, it is substituted with at least one size-limited substituent group.
  • Ring B when Ring B is substituted, it is substituted with at least one lower substituent group.
  • Ring B is N (R 2 )z2 [0180] In embodiments, Ring B . In embodiments, Ring B is N (R 2 )z2 . C 1 -C 4 alkyl. In embodiments, R 2 is independently –NH 2 or unsubstituted methyl. [0182] In embodiments, Ring B is In embodiments, Ring B is . In embodiments, Ring B In embodiments, .
  • L e.g., substituted C1-C3 alkylene
  • L 1 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.
  • when L 1 is substituted it is substituted with at least one substituent group.
  • L 1 when L 1 is substituted, it is substituted with at least one size-limited substituent group.
  • L 1 is substituted, it is substituted with at least one lower substituent group.
  • L 1 is unsubstituted C1-C3 alkylene. In embodiments, L 1 is unsubstituted methylene. In embodiments, L 1 is unsubstituted ethylene. In embodiments, L 1 is unsubstituted propylene. In embodiments, L 1 is unsubstituted n-propylene. In embodiments, L 1 is unsubstituted isopropylene.
  • a substituted R 1 (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 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. In embodiments, when R 1 is substituted, it is substituted with at least one substituent group.
  • R 1 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.
  • a substituted R 1.1 e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 1.1 is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 1.1 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 1.1 when R 1.1 is substituted, it is substituted with at least one substituent group. In embodiments, when R 1.1 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1.1 is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 1.2 (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 1.2 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. In embodiments, when R 1.2 is substituted, it is substituted with at least one substituent group.
  • R 1.2 when R 1.2 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1.2 is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 1.3 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 1.3 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.
  • R 1.3 when R 1.3 is substituted, it is substituted with at least one substituent group. In embodiments, when R 1.3 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1.3 is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 1.4 (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 1.4 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 1.4 when R 1.4 is substituted, it is substituted with at least one substituent group.
  • R 1.4 when R 1.4 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1.4 is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 1.5 e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 1.5 is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 1.5 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 1.5 when R 1.5 is substituted, it is substituted with at least one substituent group. In embodiments, when R 1.5 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1.5 is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 1A (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 1A 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 1A is substituted, it is substituted with at least one substituent group.
  • R 1A when R 1A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1A is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 1B e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 1B is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 1B 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 1B when R 1B is substituted, it is substituted with at least one substituent group. In embodiments, when R 1B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1B is substituted, it is substituted with at least one lower substituent group.
  • a substituted ring formed when R 1A and R 1B substituents bonded to the same nitrogen atom are joined e.g., substituted heterocycloalkyl and/or substituted heteroaryl
  • at least one substituent group, size-limited substituent group, or lower substituent group e.g., substituted heterocycloalkyl and/or substituted heteroaryl
  • the substituted ring formed when R 1A and R 1B 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 1A and R 1B 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 1A and R 1B 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 1A and R 1B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 1C (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 1C 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 1C is substituted, it is substituted with at least one substituent group.
  • R 1C when R 1C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1C is substituted, it is substituted with at least one lower substituent group.
  • a substituted R 1D e.g., substituted alkyl, substituted heteroalkyl, substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl, and/or substituted heteroaryl
  • R 1D is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted R 1D 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 1D when R 1D is substituted, it is substituted with at least one substituent group. In embodiments, when R 1D is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R 1D is substituted, it is substituted with at least one lower substituent group.
  • R 1 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 1 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, -NO 2 , -SH, -SO 3 H, -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, -OCH2F, -OCH2I
  • R 1 is independently halogen. In embodiments, R 1 is independently –F. In embodiments, R 1 is independently –Cl. In embodiments, R 1 is independently –Br. In embodiments, R 1 is independently –I. In embodiments, R 1 is independently -OR 1D , wherein R 1D is as described herein, including in embodiments. In embodiments, R 1 is independently – OH. In embodiments, R 1 is independently –NH2. In embodiments, R 1 is independently -B(OR 1C )(OR 1D ), wherein R 1C and R 1D are as described herein, including in embodiments.
  • R 1 is independently -B(OR 1C )(OH), wherein R 1C is as described herein, including in embodiments. In embodiments, R 1 is independently -B(OH)2. In embodiments, R 1 is independently unsubstituted C1-C4 alkyl. In embodiments, R 1 is independently unsubstituted methyl. In embodiments, R 1 is independently unsubstituted ethyl. In embodiments, R 1 is independently unsubstituted propyl. In embodiments, R 1 is independently unsubstituted n-propyl. In embodiments, R 1 is independently unsubstituted isopropyl. In embodiments, R 1 is independently unsubstituted butyl.
  • R 1 is independently unsubstituted n-butyl. In embodiments, R 1 is independently unsubstituted isobutyl. In embodiments, R 1 is independently unsubstituted tert-butyl. In embodiments, R 1 is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R 1 is independently unsubstituted methoxy. In embodiments, R 1 is independently unsubstituted ethoxy. In embodiments, R 1 is independently unsubstituted propoxy. In embodiments, R 1 is independently unsubstituted n-propoxy. In embodiments, R 1 is independently unsubstituted isopropoxy.
  • R 1 is independently unsubstituted butoxy.
  • R 1.1 , R 1.2 , R 1.3 , R 1.4 , and R 1.5 are independently hydrogen, halogen, -CX 1 3, -CHX 1 2, -CH2X 1 , -OCX 1 3, -OCH2X 1 , -OCHX 1 2, -CN, -SOn1R 1D , -SOv1NR 1A R 1B , ⁇ NR 1C NR 1A R 1B , ⁇ ONR 1A R 1B , -NR 1C C(O)NR 1A R 1B , -N(O)m1, -NR 1A R 1B , -C(O)R 1C , -C(O)OR 1C , -OC(O)R 1C , -OC(O)OR 1C , -C(O)NR 1A R 1B , -OC(O)NR 1A R 1B , -OC(O)NR
  • R 1.1 , R 1.2 , R 1.3 , R 1.4 , and R 1.5 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI 3 , -CH 2 Cl, -CH 2 Br, -CH 2 F, -CH 2 I, -CHCl 2 , -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ⁇ NHNH2, ⁇ ONH2, ⁇ NHC(O)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI 3 , -OCH 2 Cl, -OCH 2 Br, -OCH
  • R 1.1 is hydrogen. In embodiments, R 1.1 is halogen. In embodiments, R 1.1 is –F. In embodiments, R 1.1 is –Cl. In embodiments, R 1.1 is –Br. In embodiments, R 1.1 is –I. In embodiments, R 1.1 is -OR 1D , wherein R 1D is as described herein, including in embodiments. In embodiments, R 1.1 is –OH. In embodiments, R 1.1 is -B(OR 1C )(OR 1D ), wherein R 1C and R 1D are as described herein, including in embodiments.
  • R 1.1 is -B(OR 1C )(OH), wherein R 1C is as described herein, including in embodiments. In embodiments, R 1.1 is -B(OH)2. In embodiments, R 1.1 is unsubstituted C1-C4 alkyl. In embodiments, R 1.1 is unsubstituted methyl. In embodiments, R 1.1 is unsubstituted ethyl. In embodiments, R 1.1 is unsubstituted propyl. In embodiments, R 1.1 is unsubstituted n- propyl. In embodiments, R 1.1 is unsubstituted isopropyl. In embodiments, R 1.1 is unsubstituted butyl.
  • R 1.1 is unsubstituted n-butyl. In embodiments, R 1.1 is unsubstituted isobutyl. In embodiments, R 1.1 is unsubstituted tert-butyl.
  • R 1.2 is hydrogen. In embodiments, R 1.2 is halogen. In embodiments, R 1.2 is –F. In embodiments, R 1.2 is –Cl. In embodiments, R 1.2 is –Br. In embodiments, R 1.2 is –I. In embodiments, R 1.2 is -OR 1D , wherein R 1D is as described herein, including in embodiments. In embodiments, R 1.2 is –OH.
  • R 1.2 is -B(OR 1C )(OR 1D ), wherein R 1C and R 1D are as described herein, including in embodiments.
  • R 1.2 is -B(OR 1C )(OH), wherein R 1C is as described herein, including in embodiments.
  • R 1.2 is -B(OH) 2 .
  • R 1.2 is unsubstituted C 1 -C 4 alkyl.
  • R 1.2 is unsubstituted methyl.
  • R 1.2 is unsubstituted ethyl.
  • R 1.2 is unsubstituted propyl.
  • R 1.2 is unsubstituted n- propyl. In embodiments, R 1.2 is unsubstituted isopropyl. In embodiments, R 1.2 is unsubstituted butyl. In embodiments, R 1.2 is unsubstituted n-butyl. In embodiments, R 1.2 is unsubstituted isobutyl. In embodiments, R 1.2 is unsubstituted tert-butyl. [0203] In embodiments, R 1.3 is hydrogen. In embodiments, R 1.3 is halogen. In embodiments, R 1.3 is –F. In embodiments, R 1.3 is –Cl. In embodiments, R 1.3 is –Br.
  • R 1.3 is –I. In embodiments, R 1.3 is -OR 1D , wherein R 1D is as described herein, including in embodiments. In embodiments, R 1.3 is –OH. In embodiments, R 1.3 is -B(OR 1C )(OR 1D ), wherein R 1C and R 1D are as described herein, including in embodiments. In embodiments, R 1.3 is -B(OR 1C )(OH), wherein R 1C is as described herein, including in embodiments. In embodiments, R 1.3 is -B(OH) 2 . In embodiments, R 1.3 is unsubstituted C 1 -C 4 alkyl. In embodiments, R 1.3 is unsubstituted methyl.
  • R 1.3 is unsubstituted ethyl. In embodiments, R 1.3 is unsubstituted propyl. In embodiments, R 1.3 is unsubstituted n- propyl. In embodiments, R 1.3 is unsubstituted isopropyl. In embodiments, R 1.3 is unsubstituted butyl. In embodiments, R 1.3 is unsubstituted n-butyl. In embodiments, R 1.3 is unsubstituted isobutyl. In embodiments, R 1.3 is unsubstituted tert-butyl. [0204] In embodiments, R 1.4 is hydrogen. In embodiments, R 1.4 is halogen.
  • R 1.4 is –F. In embodiments, R 1.4 is –Cl. In embodiments, R 1.4 is –Br. In embodiments, R 1.4 is –I. In embodiments, R 1.4 is -OR 1D , wherein R 1D is as described herein, including in embodiments. In embodiments, R 1.4 is –OH. In embodiments, R 1.4 is -B(OR 1C )(OR 1D ), wherein R 1C and R 1D are as described herein, including in embodiments. In embodiments, R 1.4 is -B(OR 1C )(OH), wherein R 1C is as described herein, including in embodiments. In embodiments, R 1.4 is -B(OH)2.
  • R 1.4 is unsubstituted C1-C4 alkyl. In embodiments, R 1.4 is unsubstituted methyl. In embodiments, R 1.4 is unsubstituted ethyl. In embodiments, R 1.4 is unsubstituted propyl. In embodiments, R 1.4 is unsubstituted n- propyl. In embodiments, R 1.4 is unsubstituted isopropyl. In embodiments, R 1.4 is unsubstituted butyl. In embodiments, R 1.4 is unsubstituted n-butyl. In embodiments, R 1.4 is unsubstituted isobutyl.
  • R 1.4 is unsubstituted tert-butyl.
  • R 1.5 is hydrogen. In embodiments, R 1.5 is halogen. In embodiments, R 1.5 is –F. In embodiments, R 1.5 is –Cl. In embodiments, R 1.5 is –Br. In embodiments, R 1.5 is –I. In embodiments, R 1.5 is -OR 1D , wherein R 1D is as described herein, including in embodiments. In embodiments, R 1.5 is –OH. In embodiments, R 1.5 is -B(OR 1C )(OR 1D ), wherein R 1C and R 1D are as described herein, including in embodiments.
  • R 1.5 is -B(OR 1C )(OH), wherein R 1C is as described herein, including in embodiments. In embodiments, R 1.5 is -B(OH) 2 . In embodiments, R 1.5 is unsubstituted C 1 -C 4 alkyl. In embodiments, R 1.5 is unsubstituted methyl. In embodiments, R 1.5 is unsubstituted ethyl. In embodiments, R 1.5 is unsubstituted propyl. In embodiments, R 1.5 is unsubstituted n- propyl. In embodiments, R 1.5 is unsubstituted isopropyl. In embodiments, R 1.5 is unsubstituted butyl.
  • R 1.5 is unsubstituted n-butyl. In embodiments, R 1.5 is unsubstituted isobutyl. In embodiments, R 1.5 is unsubstituted tert-butyl.
  • R 1A is independently hydrogen. In embodiments, R 1A is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 1A is independently unsubstituted methyl. In embodiments, R 1A is independently unsubstituted ethyl. In embodiments, R 1A is independently unsubstituted propyl. In embodiments, R 1A is independently unsubstituted n-propyl.
  • R 1A is independently unsubstituted isopropyl. In embodiments, R 1A is independently unsubstituted butyl. In embodiments, R 1A is independently unsubstituted n-butyl. In embodiments, R 1A is independently unsubstituted isobutyl. In embodiments, R 1A is independently unsubstituted tert-butyl. [0207] In embodiments, R 1B is independently hydrogen. In embodiments, R 1B is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 1B is independently unsubstituted methyl. In embodiments, R 1B is independently unsubstituted ethyl.
  • R 1B is independently unsubstituted propyl. In embodiments, R 1B is independently unsubstituted n-propyl. In embodiments, R 1B is independently unsubstituted isopropyl. In embodiments, R 1B is independently unsubstituted butyl. In embodiments, R 1B is independently unsubstituted n-butyl. In embodiments, R 1B is independently unsubstituted isobutyl. In embodiments, R 1B is independently unsubstituted tert-butyl. [0208] In embodiments, R 1C is independently hydrogen. In embodiments, R 1C is independently unsubstituted C1-C4 alkyl.
  • R 1C is independently unsubstituted methyl. In embodiments, R 1C is independently unsubstituted ethyl. In embodiments, R 1C is independently unsubstituted propyl. In embodiments, R 1C is independently unsubstituted n-propyl. In embodiments, R 1C is independently unsubstituted isopropyl. In embodiments, R 1C is independently unsubstituted butyl. In embodiments, R 1C is independently unsubstituted n-butyl. In embodiments, R 1C is independently unsubstituted isobutyl. In embodiments, R 1C is independently unsubstituted tert-butyl.
  • R 1D is independently hydrogen. In embodiments, R 1D is independently unsubstituted C 1 -C 4 alkyl. In embodiments, R 1D is independently unsubstituted methyl. In embodiments, R 1D is independently unsubstituted ethyl. In embodiments, R 1D is independently unsubstituted propyl. In embodiments, R 1D is independently unsubstituted n-propyl. In embodiments, R 1D is independently unsubstituted isopropyl. In embodiments, R 1D is independently unsubstituted butyl. In embodiments, R 1D is independently unsubstituted n-butyl.
  • R 1D is independently unsubstituted isobutyl. In embodiments, R 1D is independently unsubstituted tert-butyl.
  • z1 is 0. In embodiments, z1 is 1. In embodiments, z1 is 2. In embodiments, z1 is 3. In embodiments, z1 is 4. In embodiments, z1 is 5. ts, ts, , , d 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)”.
  • Ring 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 group(s)”, wherein R WW , R WW.1 , R WW.2 , and R WW.3 correspond to Ring A, R A.1 , R A.2 , and R A.3 , respectively.
  • Ring B when Ring B is substituted, Ring B is substituted with one or more first substituent groups denoted by R B.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R B.1 substituent group when an R B.1 substituent group is substituted, the R B.1 substituent group is substituted with one or more second substituent groups denoted by R B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R B.2 substituent group when an R B.2 substituent group is substituted, the R B.2 substituent group is substituted with one or more third substituent groups denoted by R B.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • Ring B, R B.1 , R B.2 , and R B.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 Ring B, R B.1 , R B.2 , and R B.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 1.1 when R 1.1 is substituted, R 1.1 is substituted with one or more first substituent groups denoted by R 1.1.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1.1.1 substituent group when an R 1.1.1 substituent group is substituted, the R 1.1.1 substituent group is substituted with one or more second substituent groups denoted by R 1.1.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1.1.2 substituent group when an R 1.1.2 substituent group is substituted, the R 1.1.2 substituent group is substituted with one or more third substituent groups denoted by R 1.1.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1.1 , R 1.1.1 , R 1.1.2 , and R 1.1.3 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 1.1 , R 1.1.1 , R 1.1.2 , and R 1.1.3 , respectively.
  • R 1.2 when R 1.2 is substituted, R 1.2 is substituted with one or more first substituent groups denoted by R 1.2.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1.2.1 substituent group when an R 1.2.1 substituent group is substituted, the R 1.2.1 substituent group is substituted with one or more second substituent groups denoted by R 1.2.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1.2.2 substituent group when an R 1.2.2 substituent group is substituted, the R 1.2.2 substituent group is substituted with one or more third substituent groups denoted by R 1.2.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1.2 , R 1.2.1 , R 1.2.2 , and R 1.2.3 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 1.2 , R 1.2.1 , R 1.2.2 , and R 1.2.3 , respectively.
  • R 1.3 when R 1.3 is substituted, R 1.3 is substituted with one or more first substituent groups denoted by R 1.3.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1.3.1 substituent group when an R 1.3.1 substituent group is substituted, the R 1.3.1 substituent group is substituted with one or more second substituent groups denoted by R 1.3.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1.3.2 substituent group when an R 1.3.2 substituent group is substituted, the R 1.3.2 substituent group is substituted with one or more third substituent groups denoted by R 1.3.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1.3 , R 1.3.1 , R 1.3.2 , and R 1.3.3 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 1.3 , R 1.3.1 , R 1.3.2 , and R 1.3.3 , respectively.
  • R 1.4 when R 1.4 is substituted, R 1.4 is substituted with one or more first substituent groups denoted by R 1.4.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1.4.1 substituent group when an R 1.4.1 substituent group is substituted, the R 1.4.1 substituent group is substituted with one or more second substituent groups denoted by R 1.4.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1.4.2 substituent group when an R 1.4.2 substituent group is substituted, the R 1.4.2 substituent group is substituted with one or more third substituent groups denoted by R 1.4.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1.4 , R 1.4.1 , R 1.4.2 , and R 1.4.3 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 1.4 , R 1.4.1 , R 1.4.2 , and R 1.4.3 , respectively.
  • R 1.5 when R 1.5 is substituted, R 1.5 is substituted with one or more first substituent groups denoted by R 1.5.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1.5.1 substituent group when an R 1.5.1 substituent group is substituted, the R 1.5.1 substituent group is substituted with one or more second substituent groups denoted by R 1.5.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1.5.2 substituent group when an R 1.5.2 substituent group is substituted, the R 1.5.2 substituent group is substituted with one or more third substituent groups denoted by R 1.5.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1.5 , R 1.5.1 , R 1.5.2 , and R 1.5.3 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 1.5 , R 1.5.1 , R 1.5.2 , and R 1.5.3 , respectively.
  • R 1A when R 1A is substituted, R 1A is substituted with one or more first substituent groups denoted by R 1A.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1A.1 substituent group when an R 1A.1 substituent group is substituted, the R 1A.1 substituent group is substituted with one or more second substituent groups denoted by R 1A.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1A.2 substituent group when an R 1A.2 substituent group is substituted, the R 1A.2 substituent group is substituted with one or more third substituent groups denoted by R 1A.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1A , R 1A.1 , R 1A.2 , and R 1A.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 1A , R 1A.1 , R 1A.2 , and R 1A.3 , respectively.
  • R 1B when R 1B is substituted, R 1B is substituted with one or more first substituent groups denoted by R 1B.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R 1B.1 substituent group is substituted, the R 1B.1 substituent group is substituted with one or more second substituent groups denoted by R 1B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1B.2 substituent group when an R 1B.2 substituent group is substituted, the R 1B.2 substituent group is substituted with one or more third substituent groups denoted by R 1B.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1B , R 1B.1 , R 1B.2 , and R 1B.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 1B , R 1B.1 , R 1B.2 , and R 1B.3 , respectively.
  • R 1A and R 1B 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 1A.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1A.1 when an R 1A.1 substituent group is substituted, the R 1A.1 substituent group is substituted with one or more second substituent groups denoted by R 1A.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1A.2 substituent group when an R 1A.2 substituent group is substituted, the R 1A.2 substituent group is substituted with one or more third substituent groups denoted by R 1A.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1A.1 , R 1A.2 , and R 1A.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 1A.1 , R 1A.2 , and R 1A.3 , respectively.
  • R 1A and R 1B 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 1B.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1B.1 when an R 1B.1 substituent group is substituted, the R 1B.1 substituent group is substituted with one or more second substituent groups denoted by R 1B.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1B.2 substituent group when an R 1B.2 substituent group is substituted, the R 1B.2 substituent group is substituted with one or more third substituent groups denoted by R 1B.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1B.1 , R 1B.2 , and R 1B.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 1B.1 , R 1B.2 , and R 1B.3 , respectively.
  • R 1C when R 1C is substituted, R 1C is substituted with one or more first substituent groups denoted by R 1C.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1C.1 when an R 1C.1 substituent group is substituted, the R 1C.1 substituent group is substituted with one or more second substituent groups denoted by R 1C.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1C.2 substituent group when an R 1C.2 substituent group is substituted, the R 1C.2 substituent group is substituted with one or more third substituent groups denoted by R 1C.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1C , R 1C.1 , R 1C.2 , and R 1C.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 1C , R 1C.1 , R 1C.2 , and R 1C.3 , respectively.
  • R 1D when R 1D is substituted, R 1D is substituted with one or more first substituent groups denoted by R 1D.1 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1D.1 when an R 1D.1 substituent group is substituted, the R 1D.1 substituent group is substituted with one or more second substituent groups denoted by R 1D.2 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1D.2 substituent group when an R 1D.2 substituent group is substituted, the R 1D.2 substituent group is substituted with one or more third substituent groups denoted by R 1D.3 as explained in the definitions section above in the description of “first substituent group(s)”.
  • R 1D , R 1D.1 , R 1D.2 , and R 1D.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 1D , R 1D.1 , R 1D.2 , and R 1D.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.
  • 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.
  • the compound has the .
  • the compound has the .
  • the . has the 5 In the he In the .
  • the compound has the formula: N O In n embodiments, the compound has the formula: . the . In embodiments, the compound has the formula: In embodiments, the compound has the formula: In embodiments, the compound has the formula: [0230] In embodiments, the compound has the formula: . s the formula: . 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). [0233] In embodiments, 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). III.
  • compositions [0234] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0235] In embodiments, the pharmaceutical composition includes an effective amount of the compound. In embodiments, the pharmaceutical composition includes a therapeutically effective amount of the compound. [0236] In embodiments, the compound is a compound of formula (I) or (II), including all embodiments thereof. IV. Methods of use [0237] In an aspect is provided a method of treating a neurodegenerative 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 neurodegenerative disease is a tauopathy.
  • the neurodegenerative disease is Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, Lewy body disease, progressive supranuclear palsy, or Parkinson’s disease.
  • the neurodegenerative disease is Alzheimer’s disease.
  • the neurodegenerative disease is Huntington’s disease.
  • the neurodegenerative disease is amyotrophic lateral sclerosis.
  • the neurodegenerative disease is Lewy body disease.
  • the neurodegenerative disease is progressive supranuclear palsy.
  • the neurodegenerative disease is Parkinson’s disease.
  • a method of treating a liver disease 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 liver disease is nonalcoholic steatohepatitis.
  • a method of treating a fibrotic 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 coronavirus infection is a SARS-CoV infection.
  • the coronavirus infection is Severe Acute Respiratory Disease (SARS).
  • the coronavirus infection is a SARS-CoV-2 infection.
  • the coronavirus infection is coronavirus disease 2019 (COVID-19).
  • the coronavirus infection is a MERS-CoV infection.
  • the coronavirus infection is an HCoV-NL63 infection. In embodiments, the coronavirus infection is an HCoV-229E infection. In embodiments, the coronavirus infection is an HCoV-OC43 infection. In embodiments, the coronavirus infection is an HKU1 infection.
  • the compound is a compound of formula (I) or (II), including all embodiments thereof. [0245] In an aspect is provided a method of reducing the level of activity of caspase-6 protein in a cell, the method including contacting the cell with an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the level of activity of the caspase-6 protein is reduced 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 activity of the caspase-6 protein is reduced by about 1.5-fold relative to a control (e.g., absence of the compound).
  • the level of activity of the caspase-6 protein is reduced by about 2-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by about 5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by about 10-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by about 25-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by about 50-fold relative to a control (e.g., absence of the compound).
  • the level of activity of the caspase-6 protein is reduced by about 100-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by about 250-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by about 500-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by about 1000-fold relative to a control (e.g., absence of the compound).
  • the level of activity of the caspase-6 protein is reduced 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). In embodiments, the level of activity of the caspase-6 protein is reduced by at least 1.5-fold relative to a control (e.g., absence of the compound).
  • the level of activity of the caspase-6 protein is reduced by at least 2-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by at least 5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by at least 10-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by at least 25-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by at least 50-fold relative to a control (e.g., absence of the compound).
  • the level of activity of the caspase-6 protein is reduced by at least 100-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by at least 250-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by at least 500-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by at least 1000-fold relative to a control (e.g., absence of the compound).
  • a method of reducing the level of activation of procaspase-6 protein in a cell including contacting the cell with an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof.
  • the level of activation of the procaspase-6 protein is reduced 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).
  • the level of activation of the procaspase-6 protein is reduced by about 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by about 2-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by about 5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by about 10-fold relative to a control (e.g., absence of the compound).
  • the level of activation of the procaspase-6 protein is reduced by about 25-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by about 50-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by about 100-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by about 250-fold relative to a control (e.g., absence of the compound).
  • the level of activation of the procaspase-6 protein is reduced by about 500-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by about 1000-fold relative to a control (e.g., absence of the compound).
  • the level of activation of the procaspase-6 protein is reduced 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). In embodiments, the level of activation of the procaspase-6 protein is reduced by at least 1.5-fold relative to a control (e.g., absence of the compound).
  • the level of activation of the procaspase-6 protein is reduced by at least 2-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by at least 5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by at least 10-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by at least 25-fold relative to a control (e.g., absence of the compound).
  • the level of activation of the procaspase-6 protein is reduced by at least 50-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by at least 100-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by at least 250-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by at least 500- fold relative to a control (e.g., absence of the compound).
  • the level of activation of the procaspase-6 protein is reduced by at least 1000-fold relative to a control (e.g., absence of the compound).
  • the compound binds to Y198 A of the procaspase-6 (e.g., human procaspase-6) protein.
  • the compound binds noncovalently to Y198 A of the procaspase-6 (e.g., human procaspase-6) protein.
  • the compound binds to Y198 B of the procaspase-6 (e.g., human procaspase-6) protein.
  • the compound binds noncovalently to Y198 B of the procaspase-6 (e.g., human procaspase-6) protein.
  • Embodiment P1 A compound, or a pharmaceutically acceptable salt thereof, having the formula: ; Ring A is a substituted or unsubstituted 5 to 6 membered heteroaryl or substituted or unsubstituted 8 to 10 membered fused ring heteroaryl; L 1 is a bond or substituted or unsubstituted C1-C3 alkylene; R 1 is independently halogen, -CX 1 3, -CHX 1 2, -CH2X 1 , -OCX 1 3, -OCH2X 1 , -OCHX 1 2, -CN, -SOn1R 1D , -SOv1NR 1A R 1B , ⁇ NR 1C NR 1A R 1B , ⁇ ONR 1A R 1B , -NR 1C C(
  • Embodiment P2 The compound of embodiment P1, wherein Ring A is a substituted or unsubstituted nitrogen-containing 5 to 6 membered heteroaryl or substituted or unsubstituted nitrogen-containing 8 to 10 membered fused ring heteroaryl. [0254] Embodiment P3.
  • Ring A is substituted or unsubstituted pyridyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted imidazolyl, substituted
  • Embodiment P5. The compound of embodiment P4, wherein R 2 is independently unsubstituted C 1 -C 4 alkyl.
  • Embodiment P6 The compound of embodiment P4, wherein R 2 is independently unsubstituted methyl.
  • Embodiment P7 The compound of embodiment P4, wherein z2 is 0.
  • Embodiment P8 The compound of one of embodiments P4 to P6, wherein z2 is 1. [0260] Embodiment P9.
  • Ring A is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr 2 , -CHF 2 , -CHI 2 , -CN, -OH, -NH 2 , -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -OSO 3 H, -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, -
  • Embodiment P11 The compound of one of embodiments P1 to P9, wherein R 1 is independently halogen or -OR 1D .
  • Embodiment P12 The compound of embodiment P11, wherein R 1D is independently hydrogen or unsubstituted C1-C4 alkyl.
  • Embodiment P13 The compound of embodiment P11, wherein R 1D is hydrogen.
  • Embodiment P14 The compound of one of embodiments P1 to P9, wherein R 1 is independently –F or -OH.
  • Embodiment P15 The compound of one of embodiments P1 to P14, wherein z1 is 1.
  • Embodiment P16 The compound of one of embodiments P1 to P14, wherein z1 is 1.
  • Embodiment P17 A compound, or a pharmaceutically acceptable salt thereof, having the formula: ; Ring B is a substituted or unsubstituted pyrimidinyl; L 1 is a bond or substituted or unsubstituted C 1 -C 3 alkylene; R 1.1 , R 1.2 , R 1.3 , R 1.4 , and R 1.5 are independently hydrogen, halogen, -CX 1 3 , -CHX 1 2 , -CH2X 1 , -OCX 1 3, -OCH2X 1 , -OCHX 1 2, -CN, -SOn1R 1D , -SOv1NR 1A R 1B , ⁇ NR 1C NR 1A R 1B , ⁇ ONR 1A R 1B , -NR 1C C(O)NR 1A R 1B , -N(O)m1, -NR 1A
  • Embodiment P18 The compound of embodiment P17, wherein Ring B is N (R 2 )z2 -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 2 , -OCHBr2, -OCHF2, -OCHI2, -
  • Embodiment P19 The compound of embodiment P18, wherein R 2 is independently –NH2 or unsubstituted C1-C4 alkyl.
  • Embodiment P20 The compound of embodiment P18, wherein R 2 is independently –NH 2 or unsubstituted methyl.
  • Embodiment P21 The compound of embodiment P18, wherein z2 is 0.
  • Embodiment P22 The compound of one of embodiments P18 to P20, wherein z2 is 1.
  • Embodiment P23 The compound of embodiment P17, wherein Ring B is .
  • R 1.1 , R 1.2 , R 1.3 , R 1.4 , and R 1.5 are independently hydrogen, halogen, -CCl 3 , -CBr 3 , -CF 3 , -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -NH2, -COOH, -CONH 2 , -NO 2 , -SH, -SO 3 H, -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, -OCH2B
  • Embodiment P25 The compound of one of embodiments P17 to P24, wherein R 1.1 is -OH.
  • Embodiment P26 The compound of one of embodiments P17 to P25, wherein R 1.3 is halogen.
  • Embodiment P27 The compound of one of embodiments P17 to P25, wherein R 1.3 is -F.
  • Embodiment P28 The compound of one of embodiments P17 to P27, wherein R 1.2 , R 1.4 , and R 1.5 are hydrogen.
  • Embodiment P29 The compound of one of embodiments P1 to P28, wherein L 1 is unsubstituted C1-C3 alkylene.
  • Embodiment P30 The compound of one of embodiments P1 to P28, wherein L 1 is unsubstituted methylene.
  • Embodiment P31 A pharmaceutical composition comprising a compound of one of embodiments P1 to P30, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
  • Embodiment P32 A method of treating a neurodegenerative disease in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of embodiments P1 to P30, or a pharmaceutically acceptable salt thereof.
  • Embodiment P33 The method of embodiment P32, wherein the neurodegenerative disease is a tauopathy.
  • Embodiment P34 The method of embodiment P32, wherein the neurodegenerative disease is Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, Lewy body disease, progressive supranuclear palsy, or Parkinson’s disease.
  • Embodiment P35 The method of embodiment P32, wherein the neurodegenerative disease is Alzheimer’s disease.
  • Embodiment P36 A method of treating a liver disease in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of embodiments P1 to P30, or a pharmaceutically acceptable salt thereof.
  • Embodiment P38 A method of treating a fibrotic disease in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of embodiments P1 to P30, or a pharmaceutically acceptable salt thereof.
  • Embodiment P39 A method of treating a coronavirus infection in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of embodiments P1 to P30, or a pharmaceutically acceptable salt thereof.
  • Embodiment P40 A method of treating a coronavirus infection in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of embodiments P1 to P30, or a pharmaceutically acceptable salt thereof.
  • a method of reducing the level of activity of caspase-6 protein in a cell comprising contacting the cell with an effective amount of a compound of one of embodiments P1 to P30, or a pharmaceutically acceptable salt thereof.
  • Embodiment P41 A method of reducing the level of activation of procaspase-6 protein in a cell, said method comprising contacting the cell with an effective amount of a compound of one of embodiments P1 to P30, or a pharmaceutically acceptable salt thereof.
  • distal pyrimidine ring of 1 was previously shown to form a nearly ideal stacking interaction between tyrosine residues 198 A and 198 B , each of which project from one subunit of the dimeric zymogen (FIG.1).
  • probe heterocycles were synthesized more than two dozen new analogs of 1 bearing terminal five-membered, six-membered, or bicyclic heteroarenes as “probe heterocycles” and evaluated their binding affinities by surface plasmon resonance (SPR) methods, after first confirming a conserved binding mode and stacking interaction regardless of the nature of the probe heterocycle. We find that differences in binding affinity are largely attributable to the relative strength of the stacking interaction.
  • test ligands (2-30, FIG.2) was synthesized wherein the pyrimidine ring of 1 is replaced with diverse heterocycles commonly employed in materials, supramolecular, and medicinal chemistry.
  • probe heteroarenes with an ortho heteroatom (N or O) such that intramolecular hydrogen bond formation (as in 1) should promote a co-planar pyridine-heteroarene conformation optimal for stacking (FIG.1).
  • Air and/or moisture sensitive reagents were transferred via syringe or cannula and were introduced into reaction vessels through rubber septa. Reaction product solutions and chromatography fractions were concentrated by rotary evaporation. Thin phase chromatography was performed on EMD precoated glass-backed silica gel 60 F-2540.25 mm plate. [0306] Materials: All chemical reagents and solvents used were purchased from commercial sources, such as Sigma-Aldrich, TCI, Ambeed or Fisher Scientific. Anhydrous DMF, dichloromethane and tetrahydrofuran (EMD Drisolv) were used without further purification.
  • EMD Drisolv tetrahydrofuran

Landscapes

  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Described herein, inter alia, are inhibitors of procaspase-6 activation and uses thereof.

Description

PATENT Attorney Docket No.: 048536-753001WO INHIBITORS OF PROCASPASE-6 ACTIVATION AND USES THEREOF CROSS-REFERENCES TO RELATED APPLICATIONS [0001] This application claims the benefit of U.S. Provisional Application No.63/432,557, filed December 14, 2022, which is incorporated herein by reference in its entirety and for all purposes. REFERENCE TO AN ELECTRONIC SEQUENCE LISTING [0002] The contents of the electronic sequence listing (048536- 753001WO_Sequence_Listing_ST26.xml; Size: 2,608 bytes; and Date of Creation: November 29, 2023) is hereby incorporated by reference in its entirety. BACKGROUND [0003] Caspase-6 is implicated in several neurodegenerative conditions, including Huntington’s and Alzheimer’s disease. Expressed as an inactive zymogen form, procaspase- 6, its conversion to proteolytically active caspase-6 is observed during all stages of AD. Additionally, the activation of Casp6 correlates with a lower cognitive score in normal aged individuals. Disclosed herein, inter alia, are solutions to these and other problems in the art. BRIEF SUMMARY [0004] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula: .
Figure imgf000003_0001
substituted or unsubstituted 5 to 6 membered heteroaryl or substituted or unsubstituted 8 to 10 membered fused ring heteroaryl. [0006] L1 is a bond or substituted or unsubstituted C1-C3 alkylene. [0007] R1 is independently halogen, -CX13, -CHX12, -CH2X1, -OCX13, -OCH2X1, -OCHX1 2, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -B(OR1C)(OR1D), -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0008] R1A, R1B, R1C, and R1D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl. [0009] Each X1 is independently –F, -Cl, -Br, or –I. The symbol n1 is an integer from 0 to 4. The symbols m1 and v1 are independently 1 or 2. The symbol z1 is an integer from 0 to 5. [0010] Provided Ring A is not a substituted or unsubstituted pyrimidinyl. [0011] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula: described herein, including in embodiments. R1.1, R1.2, R1.3,
Figure imgf000004_0001
hydrogen or any value of R1 as described herein, including in embodiments. [0012] Ring B is a substituted or unsubstituted pyrimidinyl. [0013] Provided: (i) R1.1 and R1.5 are not –OH; or (ii) wherein if R1.1 or R1.5 is –OH, then Ring B is not substituted or unsubstituted 2- pyrimidinyl or unsubstituted 5-pyrimidinyl; or (iii) wherein if Ring B is 5-pyrimidinyl, then the Ring B 5-pyrimidinyl is substituted. [0014] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0015] In an aspect is provided a method of treating a neurodegenerative 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. [0016] In an aspect is provided a method of treating a liver 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. [0017] In an aspect is provided a method of treating a fibrotic 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. [0018] In an aspect is provided a method of treating a coronavirus infection 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. [0019] In an aspect is provided a method of reducing the level of activity of caspase-6 protein in a cell, the method including contacting the cell with an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. [0020] In an aspect is provided a method of reducing the level of activation of procaspase-6 protein in a cell, the method including contacting the cell with an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. BRIEF DESCRIPTION OF THE DRAWINGS [0021] FIG.1. Structure and bound conformation of compound 1, a molecular glue that binds the dimer interface of procaspase-6. The pyrimidine ring of 1 stacks between tyrosine 198A and 198B from the respective halves of the C2 symmetric dimer (PDB: 4NBL). [0022] FIG.2. Compounds 1-30 bearing diverse heteroaryl substitutions (Ring A). The grey sphere indicates the site of connection to the shared ligand scaffold present in progenitor ligand 1. [0023] FIG.3. The aligned complex crystal structures of five-membered ring analogs 7, 8, 10, 11, 19, 20, and 21 bound to procaspase-6 are shown on the left. The aligned complex crystal structures of six-membered ring analogs 1, 3, and 5 bound to procaspase-6 are on the right. Tyrosine residues are from the procaspase-6 complex structures of 11 (left) and 3 (right). [0024] FIG.4. Computed interaction energies (Eint) and experimental binding free energies ( ^G; kcal/mol) for test compounds bearing heteroarene Ring A’s with either one or two heteroatoms. Data points are labelled with compound numbers from FIG.2. [0025] FIG.5. Computed interaction energies (Eint) and experimental binding free energies ( ^G; kcal/mol) for test compounds bearing heteroarene Ring A’s with either three or four heteroatoms. Data points are labelled with compound numbers from FIG.2. [0026] FIG.6. Dose−response curves (top) and IC50 values for procaspase-6 binding as determined using homogeneous time-resolved QRET with europium-labeled probe 32. KD values determined by SPR are provided for reference. DETAILED DESCRIPTION I. Definitions [0027] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts. [0028] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH2O- is equivalent to -OCH2-. [0029] The term “alkyl,” by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e., unbranched) or branched carbon chain (or carbon), or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include mono-, di-, and multivalent radicals. 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. Examples of 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. [0030] The term “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, -CH2CH2CH2CH2-. Typically, 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. The term “alkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkene. The term “alkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from an alkyne. In embodiments, the alkylene is fully saturated. In embodiments, the alkylene is monounsaturated. In embodiments, the alkylene is polyunsaturated. An alkenylene includes one or more double bonds. An alkynylene includes one or more triple bonds. [0031] The term “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) may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Heteroalkyl is an uncyclized chain. Examples include, but are not limited to: -CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2-CH3, -S-CH2-CH2, -S(O)-CH3, -CH2-CH2-S(O)2-CH3, -CH=CH-O-CH3, -Si(CH3)3, -CH2-CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3, -O-CH2-CH3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-O-Si(CH3)3. 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. The term “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. In embodiments, the heteroalkyl is fully saturated. In embodiments, the heteroalkyl is monounsaturated. In embodiments, the heteroalkyl is polyunsaturated. [0032] Similarly, 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-. For heteroalkylene groups, 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)2R'- represents both -C(O)2R'- and -R'C(O)2-. As described above, heteroalkyl groups, as used herein, 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 -SO2R'. Where “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. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R'' or the like. The term “heteroalkenylene,” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkene. The term “heteroalkynylene” by itself or as part of another substituent, means, unless otherwise stated, a divalent radical derived from a heteroalkyne. In embodiments, the heteroalkylene is fully saturated. In embodiments, the heteroalkylene is monounsaturated. In embodiments, the heteroalkylene is polyunsaturated. A heteroalkenylene includes one or more double bonds. A heteroalkynylene includes one or more triple bonds. [0033] The terms “cycloalkyl” and “heterocycloalkyl,” by themselves or in combination with other terms, mean, unless otherwise stated, cyclic versions of “alkyl” and “heteroalkyl,” respectively. Cycloalkyl and heterocycloalkyl are not aromatic. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl 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. A “cycloalkylene” and a “heterocycloalkylene,” alone or as part of another substituent, means a divalent radical derived from a cycloalkyl and heterocycloalkyl, respectively. In embodiments, the cycloalkyl is fully saturated. In embodiments, the cycloalkyl is monounsaturated. In embodiments, the cycloalkyl is polyunsaturated. In embodiments, the heterocycloalkyl is fully saturated. In embodiments, the heterocycloalkyl is monounsaturated. In embodiments, the heterocycloalkyl is polyunsaturated. [0034] In embodiments, the term “cycloalkyl” means a monocyclic, bicyclic, or a multicyclic cycloalkyl ring system. In embodiments, 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. In embodiments, 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. [0035] In embodiments, a cycloalkyl is a cycloalkenyl. The term “cycloalkenyl” is used in accordance with its plain ordinary meaning. In embodiments, 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. [0036] In embodiments, the term “heterocycloalkyl” means a monocyclic, bicyclic, or a multicyclic heterocycloalkyl ring system. In embodiments, 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. [0037] The terms “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. For example, the term “halo(C1-C4)alkyl” includes, but is not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. [0038] The term “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. [0039] The term “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. The term “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. Thus, the term “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. Likewise, 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. And 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-imidazolyl, pyrazinyl, 2-oxazolyl, 4- oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2- thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5-isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. An “arylene” and a “heteroarylene,” alone or as part of another substituent, mean a divalent radical derived from an aryl and heteroaryl, respectively. A heteroaryl group substituent may be -O- bonded to a ring heteroatom nitrogen. [0040] 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). When referring to a spirocyclic ring system, 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. When referring to a spirocyclic ring system, substituted spirocyclic rings means that at least one ring is substituted and each substituent may optionally be different. [0041] The symbol “ ” denotes the point of attachment of a chemical moiety to the remainder of a molecule or chemical formula. [0042] The term “oxo,” as used herein, means an oxygen that is double bonded to a carbon atom. [0043] The term “alkylarylene” as an arylene moiety covalently bonded to an alkylene moiety (also referred to herein as an alkylene linker). In embodiments, the alkylarylene group has the formula: .
Figure imgf000012_0001
may (e.g., with a substituent group) on the alkylene moiety or the arylene linker (e.g., at carbons 2, 3, 4, or 6) with halogen, oxo, -N3, -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). In embodiments, the alkylarylene is unsubstituted. [0045] 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. [0046] Substituents for the alkyl and heteroalkyl radicals (including those groups often referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to, -OR', =O, =NR', =N-OR', -NR'R'', -SR', halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'C(O)NR''R''', -NR''C(O)2R', -NRC(NR'R''R''')=NR'''', -NRC(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)OR'', -NR'OR'', in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such radical. 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. When a compound described herein includes more than one R group, for example, 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. When 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. For example, -NR'R'' includes, but is not limited to, 1-pyrrolidinyl and 4- morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term “alkyl” is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and -CH2CF3) and acyl (e.g., -C(O)CH3, -C(O)CF3, -C(O)CH2OCH3, and the like). [0047] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: -OR', -NR'R'', -SR', halogen, -SiR'R''R''', -OC(O)R', -C(O)R', -CO2R', -CONR'R'', -OC(O)NR'R'', -NR''C(O)R', -NR'C(O)NR''R''', -NR''C(O)2R', -NR-C(NR'R''R''')=NR'''', -NR-C(NR'R'')=NR''', -S(O)R', -S(O)2R', -S(O)2NR'R'', -NRSO2R', -NR'NR''R''', -ONR'R'', -NR'C(O)NR''NR'''R'''', -CN, -NO2, -R', -N3, -CH(Ph)2, fluoro(C1-C4)alkoxy, and fluoro(C1-C4)alkyl, -NR'SO2R'', -NR'C(O)R'', -NR'C(O)OR'', -NR'OR'', in a number ranging from zero to the total number of open valences on the aromatic ring system; and where 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. When a compound described herein includes more than one R group, for example, 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. [0048] Substituents for rings (e.g., cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene) may be depicted as substituents on the ring rather than on a specific atom of a ring (commonly referred to as a floating substituent). In such a case, 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). When a substituent is attached to a ring, but not a specific atom (a floating substituent), and a subscript for the substituent is an integer greater than one, 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. Where 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. Where 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. Where 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. [0049] 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. In one embodiment, the ring-forming substituents are attached to adjacent members of the base structure. For example, two ring-forming substituents attached to adjacent members of a cyclic base structure create a fused ring structure. In another embodiment, the ring-forming substituents are attached to a single member of the base structure. For example, two ring- forming substituents attached to a single member of a cyclic base structure create a spirocyclic structure. In yet another embodiment, the ring-forming substituents are attached to non-adjacent members of the base structure. [0050] 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. Alternatively, two of the substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be replaced with a substituent of the formula -A-(CH2)r-B-, wherein A and B are independently -CRR'-, -O-, -NR-, -S-, -S(O)-, -S(O)2-, -S(O)2NR'-, 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. Alternatively, 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)2NR'-. The substituents 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. [0051] As used herein, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), selenium (Se), and silicon (Si). In embodiments, the terms “heteroatom” or “ring heteroatom” are meant to include oxygen (O), nitrogen (N), sulfur (S), phosphorus (P), and silicon (Si). [0052] 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, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -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, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (B) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: (i) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -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, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6- C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (ii) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6- C10 aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: (a) oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -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, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), and (b) alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), aryl (e.g., C6- C10 aryl, C10 aryl, or phenyl), heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl), substituted with at least one substituent selected from: oxo, halogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, -CN, -OH, -NH2, -COOH, -CONH2, -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, -SF5, unsubstituted alkyl (e.g., C1-C8 alkyl, C1-C6 alkyl, or C1-C4 alkyl), unsubstituted heteroalkyl (e.g., 2 to 8 membered heteroalkyl, 2 to 6 membered heteroalkyl, or 2 to 4 membered heteroalkyl), unsubstituted cycloalkyl (e.g., C3-C8 cycloalkyl, C3-C6 cycloalkyl, or C5-C6 cycloalkyl), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered heterocycloalkyl, 3 to 6 membered heterocycloalkyl, or 5 to 6 membered heterocycloalkyl), unsubstituted aryl (e.g., C6-C10 aryl, C10 aryl, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 10 membered heteroaryl, 5 to 9 membered heteroaryl, or 5 to 6 membered heteroaryl). [0053] 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 C1-C20 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 C6-C10 aryl, and each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. [0054] 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- C7 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 unsubstituted 5 to 6 membered heteroaryl. [0055] In some embodiments, 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. In other embodiments, at least one or all of these groups are substituted with at least one lower substituent group. [0056] In other embodiments of the compounds herein, each substituted or unsubstituted alkyl may be a substituted or unsubstituted C1-C20 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 C6- C10 aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 10 membered heteroaryl. In some embodiments of the compounds herein, 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 C3-C8 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, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 10 membered heteroarylene. [0057] In some embodiments, 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-C7 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 C6-C10 aryl, and/or each substituted or unsubstituted heteroaryl is a substituted or unsubstituted 5 to 9 membered heteroaryl. In some embodiments, 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 C6-C10 arylene, and/or each substituted or unsubstituted heteroarylene is a substituted or unsubstituted 5 to 9 membered heteroarylene. In some embodiments, the compound is a chemical species set forth in the Examples section, figures, or tables below. [0058] In embodiments, 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 heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, unsubstituted heteroaryl, unsubstituted alkylene, unsubstituted heteroalkylene, unsubstituted cycloalkylene, unsubstituted heterocycloalkylene, unsubstituted arylene, and/or unsubstituted heteroarylene, respectively). In embodiments, 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 alkylene, substituted heteroalkylene, substituted cycloalkylene, substituted heterocycloalkylene, substituted arylene, and/or substituted heteroarylene, respectively). [0059] In embodiments, 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. [0060] In embodiments, 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. In embodiments, if the substituted moiety is substituted with a plurality of size-limited substituent groups, each size-limited substituent group is different. [0061] In embodiments, 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 lower substituent group, wherein if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group may optionally be different. In embodiments, if the substituted moiety is substituted with a plurality of lower substituent groups, each lower substituent group is different. [0062] In embodiments, 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, size-limited substituent group, or lower substituent group; wherein if the substituted moiety 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, if the substituted moiety 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 is different. [0063] In a recited claim or chemical formula description herein, 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. [0064] The first substituent group is denoted with a corresponding first decimal point numbering system such that, for example, R1 may be substituted with one or more first substituent groups denoted by R1.1, R2 may be substituted with one or more first substituent groups denoted by R2.1, R3 may be substituted with one or more first substituent groups denoted by R3.1, R4 may be substituted with one or more first substituent groups denoted by R4.1, R5 may be substituted with one or more first substituent groups denoted by R5.1, and the like up to or exceeding an R100 that may be substituted with one or more first substituent groups denoted by R100.1. As a further example, R1A may be substituted with one or more first substituent groups denoted by R1A.1, R2A may be substituted with one or more first substituent groups denoted by R2A.1, R3A may be substituted with one or more first substituent groups denoted by R3A.1, R4A may be substituted with one or more first substituent groups denoted by R4A.1, R5A may be substituted with one or more first substituent groups denoted by R5A.1 and the like up to or exceeding an R100A may be substituted with one or more first substituent groups denoted by R100A.1. As a further example, L1 may be substituted with one or more first substituent groups denoted by RL1.1, L2 may be substituted with one or more first substituent groups denoted by RL2.1, L3 may be substituted with one or more first substituent groups denoted by RL3.1, L4 may be substituted with one or more first substituent groups denoted by RL4.1, L5 may be substituted with one or more first substituent groups denoted by RL5.1 and the like up to or exceeding an L100 which may be substituted with one or more first substituent groups denoted by RL100.1. Thus, each numbered R group or L group (alternatively referred to herein as RWW or LWW 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 RWW.1 or RLWW.1, respectively. In turn, each first substituent group (e.g., R1.1, R2.1, R3.1, R4.1, R5.1 … R100.1; R1A.1, R2A.1, R3A.1, R4A.1, R5A.1 … R100A.1; RL1.1, RL2.1, RL3.1, RL4.1, RL5.1 … RL100.1) may be further substituted with one or more second substituent groups (e.g., R1.2, R2.2, R3.2, R4.2, R5.2… R100.2; R1A.2, R2A.2, R3A.2, R4A.2, R5A.2 … R100A.2; RL1.2, RL2.2, RL3.2, RL4.2, RL5.2 … RL100.2, respectively). Thus, each first substituent group, which may alternatively be represented herein as RWW.1 as described above, may be further substituted with one or more second substituent groups, which may alternatively be represented herein as RWW.2. [0065] Finally, each second substituent group (e.g., R1.2, R2.2, R3.2, R4.2, R5.2 … R100.2; R1A.2, R2A.2, R3A.2, R4A.2, R5A.2 … R100A.2; RL1.2, RL2.2, RL3.2, RL4.2, RL5.2 … RL100.2) may be further substituted with one or more third substituent groups (e.g., R1.3, R2.3, R3.3, R4.3, R5.3 … R100.3; R1A.3, R2A.3, R3A.3, R4A.3, R5A.3 … R100A.3; RL1.3, RL2.3, RL3.3, RL4.3, RL5.3 … RL100.3; substituent group, which may alternatively be represented
Figure imgf000023_0001
herein as RWW.2 as described above, may be further substituted with one or more third substituent groups, which may alternatively be represented herein as RWW.3. Each of the first substituent groups may be optionally different. Each of the second substituent groups may be optionally different. Each of the third substituent groups may be optionally different. [0066] Thus, as used herein, RWW 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.). Likewise, LWW is a linker recited in a claim or chemical formula description herein which is openly substituted. Again, “WW” represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). As stated above, in embodiments, each RWW may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as RWW.1; each first substituent group, RWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RWW.2; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RWW.3. Similarly, each LWW linker may be unsubstituted or independently substituted with one or more first substituent groups, referred to herein as RLWW.1; each first substituent group, RLWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RLWW.2; and each second substituent group may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RLWW.3. Each first substituent group is optionally different. Each second substituent group is optionally different. Each third substituent group is optionally different. For example, if RWW is phenyl, the said phenyl group is optionally substituted by one or more RWW.1 groups as defined herein below, e.g., when RWW.1 is RWW.2-substituted or unsubstituted alkyl, examples of groups so formed include but are not limited to itself optionally substituted by 1 or more RWW.2, which RWW.2 is optionally substituted by one or more RWW.3. By way of example when the RWW group is phenyl substituted by RWW.1, which is methyl, the methyl group may be further substituted to form groups including but not limited to: . [0067]
Figure imgf000024_0001
oxo, - - - -OCXWW.1 3, -OCH2XWW.1, -OCHXWW.1 2, -CN, -OH, -NH2, -COOH, -CONH2, -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, RWW.2-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RWW.2-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RWW.2-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RWW.2-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RWW.2-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RWW.2-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RWW.1 is independently oxo, halogen, -CXWW.1 3, -CHXWW.1 2, -CH2XWW.1, -OCXWW.13, -OCH2XWW.1, -OCHXWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -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., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWW.1 is independently –F, -Cl, -Br, or –I. [0068] RWW.2 is independently oxo, halogen, -CXWW.23, -CHXWW.22, -CH2XWW.2, -OCXWW.2 3, -OCH2XWW.2, -OCHXWW.2 2, -CN, -OH, -NH2, -COOH, -CONH2, -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, RWW.3-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RWW.3-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RWW.3-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RWW.3-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RWW.3-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RWW.3-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RWW.2 is independently oxo, halogen, -CXWW.2 3, -CHXWW.2 2, -CH2XWW.2, -OCXWW.23, -OCH2XWW.2, -OCHXWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -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., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWW.2 is independently –F, -Cl, -Br, or –I. [0069] RWW.3 is independently oxo, halogen, -CXWW.3 3, -CHXWW.3 2, -CH2XWW.3, -OCXWW.33, -OCH2XWW.3, -OCHXWW.32, -CN, -OH, -NH2, -COOH, -CONH2, -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., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWW.3 is independently –F, -Cl, -Br, or –I. [0070] Where two different RWW substituents are joined together to form an openly substituted ring (e.g., substituted cycloalkyl, substituted heterocycloalkyl, substituted aryl or substituted heteroaryl), in embodiments the openly substituted ring may be independently substituted with one or more first substituent groups, referred to herein as RWW.1; each first substituent group, RWW.1, may be unsubstituted or independently substituted with one or more second substituent groups, referred to herein as RWW.2; and each second substituent group, RWW.2, may be unsubstituted or independently substituted with one or more third substituent groups, referred to herein as RWW.3; and each third substituent group, RWW.3, is unsubstituted. Each first substituent group is optionally different. Each second substituent group is optionally different. Each third substituent group is optionally different. In the context of two different RWW substituents joined together to form an openly substituted ring, the “WW” symbol in the RWW.1, RWW.2 and RWW.3 refers to the designated number of one of the two different RWW substituents. For example, in embodiments where R100A and R100B are optionally joined together to form an openly substituted ring, RWW.1 is R100A.1, RWW.2 is R100A.2, and RWW.3 is R100A.3. Alternatively, in embodiments where R100A and R100B are optionally joined together to form an openly substituted ring, RWW.1 is R100B.1, RWW.2 is R100B.2, and RWW.3 is R100B.3. RWW.1, RWW.2 and RWW.3 in this paragraph are as defined in the –NHC(NH)NH2, -NHSO2H, -NHC(O)H, -NHC(O)OH, -NHOH, -N3, RLWW.2-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RLWW.2-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RLWW.2-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RLWW.2-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RLWW.2-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RLWW.2-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RLWW.1 is independently oxo, halogen, -CXLWW.1 3, -CHXLWW.12, -CH2XLWW.1, -OCXLWW.13, -OCH2XLWW.1, -OCHXLWW.12, -CN, -OH, -NH2, -COOH, -CONH2, -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., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XLWW.1 is independently –F, -Cl, -Br, or –I. [0072] RLWW.2 is independently oxo, halogen, -CXLWW.23, -CHXLWW.22, -CH2XLWW.2, -OCXLWW.2 3, -OCH2XLWW.2, -OCHXLWW.2 2, -CN, -OH, -NH2, -COOH, -CONH2, -NO2, -SH, -SO3H, -OSO3H, -SO2NH2, ^NHNH2, ^ONH2, ^NHC(O)NHNH2, ^NHC(O)NH2, or
Figure imgf000027_0001
heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RWW.3-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RLWW.3-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RLWW.3-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RLWW.3-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). In embodiments, RLWW.2 is independently oxo, halogen, -CXLWW.2 3, -CHXLWW.22, -CH2XLWW.2, -OCXLWW.23, -OCH2XLWW.2, -OCHXLWW.22, -CN, -OH, -NH2, -COOH, -CONH2, -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., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XLWW.2 is independently –F, -Cl, -Br, or –I. [0073] RLWW.3 is independently oxo, halogen, -CXLWW.33, -CHXLWW.32, -CH2XLWW.3, -OCXLWW.3 3, -OCH2XLWW.3, -OCHXLWW.3 2, -CN, -OH, -NH2, -COOH, -CONH2, -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., C1-C8, C1-C6, C1-C4, or C1-C2), unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XLWW.3 is independently –F, -Cl, -Br, or –I. [0074] In the event that any R group recited in a claim or chemical formula description set forth herein (RWW substituent) is not specifically defined in this disclosure, then that R group (RWW group) is hereby defined as independently oxo, halogen, -CXWW 3, -CHXWW 2, -CH2XWW, -OCXWW3, -OCH2XWW, -OCHXWW2, -CN, -OH, -NH2, -COOH, -CONH2, -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, RWW.1-substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RWW.1-substituted or unsubstituted heteroalkyl (e.g., 2 to 8 membered, 2 to 6 membered, 4 to 6 membered, 2 to 3 membered, or 4 to 5 membered), RWW.1-substituted or unsubstituted cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RWW.1-substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered), RWW.1-substituted or unsubstituted aryl (e.g., C6-C12, C6-C10, or phenyl), or RWW.1-substituted or unsubstituted heteroaryl (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). XWW is independently –F, -Cl, -Br, or –I. Again, “WW” represents the stated superscript number of the subject R group (e.g., 1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). RWW.1, RWW.2, and RWW.3 are as defined above. [0075] In the event that any L linker group recited in a claim or chemical formula description set forth herein (i.e., an LWW substituent) is not explicitly defined, then that L group (LWW 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-, RLWW.1- substituted or unsubstituted alkylene (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), RLWW.1-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), RLWW.1-substituted or unsubstituted cycloalkylene (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), RLWW.1-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), RLWW.1-substituted or unsubstituted arylene (e.g., C6-C12, C6-C10, or phenyl), or RLWW.1- substituted or unsubstituted heteroarylene (e.g., 5 to 12 membered, 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). Again, “WW” represents the stated superscript number of the subject L group (1, 2, 3, 1A, 2A, 3A, 1B, 2B, 3B, etc.). RLWW.1, as well as RLWW.2 and RLWW.3 are as defined above. [0076] 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. When 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. [0077] As used herein, 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. [0078] 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. [0079] 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. [0080] Unless otherwise stated, 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. [0081] Unless otherwise stated, 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 13C- or 14C-enriched carbon are within the scope of this disclosure. [0082] 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. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (3H), iodine-125 (125I), or carbon-14 (14C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are encompassed within the scope of the present disclosure. [0083] It should be noted that throughout the application that alternatives are written in Markush groups, for example, each amino acid position that contains more than one possible amino acid. It is specifically contemplated that each member of the Markush group should be considered separately, thereby comprising another embodiment, and the Markush group is not to be read as a single unit. [0084] As used herein, the terms “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. For example, a conjugate between a first bioconjugate reactive group (e.g., –NH2, –COOH, –N- hydroxysuccinimide, or –maleimide) and a second bioconjugate reactive group (e.g., sulfhydryl, sulfur-containing amino acid, amine, amine sidechain containing amino acid, or carboxylate) provided herein can be direct, e.g., by covalent bond or linker (e.g., a first linker of second linker), or 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). In embodiments, 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). These and other useful reactions are discussed in, for example, March, ADVANCED ORGANIC CHEMISTRY, 3rd Ed., John Wiley & Sons, New York, 1985; Hermanson, BIOCONJUGATE TECHNIQUES, Academic Press, San Diego, 1996; and Feeney et al., MODIFICATION OF PROTEINS; Advances in Chemistry Series, Vol.198, American Chemical Society, Washington, D.C., 1982. In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., haloacetyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., pyridyl moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., –N- hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine). In embodiments, the first bioconjugate reactive group (e.g., maleimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., a sulfhydryl). In embodiments, the first bioconjugate reactive group (e.g., –sulfo–N-hydroxysuccinimide moiety) is covalently attached to the second bioconjugate reactive group (e.g., an amine). [0085] Useful 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 Diels-Alder reactions such as, for example, maleimido or maleimide groups; (e) aldehyde or ketone groups such that subsequent derivatization is possible via formation of carbonyl derivatives such as, for example, imines, hydrazones, semicarbazones or oximes, or via such mechanisms as Grignard addition or alkyllithium addition; (f) sulfonyl halide groups for subsequent reaction with amines, for example, to form sulfonamides; (g) thiol groups, which can be converted to disulfides, reacted with acyl halides, or bonded to metals such as gold, or react with maleimides; (h) amine or sulfhydryl groups (e.g., present in cysteine), which can be, for example, acylated, alkylated or oxidized; (i) alkenes, which can undergo, for example, cycloadditions, acylation, Michael addition, etc.; (j) epoxides, which can react with, for example, amines and hydroxyl compounds; (k) phosphoramidites and other standard functional groups useful in nucleic acid synthesis; (l) metal silicon oxide bonding; (m) metal bonding to reactive phosphorus groups (e.g., phosphines) to form, for example, phosphate diester bonds; (n) azides coupled to alkynes using copper catalyzed cycloaddition click chemistry; and (o) biotin conjugate can react with avidin or streptavidin to form an avidin- biotin complex or streptavidin-biotin complex. [0086] The bioconjugate reactive groups can be chosen such that they do not participate in, or interfere with, the chemical stability of the conjugate described herein. Alternatively, a reactive functional group can be protected from participating in the crosslinking reaction by the presence of a protecting group. In embodiments, the bioconjugate comprises a molecular entity derived from the reaction of an unsaturated bond, such as a maleimide, and a sulfhydryl group. [0087] “Analog,” “analogue,” or “derivative” 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. [0088] The terms “a” or “an”, as used in herein means one or more. In addition, the phrase “substituted with a[n]”, as used herein, means the specified group may be substituted with one or more of any or all of the named substituents. For example, where a group, such as an alkyl or heteroaryl group, is “substituted with an unsubstituted C1-C20 alkyl, or unsubstituted 2 to 20 membered heteroalkyl”, the group may contain one or more unsubstituted C1-C20 alkyls, and/or one or more unsubstituted 2 to 20 membered heteroalkyls. [0089] Moreover, 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 R13 substituents are present, each R13 substituent may be distinguished as R13A, R13B, R13C, R13D, etc., wherein each of R13A, R13B, R13C, R13D, etc. is defined within the scope of the definition of R13 and optionally differently. Where an R moiety, group, or substituent as disclosed herein is attached through the representation of a single bond and the R moiety, group, or substituent is oxo, a person having ordinary skill in the art will immediately recognize that the oxo is attached through a double bond in accordance with the normal rules of chemical valency. [0090] Descriptions of compounds of the present disclosure are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more of a number of substituents, such 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. For example, 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. [0091] The term “pharmaceutically acceptable salts” is 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. When compounds of the present disclosure contain relatively acidic functionalities, 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. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds of the present disclosure contain relatively basic functionalities, 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. Also included are 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. [0092] Thus, 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. [0093] 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. [0094] In addition to salt forms, 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. Additionally, 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. [0095] 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. [0096] 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). For example, 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. Likewise, a polynucleotide sequence that does not appear in nature, for example a variant of a naturally occurring gene, is recombinant. [0097] “Co-administer” 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). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation). [0098] 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. [0099] The terms “treating” or “treatment” 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. In embodiments, treating is preventing. In embodiments, treating does not include preventing. In embodiments, the treating or treatment is no prophylactic treatment. [0100] 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 (and grammatical equivalents of this phrase) 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. Thus, 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. The exact amounts will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols.1-3, 1992); Lloyd, The Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins). [0101] “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. In some instances, the control is used as a standard of comparison in evaluating experimental effects. In some embodiments, 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). [0102] “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. [0103] 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). In some embodiments 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. [0104] As defined herein, the term “activation,” “activate,” “activating” and the like in reference to a protein refers to conversion of a protein into a biologically active derivative from an initial inactive or deactivated state. The terms reference activation, or activating, sensitizing, or up-regulating signal transduction or enzymatic activity or the amount of a protein decreased in a disease. [0105] 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. In certain instances, 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. [0106] As defined herein, 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. In embodiments 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. In some embodiments, inhibition refers to reduction of a disease or symptoms of disease. In some embodiments, 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). Thus, 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. [0107] The terms “inhibitor,” “repressor,” “antagonist,” or “downregulator” interchangeably refer 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. In certain instances, 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. [0108] The term “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. [0109] 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.). [0110] The term “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. For example, as applied to the effects of a modulator on a target protein, to modulate means to change by increasing or decreasing a property or function of the target molecule or the amount of the target molecule. [0111] “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. In embodiments, a patient is human. In embodiments, a patient in need thereof is human. In embodiments, a subject is human. In embodiments, a subject in need thereof is human. [0112] “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. In some embodiments, 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). In embodiments, the disease is a neurodegenerative disease. In embodiments, the disease is a liver disease. In embodiments, the disease is a fibrotic disease. In embodiments, the disease is a coronavirus infection. [0113] As used herein, the term “neurodegenerative disease” refers to a disease or condition in which the function of a subject’s nervous system becomes impaired. Examples of neurodegenerative diseases that may be treated with a compound, pharmaceutical composition, or method described herein 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, Cockayne syndrome, Corticobasal degeneration, Creutzfeldt-Jakob disease, frontotemporal dementia, Gerstmann-Sträussler-Scheinker syndrome, Huntington’s disease, HIV-associated dementia, Kennedy’s disease, Krabbe’s disease, kuru, Lewy body dementia, Machado-Joseph disease (Spinocerebellar ataxia type 3), Multiple sclerosis, Multiple System Atrophy, Narcolepsy, Neuroborreliosis, Parkinson's disease, Pelizaeus-Merzbacher Disease, Pick’s disease, Primary lateral sclerosis, Prion diseases, Refsum’s disease, Sandhoff’s disease, Schilder’s disease, Subacute combined degeneration of spinal cord secondary to Pernicious Anaemia, Schizophrenia, Spinocerebellar ataxia (multiple types with varying characteristics), Spinal muscular atrophy, Steele- Richardson-Olszewski disease, or Tabes dorsalis. [0114] As used herein, the term “tauopathy” refers to a neurodegenerative disease characterized by tau deposits in the brain. Examples of tauopathies include, but are not limited to, Alzheimer’s disease, primary age-related tauopathy, chronic traumatic encephalopathy, progressive supranuclear palsy, corticobasal degeneration, frontotemporal dementia, vacuolar tauopathy, Lytico-bodig disease, ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis, lead encephalopathy, tuberous sclerosis, Pantothenate kinase-associated neurodegeneration, and lipofuscinosis. [0115] As used herein, the term “liver disease” refers to a disease or condition characterized by liver problems (e.g., an increased level of liver problems compared to a control such as a healthy person not suffering from a disease). Examples of liver diseases include, but are not limited to, Alagille syndrome, autoimmune hepatitis, biliary atresia, cirrhosis, endoscopic retrograde cholangiopancreatography (ERCP), hemochromatosis, hepatitis A, hepatitis B, hepatitis C, hepatitis D, hepatitis E, viral hepatitis, liver cancer, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), porphyria, primary biliary cholangitis, primary sclerosing cholangitis (PSC), and Wilson disease. [0116] The term “fibrosis” or “fibrotic disease” is used in accordance with its plain ordinary meaning and refers to any disease or condition characterized by the formation of excess fibrous connective tissue. The formation of excess fibrous connective tissue may be in response to a reparative or reactive process. Fibrosis may be pulmonary fibrosis, liver fibrosis, myelofibrosis, skin fibrosis (e.g., nephrogenic systemic fibrosis and keloid fibrosis), mediastinal fibrosis, cardiac fibrosis, kidney fibrosis, stromal fibrosis, epidural fibrosis, epithelial fibrosis, or idiopathic fibrosis. [0117] The term “coronavirus” is used in accordance with its plain ordinary meaning and refers to an RNA virus that in humans causes respiratory tract infections. Coronaviruses constitute the subfamily Orthocoronavirinae, in the family Coronaviridae, order Nidovirales, and realm Riboviria. In embodiments, the coronavirus is an enveloped viruses with a positive-sense single-stranded RNA genome. [0118] The term “severe acute respiratory syndrome coronavirus” or “SARS-CoV” or “SARS-CoV-1” refers to the strain of coronavirus that causes severe acute respiratory syndrome (SARS). In embodiments, SARS-CoV-1 is an enveloped, positive-sense, single- stranded RNA virus that infects the epithelial cells within the lungs. In embodiments, the virus enters the host cell by binding to the angiotensin-converting enzyme 2 (ACE2) receptor. [0119] The term “severe acute respiratory syndrome coronavirus 2” or “SARS-CoV-2” refers to the strain of coronavirus that causes coronavirus disease 2019 (COVID-19). In embodiments, SARS-CoV-2 is a positive-sense single-stranded RNA virus. [0120] As used herein, the term "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. [0121] The term "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, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid granulocytic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, multiple myeloma, plasmacytic leukemia, promyelocytic leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, or undifferentiated cell leukemia. [0122] As used herein, the term “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. There are aggressive (high grade) and indolent (low grade) types of NHL. Based on the type of cells involved, there are B-cell and T-cell NHLs. Exemplary 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. [0123] 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 hemorrhagic sarcoma, immunoblastic sarcoma of B cells, lymphoma, immunoblastic sarcoma of T-cells, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukosarcoma, malignant mesenchymoma sarcoma, parosteal sarcoma, reticulocytic sarcoma, Rous sarcoma, serocystic sarcoma, synovial sarcoma, or telangiectaltic sarcoma. [0124] The term "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. [0125] The term "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 carcinoma, epiermoid carcinoma, carcinoma epitheliale adenoides, exophytic carcinoma, carcinoma ex ulcere, carcinoma fibrosum, gelatiniforni carcinoma, gelatinous carcinoma, giant cell carcinoma, carcinoma gigantocellulare, glandular carcinoma, granulosa cell carcinoma, hair-matrix carcinoma, hematoid carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma, hyaline carcinoma, hypernephroid carcinoma, infantile embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large-cell carcinoma, lenticular carcinoma, carcinoma lenticulare, lipomatous carcinoma, lymphoepithelial carcinoma, carcinoma medullare, medullary carcinoma, melanotic carcinoma, carcinoma molle, mucinous carcinoma, carcinoma muciparum, carcinoma mucocellulare, mucoepidermoid carcinoma, carcinoma mucosum, mucous carcinoma, carcinoma myxomatodes, nasopharyngeal carcinoma, oat cell carcinoma, carcinoma ossificans, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, prickle cell carcinoma, pultaceous carcinoma, renal cell carcinoma of kidney, reserve cell carcinoma, carcinoma sarcomatodes, schneiderian carcinoma, scirrhous carcinoma, carcinoma scroti, signet-ring cell carcinoma, carcinoma simplex, small-cell carcinoma, solanoid carcinoma, spheroidal cell carcinoma, spindle cell carcinoma, carcinoma spongiosum, squamous carcinoma, squamous cell carcinoma, string carcinoma, carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, carcinoma tuberosum, tuberous carcinoma, verrucous carcinoma, or carcinoma villosum. [0126] As used herein, 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. When cancer cells metastasize, the metastatic tumor and its cells are presumed to be similar to those of the original tumor. Thus, if lung cancer metastasizes to the breast, 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. Thus, the phrase metastatic cancer refers to a disease in which a subject has or had a primary tumor and has one or more secondary tumors. The phrases 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. For example, 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. [0127] 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). In cutaneous metastasis, 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. [0128] The term “visceral metastasis” refer 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). In visceral metastasis, cancerous cells from a primary cancer site may migrate to the internal organs where they divide and cause lesions. Visceral metastasis may result from the migration of cancer cells from liver cancer tumors or head and neck tumors to internal organs. [0129] The term “drug” is used in accordance with its common meaning and refers to a substance which has a physiological effect (e.g., beneficial effect, is useful for treating a subject) when introduced into or to a subject (e.g., in or on the body of a subject or patient). A drug moiety is a radical of a drug. [0130] 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. For example, detectable agents include 18F, 32P, 33P, 45Ti, 47Sc, 52Fe, 59Fe, 62Cu, 64Cu, 67Cu, 67Ga, 68Ga, 77As, 86Y, 90Y, 89Sr, 89Zr, 94Tc, 94Tc, 99mTc, 99Mo, 105Pd, 105Rh, 111Ag, 111In, 123I, 124I, 125I, 131I, 142Pr, 143Pr, 149Pm, 153Sm, 154-1581Gd, 161Tb, 166Dy, 166Ho,
Figure imgf000046_0001
Tm, Yb, Lu, 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, digoxigenin, paramagnetic molecules, paramagnetic nanoparticles, ultrasmall superparamagnetic iron oxide ("USPIO") nanoparticles, USPIO nanoparticle aggregates, superparamagnetic iron oxide ("SPIO") nanoparticles, SPIO nanoparticle aggregates, monochrystalline iron oxide nanoparticles, monochrystalline iron oxide, nanoparticle contrast agents, liposomes or other delivery vehicles containing Gadolinium chelate ("Gd-chelate") molecules, Gadolinium, radioisotopes, radionuclides (e.g., carbon-11, nitrogen-13, oxygen-15, fluorine-18, rubidium- 82), fluorodeoxyglucose (e.g., fluorine-18 labeled), any gamma ray emitting radionuclides, positron-emitting radionuclide, radiolabeled glucose, radiolabeled water, radiolabeled ammonia, biocolloids, microbubbles (e.g., including microbubble shells including albumin, galactose, lipid, and/or polymers; microbubble gas core including air, heavy gas(es), perfluorcarbon, nitrogen, octafluoropropane, perflexane lipid microsphere, perflutren, etc.), iodinated contrast agents (e.g., iohexol, iodixanol, ioversol, iopamidol, ioxilan, iopromide, diatrizoate, metrizoate, ioxaglate), barium sulfate, thorium dioxide, gold, gold nanoparticles, gold nanoparticle aggregates, fluorophores, two-photon fluorophores, or haptens and proteins or other entities which can be made detectable, e.g., by incorporating a radiolabel into a peptide or antibody specifically reactive with a target peptide. [0131] Radioactive substances (e.g., radioisotopes) that may be used as imaging and/or labeling agents in accordance with the embodiments of the disclosure include, but are not limited to, 18F, 32P, 33P, 45Ti, 47Sc, 52Fe, 59Fe, 62Cu, 64Cu, 67Cu, 67Ga, 68Ga, 77As, 86Y, 90Y, 89Sr, 89Zr, 94Tc, 94Tc, 99mTc, 99Mo, 105Pd, 105Rh, 111Ag, 111In, 123I, 124I, 125I, 131I, 142Pr, 143Pr, 149Pm, 153Sm, 154-1581Gd, 161Tb, 166Dy, 166Ho, 169Er, 175Lu, 177Lu, 186Re, 188Re, 189Re, 194Ir, 198Au, 199Au, 211At, 211Pb, 212Bi, 212Pb, 213Bi, 223Ra and 225Ac. 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. [0132] “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. Such 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. One of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention. [0133] The term “preparation” is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration. [0134] As used herein, 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. [0135] As used herein, the term “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. By “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). Thus, the preparations can also be combined, when desired, with other active substances (e.g., to reduce metabolic degradation). The 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. [0136] 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. [0137] In some embodiments, 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. In some embodiments, co-administration can be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition including both active agents. In other embodiments, the active agents can be formulated separately. In another embodiment, the active and/or adjunctive agents may be linked or conjugated to one another. [0138] In therapeutic use for the treatment of a disease, 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. A daily dose range of about 0.01 mg/kg to about 500 mg/kg, or about 0.1 mg/kg to about 200 mg/kg, or about 1 mg/kg to about 100 mg/kg, or about 10 mg/kg to about 50 mg/kg, can be used. 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. For example, dosages can be empirically determined considering the type and stage of disease (e.g., neurodegenerative disease, liver disease, fibrotic disease, or coronavirus infection) diagnosed in a particular patient. The dose administered to a patient, in the context of the present invention, 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. Thereafter, the dosage is increased by small increments until the optimum effect under circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired. [0139] The term “associated” or “associated with” in the context of a substance or substance activity or function associated with a disease (e.g., a protein associated disease, disease associated with a cellular component) means that the disease (e.g., neurodegenerative disease, liver disease, fibrotic disease, or coronavirus infection) 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). As used herein, what is described as being associated with a disease, if a causative agent, could be a target for treatment of the disease. [0140] The term “aberrant” as used herein 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. [0141] The term “electrophilic” as used herein 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. [0142] “Nucleophilic” as used herein refers to a chemical group that is capable of donating electron density. [0143] The term “isolated,” 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. [0144] The term “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, γ- 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 α 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. [0145] 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. [0146] The terms “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. [0147] 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). Due to deletions, insertions, truncations, fusions, and the like that must be taken into account when determining an optimal alignment, in general 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. For example, in a case where a variant has a deletion relative to an aligned reference sequence, there will be no amino acid in the variant that corresponds to a position in the reference sequence at the site of deletion. Where there is an insertion in an aligned reference sequence, that insertion will not correspond to a numbered amino acid position in the reference sequence. In the case of truncations or fusions there can be stretches of amino acids in either the reference or aligned sequence that do not correspond to any amino acid in the corresponding sequence. [0148] The terms “numbered with reference to” or “corresponding to,” when used in the context of the numbering of a given amino acid or polynucleotide sequence, refers to the numbering of the residues of a specified reference sequence when the given amino acid or polynucleotide sequence is compared to the reference sequence. [0149] An amino acid residue in a protein “corresponds” to a given residue when it occupies the same essential structural position within the protein as the given residue. For example, a selected residue in a selected protein corresponds to Y198A of procaspase-6 when the selected residue occupies the same essential spatial or other structural relationship as Y198A of procaspase-6. In some embodiments, where a selected protein is aligned for maximum homology with the procaspase-6 protein, the position in the aligned selected protein aligning with Y198A is said to correspond to Y198A. Instead of a primary sequence alignment, a three dimensional structural alignment can also be used, e.g., where the structure of the selected protein is aligned for maximum correspondence with the procaspase-6 protein and the overall structures compared. In this case, an amino acid that occupies the same essential position as Y198A in the structural model is said to correspond to the Y198A residue. [0150] The term “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. In embodiments, the association between the protein and the additional substance (e.g., compound) is via non-covalent interactions. In embodiments, 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. [0151] 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). Typically, when a protein misfolds as a result of a change in the amino acid sequence or a change in the native environment which disrupts normal non-covalent interactions, and the misfolded protein is not corrected or degraded, the unfolded/misfolded protein may aggregate. There are three main types of protein aggregates that may form: amorphous aggregates, oligomers, and amyloid fibrils. In embodiments, protein aggregates are termed aggresomes. [0152] The term “procaspase 6” or “procaspase-6” refers to an inactive precursor form of caspase 6. In embodiments, procaspase-6 exhibits a dimeric structure. [0153] The term “caspase 6” or “caspase-6” or “Casp6” refers to a protein (including homologs, isoforms, and functional fragments thereof) that is a member of the cysteine- aspartic acid protease (caspase) family. Caspase-6 cleaves substrates (e.g., HTT in Huntington’s, APP in Alzheimer’s disease, tau in Alzheimer’s disease), which may result in protein aggregation of the fragments. In embodiments, caspase-6 cleaves substrates that lead to inflammation (e.g., neuroinflammation), and to cell death. In embodiments, cell death leads to cirrhosis and fibrosis (e.g., in liver or other organs). In embodiments, caspase-6 is involved in axonal degradation. The term includes any recombinant or naturally-occurring form of caspase-6 variants thereof that maintain caspase-6 activity (e.g., within at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or 100% activity compared to wildtype caspase-6). In embodiments, caspase-6 is encoded by the CASP6 gene. In embodiments, caspase-6 has the amino acid sequence set forth in or corresponding to Entrez 839, UniProt P55212, RefSeq (protein) NP_001217.2, or RefSeq (protein) NP_116787.1. In embodiments, caspase-6 has the sequence: MSSASGLRRGHPAGGEENMTETDAFYKREMFDPAEKYKMDHRRRGIALIFNHERFF WHLTLPERRGTCADRDNLTRRFSDLGFEVKCFNDLKAEELLLKIHEVSTVSHADADC FVCVFLSHGEGNHIYAYDAKIEIQTLTGLFKGDKCHSLVGKPKIFIIQACRGNQHDVP VIPLDVVDNQTEKLDTNITEVDAASVYTLPAGADFLMCYSVAEGYYSHRETVNGSW YIQDLCEMLGKYGSSLEFTELLTLVNRKVSQRRVDFCKDPSAIGKKQVPCFASMLTK KLHFFPKSN (SEQ ID NO:1). II. Compounds [0154] In an aspect is provided a compound, or a pharmaceutically acceptable salt thereof, having the formula: .
Figure imgf000053_0001
substituted or unsubstituted 5 to 6 membered heteroaryl or substituted or unsubstituted 8 to 10 membered fused ring heteroaryl. [0156] L1 is a bond or substituted or unsubstituted C1-C3 alkylene. [0157] R1 is independently halogen, -CX1 3, -CHX1 2, -CH2X1, -OCX1 3, -OCH2X1, -OCHX12, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -B(OR1C)(OR1D), -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (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 cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (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 aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0158] R1A, R1B, R1C, and R1D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (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 cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (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 aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered); R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl (e.g., 3 to 8 membered, 3 to 6 membered, 4 to 6 membered, 4 to 5 membered, or 5 to 6 membered) or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0159] Each X1 is independently –F, -Cl, -Br, or –I. [0160] The symbol n1 is an integer from 0 to 4. [0161] The symbols m1 and v1 are independently 1 or 2. [0162] The symbol z1 is an integer from 0 to 5. [0163] Ring A is not a substituted or unsubstituted pyrimidinyl. [0164] In embodiments, a substituted Ring A (e.g., substituted 5 to 6 membered heteroaryl and/or substituted 8 to 10 membered fused ring heteroaryl) 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. In embodiments, when Ring A is substituted, it is substituted with at least one substituent group. In embodiments, 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. [0165] In embodiments, Ring A is a substituted or unsubstituted nitrogen-containing 5 to 6 membered heteroaryl or substituted or unsubstituted nitrogen-containing 8 to 10 membered fused ring heteroaryl. In embodiments, Ring A is a substituted or unsubstituted nitrogen- containing 5 to 6 membered heteroaryl. In embodiments, Ring A is a substituted or unsubstituted nitrogen-containing 8 to 10 membered fused ring heteroaryl. [0166] In embodiments, Ring A is substituted or unsubstituted pyridyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted imidazopyridinyl, substituted or unsubstituted benzothiazolyl, or substituted or unsubstituted benzoimidazolyl. In embodiments, Ring A is substituted or unsubstituted pyridyl. In embodiments, Ring A is substituted or unsubstituted pyridazinyl. In embodiments, Ring A is substituted or unsubstituted pyrazinyl. In embodiments, Ring A is substituted or unsubstituted triazinyl. In embodiments, Ring A is substituted or unsubstituted imidazolyl. In embodiments, Ring A is substituted or unsubstituted pyrazolyl. In embodiments, Ring A is substituted or unsubstituted oxazolyl. In embodiments, Ring A is substituted or unsubstituted isoxazolyl. In embodiments, Ring A is substituted or unsubstituted furanyl. In embodiments, Ring A is substituted or unsubstituted thienyl. In embodiments, Ring A is substituted or unsubstituted thiazolyl. In embodiments, Ring A is substituted or unsubstituted isothiazolyl. In embodiments, Ring A is substituted or unsubstituted triazolyl. In embodiments, Ring A is substituted or unsubstituted oxadiazolyl. In embodiments, Ring A is substituted or unsubstituted tetrazolyl. In embodiments, Ring A is substituted or unsubstituted imidazopyridinyl. In embodiments, Ring A is substituted or unsubstituted benzothiazolyl. In embodiments, Ring A is substituted or unsubstituted benzoimidazolyl. [0167] In embodiments, Ring A is N N N , ,
Figure imgf000056_0001
-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, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (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 cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (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 aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0169] The symbol z2 is an integer from 0 to 5. [0170] In embodiments, a substituted R2 (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 R2 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 R2 is substituted, it is substituted with at least one substituent group. In embodiments, when R2 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R2 is substituted, it is substituted with at least one lower substituent group. [0171] In embodiments, R2 is independently unsubstituted C1-C4 alkyl. In embodiments, R2 is independently unsubstituted methyl. In embodiments, R2 is independently unsubstituted ethyl. In embodiments, R2 is independently unsubstituted propyl. In embodiments, R2 is independently unsubstituted n-propyl. In embodiments, R2 is independently unsubstituted isopropyl. In embodiments, R2 is independently unsubstituted butyl. In embodiments, R2 is independently unsubstituted n-butyl. In embodiments, R2 is independently unsubstituted isobutyl. In embodiments, R2 is independently unsubstituted tert-butyl. In embodiments, R2 is independently –NH2. [0172] In embodiments, z2 is 0. In embodiments, z2 is 1. In embodiments, z2 is 2. In embodiments, z2 is 3. In embodiments, z2 is 4. In embodiments, z2 is 5. [0173] In embodiments, Ring A . In embodiments, Ring A is
Figure imgf000057_0001
. In embodiments, Ring A is
Figure imgf000057_0002
In embodiments, Ring A z2. In embodiments, Ring A is
Figure imgf000057_0003
NH embodiments, Ring A z2. In embodiments, Ring A is
Figure imgf000057_0004
embodiments, In embodiments, Ring A is
Figure imgf000057_0005
Figure imgf000057_0006
O N is
Figure imgf000058_0007
. In embodiments, Ring A . In embodiments, Ring A is
Figure imgf000058_0001
. In embodiments, Ring A . In embodiments, Ring A is
Figure imgf000058_0002
. In embodiments, Ring A . In embodiments, Ring A is
Figure imgf000058_0004
. In embodiments, Ring A . In embodiments, Ring A
Figure imgf000058_0003
Figure imgf000058_0005
.
Figure imgf000058_0006
, . In embodiments, Ring A is
Figure imgf000059_0001
Figure imgf000059_0002
. In embodiments, Ring A is . In embodiments, Ring A is . In embodiments, Ring A . In embodiments, Ring A In
Figure imgf000059_0004
Figure imgf000059_0003
embodiments, Ring A . In embodiments, Ring A In
Figure imgf000059_0006
Figure imgf000059_0005
embodiments, Ring A . In embodiments, Ring A In
Figure imgf000059_0007
Figure imgf000059_0008
Figure imgf000059_0010
.
Figure imgf000059_0009
Figure imgf000059_0011
In embodiments, Ring A . In embodiments, Ring A In
Figure imgf000060_0001
Figure imgf000060_0002
embodiments, Ring A . In embodiments, Ring A . In
Figure imgf000060_0003
Figure imgf000060_0004
embodiments, Ring A . In embodiments, Ring A In
Figure imgf000060_0005
Figure imgf000060_0006
embodiments, Ring A . In embodiments, Ring A In
Figure imgf000060_0008
Figure imgf000060_0007
embodiments, Ring A . In embodiments, Ring A In
Figure imgf000060_0010
Figure imgf000060_0009
embodiments, In
Figure imgf000060_0011
embodiments, . [0175] In an
Figure imgf000060_0012
or a pharmaceutically acceptable salt thereof, having the formula: described herein, including in embodiments. R1.1, R1.2, R1.3,
Figure imgf000060_0013
hydrogen or any value of R1 as described herein, including in embodiments. [0176] Ring B is a substituted or unsubstituted pyrimidinyl. [0177] Provided: (i) R1.1 and R1.5 are not –OH; or (ii) wherein if R1.1 or R1.5 is –OH, then Ring B is not substituted or unsubstituted 2- pyrimidinyl or unsubstituted 5-pyrimidinyl; or (iii) wherein if Ring B is 5-pyrimidinyl, then the Ring B 5-pyrimidinyl is substituted. [0178] In embodiments, a substituted Ring B (e.g., substituted pyrimidinyl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted Ring B 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 Ring B is substituted, it is substituted with at least one substituent group. In embodiments, when Ring B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when Ring B is substituted, it is substituted with at least one lower substituent group. [0179] In embodiments, Ring B is N (R 2 )z2
Figure imgf000061_0001
[0180] In embodiments, Ring B . In embodiments, Ring B is
Figure imgf000061_0002
N (R 2 )z2 .
Figure imgf000061_0003
C1-C4 alkyl. In embodiments, R2 is independently –NH2 or unsubstituted methyl. [0182] In embodiments, Ring B is In embodiments, Ring B is . In embodiments, Ring B In
Figure imgf000062_0001
embodiments, . [0183] In 1
Figure imgf000062_0002
L (e.g., substituted C1-C3 alkylene) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted L1 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 L1 is substituted, it is substituted with at least one substituent group. In embodiments, when L1 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when L1 is substituted, it is substituted with at least one lower substituent group. [0184] In embodiments, L1 is unsubstituted C1-C3 alkylene. In embodiments, L1 is unsubstituted methylene. In embodiments, L1 is unsubstituted ethylene. In embodiments, L1 is unsubstituted propylene. In embodiments, L1 is unsubstituted n-propylene. In embodiments, L1 is unsubstituted isopropylene. [0185] In embodiments, a substituted R1 (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 R1 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 R1 is substituted, it is substituted with at least one substituent group. In embodiments, when R1 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1 is substituted, it is substituted with at least one lower substituent group. [0186] In embodiments, a substituted R1.1 (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 R1.1 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. In embodiments, when R1.1 is substituted, it is substituted with at least one substituent group. In embodiments, when R1.1 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1.1 is substituted, it is substituted with at least one lower substituent group. [0187] In embodiments, a substituted R1.2 (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 R1.2 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. In embodiments, when R1.2 is substituted, it is substituted with at least one substituent group. In embodiments, when R1.2 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1.2 is substituted, it is substituted with at least one lower substituent group. [0188] In embodiments, a substituted R1.3 (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 R1.3 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 R1.3 is substituted, it is substituted with at least one substituent group. In embodiments, when R1.3 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1.3 is substituted, it is substituted with at least one lower substituent group. [0189] In embodiments, a substituted R1.4 (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 R1.4 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 R1.4 is substituted, it is substituted with at least one substituent group. In embodiments, when R1.4 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1.4 is substituted, it is substituted with at least one lower substituent group. [0190] In embodiments, a substituted R1.5 (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 R1.5 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. In embodiments, when R1.5 is substituted, it is substituted with at least one substituent group. In embodiments, when R1.5 is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1.5 is substituted, it is substituted with at least one lower substituent group. [0191] In embodiments, a substituted R1A (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 R1A 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 R1A is substituted, it is substituted with at least one substituent group. In embodiments, when R1A is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1A is substituted, it is substituted with at least one lower substituent group. [0192] In embodiments, a substituted R1B (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 R1B 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 R1B is substituted, it is substituted with at least one substituent group. In embodiments, when R1B is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1B is substituted, it is substituted with at least one lower substituent group. [0193] In embodiments, a substituted ring formed when R1A and R1B substituents bonded to the same nitrogen atom are joined (e.g., substituted heterocycloalkyl and/or substituted heteroaryl) is substituted with at least one substituent group, size-limited substituent group, or lower substituent group; wherein if the substituted ring formed when R1A and R1B 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. In embodiments, when the substituted ring formed when R1A and R1B 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 R1A and R1B 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 R1A and R1B substituents bonded to the same nitrogen atom are joined is substituted, it is substituted with at least one lower substituent group. [0194] In embodiments, a substituted R1C (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 R1C 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 R1C is substituted, it is substituted with at least one substituent group. In embodiments, when R1C is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1C is substituted, it is substituted with at least one lower substituent group. [0195] In embodiments, a substituted R1D (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 R1D 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 R1D is substituted, it is substituted with at least one substituent group. In embodiments, when R1D is substituted, it is substituted with at least one size-limited substituent group. In embodiments, when R1D is substituted, it is substituted with at least one lower substituent group. [0196] In embodiments, R1 is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -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, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -B(OH)2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0197] In embodiments, R1 is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -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, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -B(OH)2, -SF5, -N3, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted 2 to 6 membered heteroalkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted 3 to 8 membered heterocycloalkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted 5 to 6 membered heteroaryl. [0198] In embodiments, R1 is independently halogen. In embodiments, R1 is independently –F. In embodiments, R1 is independently –Cl. In embodiments, R1 is independently –Br. In embodiments, R1 is independently –I. In embodiments, R1 is independently -OR1D, wherein R1D is as described herein, including in embodiments. In embodiments, R1 is independently – OH. In embodiments, R1 is independently –NH2. In embodiments, R1 is independently -B(OR1C)(OR1D), wherein R1C and R1D are as described herein, including in embodiments. In embodiments, R1 is independently -B(OR1C)(OH), wherein R1C is as described herein, including in embodiments. In embodiments, R1 is independently -B(OH)2. In embodiments, R1 is independently unsubstituted C1-C4 alkyl. In embodiments, R1 is independently unsubstituted methyl. In embodiments, R1 is independently unsubstituted ethyl. In embodiments, R1 is independently unsubstituted propyl. In embodiments, R1 is independently unsubstituted n-propyl. In embodiments, R1 is independently unsubstituted isopropyl. In embodiments, R1 is independently unsubstituted butyl. In embodiments, R1 is independently unsubstituted n-butyl. In embodiments, R1 is independently unsubstituted isobutyl. In embodiments, R1 is independently unsubstituted tert-butyl. In embodiments, R1 is independently unsubstituted 2 to 6 membered heteroalkyl. In embodiments, R1 is independently unsubstituted methoxy. In embodiments, R1 is independently unsubstituted ethoxy. In embodiments, R1 is independently unsubstituted propoxy. In embodiments, R1 is independently unsubstituted n-propoxy. In embodiments, R1 is independently unsubstituted isopropoxy. In embodiments, R1 is independently unsubstituted butoxy. [0199] In embodiments, R1.1, R1.2, R1.3, R1.4, and R1.5 are independently hydrogen, halogen, -CX13, -CHX12, -CH2X1, -OCX13, -OCH2X1, -OCHX12, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -B(OR1C)(OR1D), -SF5, -N3, substituted or unsubstituted alkyl (e.g., C1-C8, C1-C6, C1-C4, or C1-C2), substituted or unsubstituted heteroalkyl (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 cycloalkyl (e.g., C3-C8, C3-C6, C4-C6, or C5-C6), substituted or unsubstituted heterocycloalkyl (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 aryl (e.g., C6-C10 or phenyl), or substituted or unsubstituted heteroaryl (e.g., 5 to 10 membered, 5 to 9 membered, or 5 to 6 membered). [0200] In embodiments, R1.1, R1.2, R1.3, R1.4, and R1.5 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -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, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -B(OH)2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0201] In embodiments, R1.1 is hydrogen. In embodiments, R1.1 is halogen. In embodiments, R1.1 is –F. In embodiments, R1.1 is –Cl. In embodiments, R1.1 is –Br. In embodiments, R1.1 is –I. In embodiments, R1.1 is -OR1D, wherein R1D is as described herein, including in embodiments. In embodiments, R1.1 is –OH. In embodiments, R1.1 is -B(OR1C)(OR1D), wherein R1C and R1D are as described herein, including in embodiments. In embodiments, R1.1 is -B(OR1C)(OH), wherein R1C is as described herein, including in embodiments. In embodiments, R1.1 is -B(OH)2. In embodiments, R1.1 is unsubstituted C1-C4 alkyl. In embodiments, R1.1 is unsubstituted methyl. In embodiments, R1.1 is unsubstituted ethyl. In embodiments, R1.1 is unsubstituted propyl. In embodiments, R1.1 is unsubstituted n- propyl. In embodiments, R1.1 is unsubstituted isopropyl. In embodiments, R1.1 is unsubstituted butyl. In embodiments, R1.1 is unsubstituted n-butyl. In embodiments, R1.1 is unsubstituted isobutyl. In embodiments, R1.1 is unsubstituted tert-butyl. [0202] In embodiments, R1.2 is hydrogen. In embodiments, R1.2 is halogen. In embodiments, R1.2 is –F. In embodiments, R1.2 is –Cl. In embodiments, R1.2 is –Br. In embodiments, R1.2 is –I. In embodiments, R1.2 is -OR1D, wherein R1D is as described herein, including in embodiments. In embodiments, R1.2 is –OH. In embodiments, R1.2 is -B(OR1C)(OR1D), wherein R1C and R1D are as described herein, including in embodiments. In embodiments, R1.2 is -B(OR1C)(OH), wherein R1C is as described herein, including in embodiments. In embodiments, R1.2 is -B(OH)2. In embodiments, R1.2 is unsubstituted C1-C4 alkyl. In embodiments, R1.2 is unsubstituted methyl. In embodiments, R1.2 is unsubstituted ethyl. In embodiments, R1.2 is unsubstituted propyl. In embodiments, R1.2 is unsubstituted n- propyl. In embodiments, R1.2 is unsubstituted isopropyl. In embodiments, R1.2 is unsubstituted butyl. In embodiments, R1.2 is unsubstituted n-butyl. In embodiments, R1.2 is unsubstituted isobutyl. In embodiments, R1.2 is unsubstituted tert-butyl. [0203] In embodiments, R1.3 is hydrogen. In embodiments, R1.3 is halogen. In embodiments, R1.3 is –F. In embodiments, R1.3 is –Cl. In embodiments, R1.3 is –Br. In embodiments, R1.3 is –I. In embodiments, R1.3 is -OR1D, wherein R1D is as described herein, including in embodiments. In embodiments, R1.3 is –OH. In embodiments, R1.3 is -B(OR1C)(OR1D), wherein R1C and R1D are as described herein, including in embodiments. In embodiments, R1.3 is -B(OR1C)(OH), wherein R1C is as described herein, including in embodiments. In embodiments, R1.3 is -B(OH)2. In embodiments, R1.3 is unsubstituted C1-C4 alkyl. In embodiments, R1.3 is unsubstituted methyl. In embodiments, R1.3 is unsubstituted ethyl. In embodiments, R1.3 is unsubstituted propyl. In embodiments, R1.3 is unsubstituted n- propyl. In embodiments, R1.3 is unsubstituted isopropyl. In embodiments, R1.3 is unsubstituted butyl. In embodiments, R1.3 is unsubstituted n-butyl. In embodiments, R1.3 is unsubstituted isobutyl. In embodiments, R1.3 is unsubstituted tert-butyl. [0204] In embodiments, R1.4 is hydrogen. In embodiments, R1.4 is halogen. In embodiments, R1.4 is –F. In embodiments, R1.4 is –Cl. In embodiments, R1.4 is –Br. In embodiments, R1.4 is –I. In embodiments, R1.4 is -OR1D, wherein R1D is as described herein, including in embodiments. In embodiments, R1.4 is –OH. In embodiments, R1.4 is -B(OR1C)(OR1D), wherein R1C and R1D are as described herein, including in embodiments. In embodiments, R1.4 is -B(OR1C)(OH), wherein R1C is as described herein, including in embodiments. In embodiments, R1.4 is -B(OH)2. In embodiments, R1.4 is unsubstituted C1-C4 alkyl. In embodiments, R1.4 is unsubstituted methyl. In embodiments, R1.4 is unsubstituted ethyl. In embodiments, R1.4 is unsubstituted propyl. In embodiments, R1.4 is unsubstituted n- propyl. In embodiments, R1.4 is unsubstituted isopropyl. In embodiments, R1.4 is unsubstituted butyl. In embodiments, R1.4 is unsubstituted n-butyl. In embodiments, R1.4 is unsubstituted isobutyl. In embodiments, R1.4 is unsubstituted tert-butyl. [0205] In embodiments, R1.5 is hydrogen. In embodiments, R1.5 is halogen. In embodiments, R1.5 is –F. In embodiments, R1.5 is –Cl. In embodiments, R1.5 is –Br. In embodiments, R1.5 is –I. In embodiments, R1.5 is -OR1D, wherein R1D is as described herein, including in embodiments. In embodiments, R1.5 is –OH. In embodiments, R1.5 is -B(OR1C)(OR1D), wherein R1C and R1D are as described herein, including in embodiments. In embodiments, R1.5 is -B(OR1C)(OH), wherein R1C is as described herein, including in embodiments. In embodiments, R1.5 is -B(OH)2. In embodiments, R1.5 is unsubstituted C1-C4 alkyl. In embodiments, R1.5 is unsubstituted methyl. In embodiments, R1.5 is unsubstituted ethyl. In embodiments, R1.5 is unsubstituted propyl. In embodiments, R1.5 is unsubstituted n- propyl. In embodiments, R1.5 is unsubstituted isopropyl. In embodiments, R1.5 is unsubstituted butyl. In embodiments, R1.5 is unsubstituted n-butyl. In embodiments, R1.5 is unsubstituted isobutyl. In embodiments, R1.5 is unsubstituted tert-butyl. [0206] In embodiments, R1A is independently hydrogen. In embodiments, R1A is independently unsubstituted C1-C4 alkyl. In embodiments, R1A is independently unsubstituted methyl. In embodiments, R1A is independently unsubstituted ethyl. In embodiments, R1A is independently unsubstituted propyl. In embodiments, R1A is independently unsubstituted n-propyl. In embodiments, R1A is independently unsubstituted isopropyl. In embodiments, R1A is independently unsubstituted butyl. In embodiments, R1A is independently unsubstituted n-butyl. In embodiments, R1A is independently unsubstituted isobutyl. In embodiments, R1A is independently unsubstituted tert-butyl. [0207] In embodiments, R1B is independently hydrogen. In embodiments, R1B is independently unsubstituted C1-C4 alkyl. In embodiments, R1B is independently unsubstituted methyl. In embodiments, R1B is independently unsubstituted ethyl. In embodiments, R1B is independently unsubstituted propyl. In embodiments, R1B is independently unsubstituted n-propyl. In embodiments, R1B is independently unsubstituted isopropyl. In embodiments, R1B is independently unsubstituted butyl. In embodiments, R1B is independently unsubstituted n-butyl. In embodiments, R1B is independently unsubstituted isobutyl. In embodiments, R1B is independently unsubstituted tert-butyl. [0208] In embodiments, R1C is independently hydrogen. In embodiments, R1C is independently unsubstituted C1-C4 alkyl. In embodiments, R1C is independently unsubstituted methyl. In embodiments, R1C is independently unsubstituted ethyl. In embodiments, R1C is independently unsubstituted propyl. In embodiments, R1C is independently unsubstituted n-propyl. In embodiments, R1C is independently unsubstituted isopropyl. In embodiments, R1C is independently unsubstituted butyl. In embodiments, R1C is independently unsubstituted n-butyl. In embodiments, R1C is independently unsubstituted isobutyl. In embodiments, R1C is independently unsubstituted tert-butyl. [0209] In embodiments, R1D is independently hydrogen. In embodiments, R1D is independently unsubstituted C1-C4 alkyl. In embodiments, R1D is independently unsubstituted methyl. In embodiments, R1D is independently unsubstituted ethyl. In embodiments, R1D is independently unsubstituted propyl. In embodiments, R1D is independently unsubstituted n-propyl. In embodiments, R1D is independently unsubstituted isopropyl. In embodiments, R1D is independently unsubstituted butyl. In embodiments, R1D is independently unsubstituted n-butyl. In embodiments, R1D is independently unsubstituted isobutyl. In embodiments, R1D is independently unsubstituted tert-butyl. [0210] In embodiments, z1 is 0. In embodiments, z1 is 1. In embodiments, z1 is 2. In embodiments, z1 is 3. In embodiments, z1 is 4. In embodiments, z1 is 5. ts, ts, , , d with one or more first substituent groups denoted by RA.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RA.1 substituent group is substituted, the RA.1 substituent group is substituted with one or more second substituent groups denoted by RA.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RA.2 substituent group is substituted, the RA.2 substituent group is substituted with one or more third substituent groups denoted by RA.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, Ring A, RA.1, RA.2, and RA.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of
Figure imgf000071_0001
group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to Ring A, RA.1, RA.2, and RA.3, respectively. [0214] In embodiments, when Ring B is substituted, Ring B is substituted with one or more first substituent groups denoted by RB.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RB.1 substituent group is substituted, the RB.1 substituent group is substituted with one or more second substituent groups denoted by RB.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RB.2 substituent group is substituted, the RB.2 substituent group is substituted with one or more third substituent groups denoted by RB.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, Ring B, RB.1, RB.2, and RB.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to Ring B, RB.1, RB.2, and RB.3, respectively. [0215] In embodiments, when R1 is substituted, R1 is substituted with one or more first substituent groups denoted by R1.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.1 substituent group is substituted, the R1.1 substituent group is substituted with one or more second substituent groups denoted by R1.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.2 substituent group is substituted, the R1.2 substituent group is substituted with one or more third substituent groups denoted by R1.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1, R1.1, R1.2, and R1.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R1, R1.1, R1.2, and R1.3, respectively. [0216] In embodiments, when R1.1 is substituted, R1.1 is substituted with one or more first substituent groups denoted by R1.1.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.1.1 substituent group is substituted, the R1.1.1 substituent group is substituted with one or more second substituent groups denoted by R1.1.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.1.2 substituent group is substituted, the R1.1.2 substituent group is substituted with one or more third substituent groups denoted by R1.1.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1.1, R1.1.1, R1.1.2, and R1.1.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R1.1, R1.1.1, R1.1.2, and R1.1.3, respectively. [0217] In embodiments, when R1.2 is substituted, R1.2 is substituted with one or more first substituent groups denoted by R1.2.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.2.1 substituent group is substituted, the R1.2.1 substituent group is substituted with one or more second substituent groups denoted by R1.2.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.2.2 substituent group is substituted, the R1.2.2 substituent group is substituted with one or more third substituent groups denoted by R1.2.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1.2, R1.2.1, R1.2.2, and R1.2.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R1.2, R1.2.1, R1.2.2, and R1.2.3, respectively. [0218] In embodiments, when R1.3 is substituted, R1.3 is substituted with one or more first substituent groups denoted by R1.3.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.3.1 substituent group is substituted, the R1.3.1 substituent group is substituted with one or more second substituent groups denoted by R1.3.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.3.2 substituent group is substituted, the R1.3.2 substituent group is substituted with one or more third substituent groups denoted by R1.3.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1.3, R1.3.1, R1.3.2, and R1.3.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R1.3, R1.3.1, R1.3.2, and R1.3.3, respectively. [0219] In embodiments, when R1.4 is substituted, R1.4 is substituted with one or more first substituent groups denoted by R1.4.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.4.1 substituent group is substituted, the R1.4.1 substituent group is substituted with one or more second substituent groups denoted by R1.4.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.4.2 substituent group is substituted, the R1.4.2 substituent group is substituted with one or more third substituent groups denoted by R1.4.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1.4, R1.4.1, R1.4.2, and R1.4.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R1.4, R1.4.1, R1.4.2, and R1.4.3, respectively. [0220] In embodiments, when R1.5 is substituted, R1.5 is substituted with one or more first substituent groups denoted by R1.5.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.5.1 substituent group is substituted, the R1.5.1 substituent group is substituted with one or more second substituent groups denoted by R1.5.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1.5.2 substituent group is substituted, the R1.5.2 substituent group is substituted with one or more third substituent groups denoted by R1.5.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1.5, R1.5.1, R1.5.2, and R1.5.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R1.5, R1.5.1, R1.5.2, and R1.5.3, respectively. [0221] In embodiments, when R1A is substituted, R1A is substituted with one or more first substituent groups denoted by R1A.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1A.1 substituent group is substituted, the R1A.1 substituent group is substituted with one or more second substituent groups denoted by R1A.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1A.2 substituent group is substituted, the R1A.2 substituent group is substituted with one or more third substituent groups denoted by R1A.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1A, R1A.1, R1A.2, and R1A.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R1A, R1A.1, R1A.2, and R1A.3, respectively. [0222] In embodiments, when R1B is substituted, R1B is substituted with one or more first substituent groups denoted by R1B.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1B.1 substituent group is substituted, the R1B.1 substituent group is substituted with one or more second substituent groups denoted by R1B.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1B.2 substituent group is substituted, the R1B.2 substituent group is substituted with one or more third substituent groups denoted by R1B.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1B, R1B.1, R1B.2, and R1B.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R1B, R1B.1, R1B.2, and R1B.3, respectively. [0223] In embodiments, when R1A and R1B 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 R1A.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1A.1 substituent group is substituted, the R1A.1 substituent group is substituted with one or more second substituent groups denoted by R1A.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1A.2 substituent group is substituted, the R1A.2 substituent group is substituted with one or more third substituent groups denoted by R1A.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1A.1, R1A.2, and R1A.3 have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3 correspond to R1A.1, R1A.2, and R1A.3, respectively. [0224] In embodiments, when R1A and R1B 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 R1B.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1B.1 substituent group is substituted, the R1B.1 substituent group is substituted with one or more second substituent groups denoted by R1B.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1B.2 substituent group is substituted, the R1B.2 substituent group is substituted with one or more third substituent groups denoted by R1B.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1B.1, R1B.2, and R1B.3 have values corresponding to the values of RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW.1, RWW.2, and RWW.3 correspond to R1B.1, R1B.2, and R1B.3, respectively. [0225] In embodiments, when R1C is substituted, R1C is substituted with one or more first substituent groups denoted by R1C.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1C.1 substituent group is substituted, the R1C.1 substituent group is substituted with one or more second substituent groups denoted by R1C.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1C.2 substituent group is substituted, the R1C.2 substituent group is substituted with one or more third substituent groups denoted by R1C.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1C, R1C.1, R1C.2, and R1C.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R1C, R1C.1, R1C.2, and R1C.3, respectively. [0226] In embodiments, when R1D is substituted, R1D is substituted with one or more first substituent groups denoted by R1D.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1D.1 substituent group is substituted, the R1D.1 substituent group is substituted with one or more second substituent groups denoted by R1D.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R1D.2 substituent group is substituted, the R1D.2 substituent group is substituted with one or more third substituent groups denoted by R1D.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R1D, R1D.1, R1D.2, and R1D.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R1D, R1D.1, R1D.2, and R1D.3, respectively. [0227] In embodiments, when R2 is substituted, R2 is substituted with one or more first substituent groups denoted by R2.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2.1 substituent group is substituted, the R2.1 substituent group is substituted with one or more second substituent groups denoted by R2.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an R2.2 substituent group is substituted, the R2.2 substituent group is substituted with one or more third substituent groups denoted by R2.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, R2, R2.1, R2.2, and R2.3 have values corresponding to the values of RWW, RWW.1, RWW.2, and RWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein RWW, RWW.1, RWW.2, and RWW.3 correspond to R2, R2.1, R2.2, and R2.3, respectively. [0228] In embodiments, when L1 is substituted, L1 is substituted with one or more first substituent groups denoted by RL1.1 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL1.1 substituent group is substituted, the RL1.1 substituent group is substituted with one or more second substituent groups denoted by RL1.2 as explained in the definitions section above in the description of “first substituent group(s)”. In embodiments, when an RL1.2 substituent group is substituted, the RL1.2 substituent group is substituted with one or more third substituent groups denoted by RL1.3 as explained in the definitions section above in the description of “first substituent group(s)”. In the above embodiments, L1, RL1.1, RL1.2, and RL1.3 have values corresponding to the values of LWW, RLWW.1, RLWW.2, and RLWW.3, respectively, as explained in the definitions section above in the description of “first substituent group(s)”, wherein LWW, RLWW.1, RLWW.2, and RLWW.3 are L1, RL1.1, RL1.2, and RL1.3, respectively. [0229] In embodiments, the compound has the . In
Figure imgf000077_0001
embodiments, the compound has the . In embodiments, the
Figure imgf000077_0002
. In embodiments, the compound has the
Figure imgf000078_0002
5 In
Figure imgf000078_0001
the he In
Figure imgf000079_0001
the .
Figure imgf000080_0001
5
Figure imgf000080_0002
n embodiments, the compound has the formula: N O In
Figure imgf000081_0001
n embodiments, the compound has the formula: .
Figure imgf000082_0001
the
Figure imgf000082_0002
. In embodiments, the compound has the formula: In embodiments, the compound has the formula: In embodiments, the compound has the formula: [0230] In embodiments, the compound has the formula: . s the formula: .
Figure imgf000084_0001
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). [0233] In embodiments, 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). III. Pharmaceutical compositions [0234] In an aspect is provided a pharmaceutical composition including a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0235] In embodiments, the pharmaceutical composition includes an effective amount of the compound. In embodiments, the pharmaceutical composition includes a therapeutically effective amount of the compound. [0236] In embodiments, the compound is a compound of formula (I) or (II), including all embodiments thereof. IV. Methods of use [0237] In an aspect is provided a method of treating a neurodegenerative 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. [0238] In embodiments, the neurodegenerative disease is a tauopathy. In embodiments, the neurodegenerative disease is Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, Lewy body disease, progressive supranuclear palsy, or Parkinson’s disease. In embodiments, the neurodegenerative disease is Alzheimer’s disease. In embodiments, the neurodegenerative disease is Huntington’s disease. In embodiments, the neurodegenerative disease is amyotrophic lateral sclerosis. In embodiments, the neurodegenerative disease is Lewy body disease. In embodiments, the neurodegenerative disease is progressive supranuclear palsy. In embodiments, the neurodegenerative disease is Parkinson’s disease. [0239] In an aspect is provided a method of treating a liver 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. [0240] In embodiments, the liver disease is nonalcoholic steatohepatitis. [0241] In an aspect is provided a method of treating a fibrotic 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. [0242] In an aspect is provided a method of treating a coronavirus infection 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. [0243] In embodiments, the coronavirus infection is a SARS-CoV infection. In embodiments, the coronavirus infection is Severe Acute Respiratory Disease (SARS). In embodiments, the coronavirus infection is a SARS-CoV-2 infection. In embodiments, the coronavirus infection is coronavirus disease 2019 (COVID-19). In embodiments, the coronavirus infection is a MERS-CoV infection. In embodiments, the coronavirus infection is an HCoV-NL63 infection. In embodiments, the coronavirus infection is an HCoV-229E infection. In embodiments, the coronavirus infection is an HCoV-OC43 infection. In embodiments, the coronavirus infection is an HKU1 infection. [0244] In embodiments, the compound is a compound of formula (I) or (II), including all embodiments thereof. [0245] In an aspect is provided a method of reducing the level of activity of caspase-6 protein in a cell, the method including contacting the cell with an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. [0246] In embodiments, the level of activity of the caspase-6 protein is reduced 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 activity of the caspase-6 protein is reduced by about 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by about 2-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by about 5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by about 10-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by about 25-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by about 50-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by about 100-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by about 250-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by about 500-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by about 1000-fold relative to a control (e.g., absence of the compound). [0247] In embodiments, the level of activity of the caspase-6 protein is reduced 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). In embodiments, the level of activity of the caspase-6 protein is reduced by at least 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by at least 2-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by at least 5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by at least 10-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by at least 25-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by at least 50-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by at least 100-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by at least 250-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by at least 500-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activity of the caspase-6 protein is reduced by at least 1000-fold relative to a control (e.g., absence of the compound). [0248] In an aspect is provided a method of reducing the level of activation of procaspase-6 protein in a cell, the method including contacting the cell with an effective amount of a compound as described herein, or a pharmaceutically acceptable salt thereof. [0249] In embodiments, the level of activation of the procaspase-6 protein is reduced 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 activation of the procaspase-6 protein is reduced by about 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by about 2-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by about 5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by about 10-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by about 25-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by about 50-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by about 100-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by about 250-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by about 500-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by about 1000-fold relative to a control (e.g., absence of the compound). [0250] In embodiments, the level of activation of the procaspase-6 protein is reduced 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). In embodiments, the level of activation of the procaspase-6 protein is reduced by at least 1.5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by at least 2-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by at least 5-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by at least 10-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by at least 25-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by at least 50-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by at least 100-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by at least 250-fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by at least 500- fold relative to a control (e.g., absence of the compound). In embodiments, the level of activation of the procaspase-6 protein is reduced by at least 1000-fold relative to a control (e.g., absence of the compound). [0251] In embodiments, the compound binds to Y198A of the procaspase-6 (e.g., human procaspase-6) protein. In embodiments, the compound binds noncovalently to Y198A of the procaspase-6 (e.g., human procaspase-6) protein. In embodiments, the compound binds to Y198B of the procaspase-6 (e.g., human procaspase-6) protein. In embodiments, the compound binds noncovalently to Y198B of the procaspase-6 (e.g., human procaspase-6) protein. V. Embodiments [0252] Embodiment P1. A compound, or a pharmaceutically acceptable salt thereof, having the formula: ;
Figure imgf000089_0001
Ring A is a substituted or unsubstituted 5 to 6 membered heteroaryl or substituted or unsubstituted 8 to 10 membered fused ring heteroaryl; L1 is a bond or substituted or unsubstituted C1-C3 alkylene; R1 is independently halogen, -CX13, -CHX12, -CH2X1, -OCX13, -OCH2X1, -OCHX12, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -B(OR1C)(OR1D), -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A, R1B, R1C, and R1D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1 is independently –F, -Cl, -Br, or –I; n1 is an integer from 0 to 4; m1 and v1 are independently 1 or 2; and z1 is an integer from 0 to 5; wherein Ring A is not a substituted or unsubstituted pyrimidinyl. [0253] Embodiment P2. The compound of embodiment P1, wherein Ring A is a substituted or unsubstituted nitrogen-containing 5 to 6 membered heteroaryl or substituted or unsubstituted nitrogen-containing 8 to 10 membered fused ring heteroaryl. [0254] Embodiment P3. The compound of embodiment P1, wherein Ring A is substituted or unsubstituted pyridyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted imidazopyridinyl, substituted or unsubstituted benzothiazolyl, or substituted or unsubstituted benzoimidazolyl. [0255] Embodiment P4. The compound of embodiment P1, wherein Ring A is
N N N , ,
Figure imgf000091_0001
-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, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and z2 is an integer from 0 to 5. [0256] Embodiment P5. The compound of embodiment P4, wherein R2 is independently unsubstituted C1-C4 alkyl. [0257] Embodiment P6. The compound of embodiment P4, wherein R2 is independently unsubstituted methyl. [0258] Embodiment P7. The compound of embodiment P4, wherein z2 is 0. [0259] Embodiment P8. The compound of one of embodiments P4 to P6, wherein z2 is 1. [0260] Embodiment P9. The compound of embodiment P1, wherein Ring A is ,
Figure imgf000092_0001
is independently halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -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, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -B(OH)2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0262] Embodiment P11. The compound of one of embodiments P1 to P9, wherein R1 is independently halogen or -OR1D. [0263] Embodiment P12. The compound of embodiment P11, wherein R1D is independently hydrogen or unsubstituted C1-C4 alkyl. [0264] Embodiment P13. The compound of embodiment P11, wherein R1D is hydrogen. [0265] Embodiment P14. The compound of one of embodiments P1 to P9, wherein R1 is independently –F or -OH. [0266] Embodiment P15. The compound of one of embodiments P1 to P14, wherein z1 is 1. [0267] Embodiment P16. The compound of one of embodiments P1 to P14, wherein z1 is 2. [0268] Embodiment P17. A compound, or a pharmaceutically acceptable salt thereof, having the formula: ;
Figure imgf000093_0001
Ring B is a substituted or unsubstituted pyrimidinyl; L1 is a bond or substituted or unsubstituted C1-C3 alkylene; R1.1, R1.2, R1.3, R1.4, and R1.5 are independently hydrogen, halogen, -CX1 3, -CHX1 2, -CH2X1, -OCX13, -OCH2X1, -OCHX12, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -B(OR1C)(OR1D), -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R1A, R1B, R1C, and R1D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1 is independently –F, -Cl, -Br, or –I; each n1 is an integer from 0 to 4; and each m1 and v1 are independently 1 or 2; wherein: (i) R1.1 and R1.5 are not –OH; or (ii) wherein if R1.1 or R1.5 is –OH, then Ring B is not substituted or unsubstituted 2- pyrimidinyl or unsubstituted 5-pyrimidinyl; or (iii) wherein if Ring B is 5-pyrimidinyl, then the Ring B 5-pyrimidinyl is substituted. [0269] Embodiment P18. The compound of embodiment P17, wherein Ring B is N (R 2 )z2
Figure imgf000094_0001
-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, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and z2 is an integer from 0 to 3. [0270] Embodiment P19. The compound of embodiment P18, wherein R2 is independently –NH2 or unsubstituted C1-C4 alkyl. [0271] Embodiment P20. The compound of embodiment P18, wherein R2 is independently –NH2 or unsubstituted methyl. [0272] Embodiment P21. The compound of embodiment P18, wherein z2 is 0. [0273] Embodiment P22. The compound of one of embodiments P18 to P20, wherein z2 is 1. [0274] Embodiment P23. The compound of embodiment P17, wherein Ring B is .
Figure imgf000095_0001
wherein R1.1, R1.2, R1.3, R1.4, and R1.5 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -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, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -B(OH)2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. [0276] Embodiment P25. The compound of one of embodiments P17 to P24, wherein R1.1 is -OH. [0277] Embodiment P26. The compound of one of embodiments P17 to P25, wherein R1.3 is halogen. [0278] Embodiment P27. The compound of one of embodiments P17 to P25, wherein R1.3 is -F. [0279] Embodiment P28. The compound of one of embodiments P17 to P27, wherein R1.2, R1.4, and R1.5 are hydrogen. [0280] Embodiment P29. The compound of one of embodiments P1 to P28, wherein L1 is unsubstituted C1-C3 alkylene. [0281] Embodiment P30. The compound of one of embodiments P1 to P28, wherein L1 is unsubstituted methylene. [0282] Embodiment P31. A pharmaceutical composition comprising a compound of one of embodiments P1 to P30, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. [0283] Embodiment P32. A method of treating a neurodegenerative disease in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of embodiments P1 to P30, or a pharmaceutically acceptable salt thereof. [0284] Embodiment P33. The method of embodiment P32, wherein the neurodegenerative disease is a tauopathy. [0285] Embodiment P34. The method of embodiment P32, wherein the neurodegenerative disease is Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, Lewy body disease, progressive supranuclear palsy, or Parkinson’s disease. [0286] Embodiment P35. The method of embodiment P32, wherein the neurodegenerative disease is Alzheimer’s disease. [0287] Embodiment P36. A method of treating a liver disease in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of embodiments P1 to P30, or a pharmaceutically acceptable salt thereof. [0288] Embodiment P37. The method of embodiment P36, wherein the liver disease is nonalcoholic steatohepatitis. [0289] Embodiment P38. A method of treating a fibrotic disease in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of embodiments P1 to P30, or a pharmaceutically acceptable salt thereof. [0290] Embodiment P39. A method of treating a coronavirus infection in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of embodiments P1 to P30, or a pharmaceutically acceptable salt thereof. [0291] Embodiment P40. A method of reducing the level of activity of caspase-6 protein in a cell, said method comprising contacting the cell with an effective amount of a compound of one of embodiments P1 to P30, or a pharmaceutically acceptable salt thereof. [0292] Embodiment P41. A method of reducing the level of activation of procaspase-6 protein in a cell, said method comprising contacting the cell with an effective amount of a compound of one of embodiments P1 to P30, or a pharmaceutically acceptable salt thereof. [0293] It is understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and scope of the appended claims. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety for all purposes. EXAMPLES Example 1: A protein-ligand model system for the study of heteroarene-aryl stacking under physiological conditions [0294] The empirical study of (hetero)aryl-aryl stacking proteins and in ligand-protein interaction has largely been approached through bioinformatic analyses of large crystallographic databases. When taken in the aggregate, these large data sets provide useful insight into preferred stacking orientations and geometries. Such analyses are qualitative in nature, since absolute (or even relative) interaction energies cannot be extracted from purely structural information. Filling this void have been computational approaches involving various levels of theory, from the early work of Hunter and Sanders on the optimal geometry of these interactions, to an improved understanding of substituent effects using the methods of Houk and Wheeler. Recently, Wheeler described molecular descriptors that enable predictions of the strength of diverse heteroarene stacking interactions without computationally costly ab initio computations. [0295] Various experimental systems have been employed to study heteroarene-aryl stacking, including synthetic host-guest systems, intramolecular arene stacking in 1,8- diarylnaphthlenes, and various molecular “torsion balance”. Applications of the latter to heteroarene stacking include Shimizu’s cleft-like N-aryl imides, Gung’s triptycenes, and Gellman’s tertiary amide foldamers. Study of the conformational equilibrium between ‘closed’ and ‘open’ states, typically by NMR, is used to determine the binding enthalpy of the stacking interaction (closed state). On the other hand, the architecture of these systems imposes constraints on the orientation and approach of the interacting arenes, such that stacking interactions may form with sub-optimal geometries and distances. With a few exceptions, prior studies with torsion balances are performed in organic or polar aprotic solvent, due to a lack of sufficient aqueous solubility. [0296] The use of a protein-ligand interaction to study intermolecular interactions is attractive in principle, but also fraught with experimental challenges. Comparisons of binding affinities are confounded by disparate contributions of desolvation/hydrophobic effects in even very similar ligands. It can also be difficult to disentangle the contribution of the binding enthalpies for the interaction under investigation from effects on distal ligand- protein interactions. The challenge is correspondingly greater when studying interactions with precise geometric and spatial requirements. Thus, ligand-protein systems were used successfully by both Dougherty and Diederich to study cation- ^ interactions, while attempts by Diederich to use factor Xa and cathepsin B ligands to interrogate heteroarene-amide stacking largely failed. [0297] Inspired by such seminal efforts, we have sought to identify new protein-ligand model systems of utility for the study of intermolecular interactions. We judge as key criteria for the protein component, a highly shape-persistent binding site that can be readily assessed crystallographically. Criteria for the ligand component include adoption of a highly conserved binding mode and ability to modify the group/moiety of interest without impacting global ligand conformation or the interactions of distal groups. Illustrative of this approach is our recent report of the bacterial serine hydrolase CTX-M and a cognate ligand to study heteroarene-amide stacking interactions. Thus, we found with congeneric analogs differing only in a terminal heteroarene substitution (e.g., all possible regioisomers of pyridine and pyrimidine), that ligand binding affinities could be correlated with the predicted favorable effect of opposing dipole-dipole interaction of the amide and heteroarene substituents. Thus, the first experimental validation of computational predictions concerning these interactions was achieved. [0298] We explore herein, inter alia, heteroarene-tyrosine stacking using congeneric analogs of compound 1, a “molecular glue” that binds and stabilizes procaspase-6 toward proteolytic processing and activation. Relevant to its application in the current work is that the distal pyrimidine ring of 1 was previously shown to form a nearly ideal stacking interaction between tyrosine residues 198A and 198B, each of which project from one subunit of the dimeric zymogen (FIG.1). We synthesized more than two dozen new analogs of 1 bearing terminal five-membered, six-membered, or bicyclic heteroarenes as “probe heterocycles” and evaluated their binding affinities by surface plasmon resonance (SPR) methods, after first confirming a conserved binding mode and stacking interaction regardless of the nature of the probe heterocycle. We find that differences in binding affinity are largely attributable to the relative strength of the stacking interaction. To our knowledge, the current study represents the most comprehensive examination of heteroarene-aryl stacking interactions in a protein-ligand system, and validates a new model system for future studies of diverse intermolecular interactions under physiologically relevant conditions. [0299] A set of test ligands (2-30, FIG.2) was synthesized wherein the pyrimidine ring of 1 is replaced with diverse heterocycles commonly employed in materials, supramolecular, and medicinal chemistry. With a few exceptions, we selected probe heteroarenes with an ortho heteroatom (N or O) such that intramolecular hydrogen bond formation (as in 1) should promote a co-planar pyridine-heteroarene conformation optimal for stacking (FIG.1). Pyrazole 12, bearing an ortho methyl substituent, was prepared as a negative control that was unlikely to form a productive stacking interaction. For many of the new compounds, the probe heteroarene could be introduced via a late-stage Suzuki coupling employing a common intermediate. Other heteroarene systems required bespoke syntheses from acyclic precursors. All test compounds were purified to >95% purity and fully characterized prior to crystallographic and SPR studies. [0300] The expectation that probe heteroarenes would stack between two symmetry-related tyrosine residues was viewed as an important feature of this system, since the double-stack significantly reduces the wetted surface of probe heteroarene and was thus expected to reduce the contribution of desolvation energies in the binding of the diverse heterocycles. To confirm that binding poses and stacking interactions were conserved across compounds 1-30, we solved the complex crystal structures of fully a third of the analogs bound to procaspase- 6. All ten structures revealed binding poses nearly identical to that of 1, and all placed their probe heterocycles in productive stacking interactions with tyrosines 198A and 198B (FIG.3). [0301] We used SPR to assess the binding affinity of test compounds, using an avi-tagged (biotinylated) procaspase-6 construct that was captured onto a neutravidin-coated sensor chip in a Biacore 8K instrument. Preliminary sensorgrams were recorded for all compounds at a top concentration of 50 ^M to assess binding behavior and estimate preliminary KD values when possible. Next, a definitive data set of KD values, determined in triplicate, was generated for all compounds, using the most appropriate concentration range based on the preliminary KD values obtained (see Table 1). The average of the triplicate KD values for each analog was furthermore used to calculate the experimental binding energies ( ^G) provided in the figures that follow. For three weak-binding analogs (11, 12, and 26), a KD was estimated based on the SPR response measured at the highest concentration and the theoretical maximum response (Rmax) for the series. The higher KD value of compound 12 was not unexpected, as we had predicted a priori that this analog would be unable to form productive stacking interactions (vide supra). We thus excluded analog 12 from the analysis below since its experimental binding affinity is likely disconnected from the stacking interaction under study. [0302] We next compared predicted E_int values to experimental ^G values, regardless of the ring size or the number of heteroatoms in the probe arene and observed only a modest correlation (R2 = 0.24). Considering this, we speculated that differences in desolvation energies could be a root cause of the poor correlation. For example, the four analogs for which E_int most overpredicted binding affinties (6, and 28-30) all possessed hydrophobic functionality expected to extend beyond the periphery of the tyrosine stacking surface. Conversely, among analogs for which E_int underpredicted binding affinities were analogs 20-23 with hydrophilic probe arenes possessing a high heteroatom count relative to ring size. When the data were reevaluated taking into account the number of heteroatoms in the probe arene (a surrogate measure of desolvation penalties), a more robust correlation of the experimental and computed data was observed. Thus, among analogs bearing one or two heteroatoms in a five- or six-membered probe arene, the correlation of experimental and computed data was quite reasonable (R2 = 0.55; FIG.4). The correlation among the set of analogs bearing three or four heteroatoms was even better (R2 = 0.78; FIG.5). Finally, analyzing the bicyclic analogs 28-30 separately on account of their much greater wetted surface compared to monocyclic analogs returned the strongest correlation of all (R2 = 0.86) albeit with a limited number of data points. [0303] Overall, the correlation of computed and experimental data suggested that experimental ^G values determined with this ligand-protein model system are largely reflective of differences in the relative strength of the stacking interaction involving the respective probe heteroarene. Thus, comparing pyridine analog 5 with isosteric diazenes (1- 4) and triazene (25) analogs, we observe the diazenes and triazine to all bind significantly more potently than the pyridine (FIG.4 and FIG.5). This result conforms well with the expectation that more electron deficient heteroarenes should form stronger stacking interactions with an electron-rich tyrosine side chain. The trend of increasing binding affinities when moving from thiophene (26) to furan (27), to indazole (9) and imidazole (7) is also consistent with expectations (FIG.4). Finally, the favorable effect of N-methylation of nitrogen heterocycles is a striking and consistent effect across indazole (cf. 9 vs.15), imidazole (cf.8 vs 18), and triazole (cf.22 vs.24) comparators. These data suggest the potential utility of this model system for studies of substituent effects in heteroarene stacking, and area of considerable recent interest in the computational arena. [0304] Other findings of this study may surprise the empiricist medicinal chemist, such as the dramatically improved ^G value (nearly 4 kcal/mol) for oxazole 10 as compared to isoxazole 11. Notably, this effect is reasonably well predicted by the computed E_int values, and likely reflects the greater basicity of the oxygen atom in oxazole, combined with its proximity to, and possible interaction with, the polar OH function of the tyrosine ring. Example 2: Experimental procedures and characterization data [0305] General Procedures: Reactions were magnetically stirred or microwave irradiation unless otherwise indicated. Air and/or moisture sensitive reactions were carried out under an argon atmosphere using anhydrous solvents from commercial suppliers. Air and/or moisture sensitive reagents were transferred via syringe or cannula and were introduced into reaction vessels through rubber septa. Reaction product solutions and chromatography fractions were concentrated by rotary evaporation. Thin phase chromatography was performed on EMD precoated glass-backed silica gel 60 F-2540.25 mm plate. [0306] Materials: All chemical reagents and solvents used were purchased from commercial sources, such as Sigma-Aldrich, TCI, Ambeed or Fisher Scientific. Anhydrous DMF, dichloromethane and tetrahydrofuran (EMD Drisolv) were used without further purification. [0307] Instrumentation: 1H NMR spectra were recorded on a Varian INOVA-400400 MHz spectrometer. Chemical shifts are reported in δ units (ppm). NMR spectra were referenced relative to residual NMR solvent peaks. Coupling constants (J) are reported in hertz (Hz). When an NMR resonance is unambiguously attributable to a minor diastereomer this is indicated as “(minor)”, but otherwise is not. Column chromatography was performed on Silicycle Sili-prep cartridges using a Biotage Isolera Four automated flash chromatography system. Compound purity and molecular weight was determined using a Waters Acquity UPLC/MS system, equipped with Waters ELSD and PDA detectors. Separations were carried out with an XTerra® MS C18, 5 μm, 4.6 x 50 mm column, at ambient temperature (unregulated) using a mobile phase of water-methanol containing a constant 0.1% formic acid. [0308]
Figure imgf000102_0001
[0309] Intermediates S1, S2, and compound 1 were prepared by the reported procedure (1). [0310] Synthesis of 3-(3-bromopyridin-2-yl)-7-fluoro-3,4-dihydro-2H- benzo[e][1,3]oxazin-2-one (S3)
Figure imgf000102_0002
[0311] In a round-bottom flask with a stirred solution of 2-(((3-bromopyridin-2- yl)amino)methyl)-5-fluorophenol (S2) in acetonitrile (125 mL) was added triphosgene portion-wise. The reaction is heated to 80 °C for 1 hour and the reaction is monitored using thin layer chromatography. Once the reaction is completed, 5% NaHCO3 aqueous solution (25 mL) was added and the reaction is cooled to 0 °C. A white solid (S3) was obtained after vacuum filtration and was used in the next step without further purification. [0312] Synthesis of 7-fluoro-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2- yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one (S4) [0313]
Figure imgf000103_0001
yl)-7- fluoro-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one (S3) (6.54 g, 20.2 mmol), B2Pin2 (10.3 g, 40.5 mmol), Pd(dppf)Cl2 (1.48 g, 2.0 mmol) and KOAc (5.96 g, 60.7 mmol) was equipped with a reflux condensor an Argon balloon. The mixture was dissolved in anhydrous dioxane (50 mL) and stirred overnight at 85 °C. The crude reaction was filtered over a pad of silica and celite, concentrated in vacuo, and purified by silica gel chromatography (EtOAc in hexane = 0 ~ 40%) to provide S4 as yellow solid (3.6 g, 48%). 1H NMR (400 MHz, Chloroform-d) δ 8.54 (dd, J = 4.9, 2.0 Hz, 1H), 8.14 (dd, J = 7.3, 2.1 Hz, 1H), 7.26 (dd, 1H), 7.22 – 7.17 (m, 1H), 6.96 – 6.87 (m, 2H), 5.04 (s, 2H), 1.30 (s, 12H). 13C NMR (100 MHz, CDCl3) δ 162.52 (d, J = 247.2 Hz), 156.51, 151.30, 150.44 (d, J = 12.1 Hz), 149.68, 144.57, 126.83 (d, J = 9.6 Hz), 121.87, 114.84 (d, J = 3.4 Hz), 111.65 (d, J = 22.1 Hz), 103.90 (d, J = 25.6 Hz), 84.15f, 47.40, 24.98. LC-MS (ESI) calculated for C19H20BFN2O4 m/z [M+H]+ =371.19, found 371.19. [0314] Synthetic Procedure of S5 from S2 (Direct Suzuki Coupling), for compound 9, 12, 13, 15, 26 [0315] Synthesis of 2-(((3-(1H-pyrazol-3-yl)pyridin-2-yl)amino)methyl)-5-fluorophenol (compound 9)
[0316] A mixture of S2 (200 mg, 0.67 mmol), 3‐(4,4,5,5‐tetramethyl‐1,3,2‐dioxaborolan‐2‐ yl)‐1H‐pyrazole (160 mg, 0.81 mmol), Pd(dppf)Cl2 (50 mg, 0.067 mmol) and KOAc (80 mg, 0.81 mmol) in 2 mL of mixed solvent (dioxane/H2O = 10/1) was stirred at 100 oC for 1 hour. Subsequently, the mixture was extracted with EtOAc by three times, the combined organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography (EtOAc in PE = 20 ~ 40%) to provide 120 mg of product. The compound was further purified with prep-HPLC, 40 mg of 2-(((3-(1H-pyrazol- 3-yl)pyridin-2-yl)amino)methyl)-5-fluorophenol (9) was achieved in high purity. 1H NMR (400 MHz, DMSO-d6) δ 13.06 (br, 1H), 10.93 (br s, 1H), 8.71 (s, 1H), 8.01 - 7.99 (m, 2H), 7.87 (d, J = 2.0 Hz), 7.25 (t, J = 8.4 Hz, 1H), 6.86 (d, J = 6 Hz, 1H), 6.65 (dd, J = 7.6, 5.2 Hz, 1H), 6.61-6.53 (m, 2H), 4.56 (d, J = 5.6 Hz, 2H). MS (ESI+, m/z): Calcd for C15H13FN4O: 284.1; found 285.2 [M+H]+. [0317] Synthesis of 5-fluoro-2-(((3-(1-methyl-1H-pyrazol-5-yl)pyridin-2- yl)amino)methyl)phenol (compound 12) [0318]
Figure imgf000104_0001
- mg, 0.17 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (88 mg, 0.42 mmol), Pd(dppf)Cl2 (3.1 mg, 4.2 µmol) and Cs2CO3 (140 mg, 0.42 mmol) in 0.58 mL of mixed solvent (dioxane/H2O = 10/1) was stirred at 130 °C for 1 hour using microwave irradiation. Subsequently, the mixture was extracted with EtOAc and this crude compound was purified by silica gel chromatography (EtOAc in hexane = 0 ~ 50%) to provide 5-fluoro- 2-(((3-(1-methyl-1H-pyrazol-5-yl)pyridin-2-yl)amino)methyl)phenol (compound 12) as yellow solid (40.7 mg, 81%). 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 5.4, 1.8 Hz, 1H), 7.59 (d, J = 1.6 Hz, 1H), 7.37 (dd, J = 7.3, 1.8 Hz, 1H), 7.07 (dd, J = 8.3, 6.6 Hz, 1H), 6.75 (dd, J = 7.2, 5.4 Hz, 1H), 6.64 (d, J = 10.6, 2.6 Hz, 1H), 6.53 (ddd, J = 8.3, 8.3, 2.6 Hz, 1H), 6.32 (d, J = 1.6 Hz, 1H), 5.28 (brs, 1H), 4.41 (d, J = 6.4 Hz, 2H), 3.68 (s, 3H).13C NMR (100 MHz, acetone-d6) δ 163.3 (d, J = 242.4 Hz), 158.2(d, J = 12.9 Hz), 155.6, 146.7, 139.9, 138.4, 137.3, 132.5 (d, J = 10.3 Hz), 123.0 (d, J = 3.1 Hz),112.2, 111.9, 106.8, 105.8 (d, J = 21.4 Hz), 104.1 (d, J = 23.3 Hz), 40.6, 36.2. LRMS (ESI+) calcd for C16H16FN4O ([M+H]+): 299.12; found: 299.14. [0319] Synthesis of 5-fluoro-2-(((3-(thiazol-5-yl)pyridin-2-yl)amino)methyl)phenol (compound 13)
Figure imgf000105_0001
[0320] To a mg, , 1,3,2- dioxaborolan-2-yl)thiazole (500 mg, 2.37 mmol) and K2CO3 (654 mg, 4.734 mmol) in dioxane (5 mL) and H2O (0.5 mL) was added Pd(dppf)Cl2 (173 mg, 0.237 mmol) under nitrogen atmosphere. The reaction was stirred at 100 oC with microwave for 4 hours. The mixture was partitioned between DCM (10 mL) and water (10 mL). The organic layer was separated. The aqueous layer was extracted with DCM (2×10 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography using a mixture of petroleum ether-ethyl acetate (100:0 to 90:10 v/v) as eluent to afford compound 13 (50 mg, yield: 7%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 9.21 (s, 1H), 8.06–8.05 (m, 2H), 7.52–7.50 (m, 1H), 7.15 (d, J = 4.0 Hz, 1H), 6.69–6.53 (m, 4H), 4.39 (d, J = 8.0 Hz, 2H).13C NMR (101 MHz, DMSO-d6) δ 162.3 (d, J = 242.3 Hz), 157.2 (d, J = 11.3 Hz), 155.7, 155.1, 147.8, 142.5, 139.6, 133.7, 130.8 (d, J = 9.9 Hz), 123.2 (d, J = 2.8 Hz), 112.7, 111.7, 105.7 (d, J = 21.0 Hz), 103.2 (d, J = 23.5 Hz), 40.4. MS Calcd for C15H12FN3OS: 301.07; MS Found: 302.1 [M+H]+. [0321] Synthesis of 5-fluoro-2-(((3-(1-methyl-1H-pyrazol-3-yl)pyridin-2- yl)amino)methyl)phenol (compound 15) [0322] A 2)(30 mg, 0.10 mmol), 1-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (53 mg, 0.25 mmol), Pd(dppf)Cl2 (3.7 mg, 5.0 µmol) and Cs2CO3 (82 mg, 0.25 mmol) in 0.35 mL of mixed solvent (dioxane/H2O = 10/1) was stirred at 130 °C for 1 hour using microwave irradiation. Subsequently, the mixture was extracted with EtOAc and this crude compound was purified by silica gel chromatography (EtOAc in hexane = 0 ~ 50%) to provide 5-fluoro- 2-(((3-(1-methyl-1H-pyrazol-3-yl)pyridin-2-yl)amino)methyl)phenol (25.2 mg, 84%). 1H NMR (400 MHz, CDCl3) δ 8.79 (t, J = 5.9 Hz, 1H), 8.03 (dd, J = 5.2, 1.8 Hz, 1H), 7.76 (dd, J = 7.5, 1.8 Hz, 1H), 7.39 (d, J = 2.4 Hz, 1H), 7.22 (dd, J = 8.4, 6.8 Hz, 1H), 6.66-6.61 (m, 2H), 6.57 (d, J = 2.4 Hz, 1H), 6.53 (ddd, J = 8.4, 8.4, 2.6 Hz, 1H), 4.56 (d, J = 6.5 Hz, 2H), 3.98 (s, 3H); 13C NMR (100 MHz, acetone-d6) δ 164.2 (d, J = 242.3 Hz), 159.4, 155.1 (d, J = 7.7 Hz), 149.7, 145.3, 136.3, 133.2 (d, J = 10.3 Hz), 132.5, 124.3 (d, J = 3.1 Hz),113.8, 112.6, 106.4 (d, J = 21.5 Hz), 104.9 (d, J = 23.1 Hz), 104.1, 41.5, 39.2. LRMS (ESI+) calcd for C16H16FN4O ([M+H]+): 299.12; found: 299.14. [0323] Synthesis of 5-fluoro-2-(((3-(thiophen-2-yl)pyridin-2-yl)amino)methyl)phenol (compound 26).
Figure imgf000106_0001
[0324] To a solution of S2 (400 mg, 1.35 mmol), 4,4,5,5-tetramethyl-2-(thiophen-2-yl)- 1,3,2-dioxaborolane (311 mg, 1.48 mmol) and K2CO3 (372 mg, 2.7 mmol) in dioxane (5 mL) and H2O (0.5 mL) was added Pd(dppf)Cl2 (99 mg, 0.135 mmol) under nitrogen atmosphere. The reaction was stirred at 120 oC with microwave for 1 hours. The mixture was partitioned between DCM (10 mL) and water (10 mL). The organic layer was separated. The aqueous layer was extracted with DCM (2×10 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography using a mixture of petroleum ether-ethyl acetate (100:0 to 90:10 v/v) as eluent to afford crude product, and further purification was conducted by using prep-HPLC to give compound 26 (60 mg, yield: 15%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.03–8.02 (m, 1H), 7.66–7.65 (m, 1H), 7.50–7.47 (m, 1H), 7.30–7.29 (m, 1H), 7.21–7.19 (m, 2H), 6.68–6.64 (m, 1H), 6.58–6.53 (m, 3H), 4.41 (d, J = 8.0 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 162.4 (d, J = 242.4 Hz), 157.4 (d, J = 11.1 Hz), 155.2, 146.9, 138.7, 138.6, 131.1 (d, J = 13.0 Hz), 128.6, 127.0, 126.9, 123.3 (d, J = 2.7 Hz), 115.2, 112.8, 105.7 (d, J = 21.0 Hz), 103.2 (d, J = 23.9 Hz), 40.6. MS Calcd for C16H13FN2OS: 300.07; MS Found: 301.3 [M+H]+. [0325] Synthetic Procedure of S5 from S4 (Swapping Suzuki coupling), for compound 2, 4-8, 14, 16-20, 25, 28-30 [0326] The synthesis of 5-fluoro-2-(((3-(pyridazin-3-yl)pyridin-2-yl)amino)methyl)phenol (compound 2) F N N F N N [0327] To a
Figure imgf000107_0001
mg, , mg, 1.40 mmol) and K2CO3 (93 mg, 1.40 mmol) in dioxane (5 mL) and H2O (0.5 mL) was added Pd(dppf)Cl2 (85 mg, 0.116 mmol) under nitrogen atmosphere. The reaction was stirred at 100 oC for 2 hours. The mixture was partitioned between DCM (10 mL) and water (10 mL). The organic layer was separated. The aqueous layer was extracted with DCM (2×10 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by prep-HPLC to afford 2 (120 mg, yield: 35%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.68 (br s, 1H), 9.55 (t, J = 5.6 Hz, 1H), 9.18 (t, J = 3.6 Hz, 1H), 8.31 (d, J = 1.6 Hz, 1H), 8.21–8.16 (m, 2H), 7.84–7.79 (m, 1H), 7.25 (t, J = 8.4 Hz, 1H), 6.78–6.75 (m, 1H), 6.62–6.54 (m, 2H), 4.62 (d, J = 5.6 Hz, 2H).13C NMR (101 MHz, DMSO-d6) δ 162.4 (d, J = 241.4 Hz), 159.8, 157.4 (d, J = 11.4 Hz), 156.2, 150.3, 149.7, 138.0, 130.9 (d, J = 10.2 Hz), 128.3, 126.1, 123.0 (d, J = 2.8 Hz), 113.3, 112.3, 105.6 (d, J = 21.0 Hz), 103.0 (d, J = 23.6 Hz), 40.6. MS Calcd: 296.11; MS Found: 297.2 [M+H]+. [0328] Synthesis of 5-fluoro-2-(((3-(pyrazin-2-yl)pyridin-2-yl)amino)methyl)phenol (compound 4) [0329] A
Figure imgf000108_0001
mmol), Pd(dppf)Cl2 (137 mg, 0.188 mmol), K2CO3 (328.5 mg, 2.377 mmol) in dioxane (3 mL) and H2O (0.3 mL) was stirred at 110 oC with mw for 2 hours. The crude product was purified by silica gel chromatography to provide the product (4, 332 mg, yield: 94%). 1H NMR (400 MHz, DMSO) δ 10.66 (s, 1H), 9.26 (d, J = 1.2 Hz, 1H), 9.11 (t, J = 5.9 Hz, 1H), 8.70 – 8.63 (m, 1H), 8.59 (d, J = 2.6 Hz, 1H), 8.24 (dd, J = 7.6, 1.5 Hz, 1H), 8.17 (dd, J = 4.9, 1.7 Hz, 1H), 7.21 (t, J = 8.4 Hz, 1H), 6.73 (dd, J = 7.6, 4.9 Hz, 1H), 6.63 – 6.51 (m, 2H), 4.57 (d, J = 5.9 Hz, 2H). MS (ESI+, m/z): Calcd for C16H13FN4O: 296.1; found 297.1 [M+H]+. [0330] Synthesis of 2-(([2,3'-bipyridin]-2'-ylamino)methyl)-5-fluorophenol (compound 5) F N F N
Figure imgf000108_0002
[0331] To a mg, , mg, 1.40 mmol) and K2CO3 (193 mg, 1.40 mmol) in dioxane (5 mL) and H2O (0.5 mL) was added Pd(dppf)Cl2 (91 mg, 0.127 mmol) under nitrogen atmosphere. The reaction was stirred at 100 oC for 2 hours. The mixture was partitioned between DCM (10 mL) and water (10 mL). The organic layer was separated. The aqueous layer was extracted with DCM (2×10 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by prep-HPLC to afford compound 5 (150 mg, yield: 44%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.86 (s, 1H), 9.67 (t, J = 6.0 Hz, 1H), 8.65–8.63 (m, 1H), 8.11–8.08 (m, 2H), 7.97–7.78 (m, 2H), 7.38–7.36 (m, 1H), 7.23–7.21 (m, 1H), 6.71–6.68 (m, 1H), 6.61–6.53 (m, 2H), 4.56 (d, J = 6.0 Hz, 1H). 13C NMR (101 MHz, DMSO-d6) δ 162.4 (d, J = 241.3 Hz), 157.4 (d, J = 11.4 Hz), 156.7, 156.3, 148.4, 148.0, 138.1, 137.2, 130.9 (d, J = 10.3 Hz), 123.4 (d, J = 2.8 Hz), 122.3, 122.3, 116.1, 112.2, 105.7 (d, J = 21.0 Hz), 103.1 (d, J = 23.4 Hz), 40.6. MS Calcd for C17H14FN3O: 295.11, MS Found: 296.2 [M+H]+. [0332] Synthesis of 5-fluoro-2-(((3-(5-methylpyrimidin-2-yl)pyridin-2- yl)amino)methyl)phenol (compound 6) [0333] A
Figure imgf000109_0001
S4 (24.0 mg, 0.065 mmol), Pd(dppf)Cl2 (3.0 mg, 4.1 µmol) and Cs2CO3 (44 mg, 0.135 mmol) in 0.23 mL of mixed solvent (dioxane/H2O = 10/1) was stirred at 130 °C for 1 hour using microwave irradiation. Subsequently, the mixture was extracted with EtOAc and this crude compound was purified by silica gel chromatography (EtOAc in hexane = 0 ~ 50%) to provide 5-fluoro- 2-(((3-(5-methylpyrimidin-2-yl)pyridin-2-yl)amino)methyl)phenol (16.1 mg, 96%). 1H NMR (400 MHz, CDCl3) δ 10.04 (brs, 1H), 8.81 (dd, J = 7.7, 1.8 Hz, 1H), 8.63 (s, 2H), 8.19 (dd, J = 5.1, 1.8 Hz, 1H), 7.23 (dd, J = 8.4, 6.7 Hz, 1H), 6.72 (dd, J = 7.7, 5.1 Hz, 1H), 6.63 (dd, J = 10.7, 2.7 Hz, 1H), 6.54 (ddd, J = 8.4, 8.4, 2.7 Hz, 1H), 4.58 (d, J = 6.4 Hz, 2H), 2.36 (s, 3H); 13C NMR (100 MHz, CD3OD) δ 163.2 (d, J = 242.8 Hz), 160.9, 157.3 (d, J = 11.6 Hz), 156.6, 156.4, 148.2, 139.0, 131.2 (d, J = 10.2 Hz), 128.3, 122.6 (d, J = 3.0 Hz), 114.9, 111.3, 105.6 (d, J = 21.4 Hz), 103.2 (d, J = 23.6 Hz), 40.1, 13.9. LRMS (ESI+) calcd for C17H16FN4O ([M+H]+): 311.13; found: 311.15 [0334] Synthesis of 2-(((3-(1H-imidazol-2-yl)pyridin-2-yl)amino)methyl)-5-fluorophenol (compound 7) [0335] To a 200 mg, 1.40 mmol) and K2CO3 (93 mg, 1.40 mmol) in dioxane (5 mL) and H2O (0.5 mL) was added Pd(dppf)Cl2 (85 mg, 0.116 mmol) under nitrogen atmosphere. The reaction was stirred at 100 oC for 2 hours. The mixture was partitioned between DCM (10 mL) and water (10 mL). The organic layer was separated. The aqueous layer was extracted with DCM (2×10 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by prep-HPLC to afford compound (110 mg, yield: 33%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.63 (br s, 1H), 10.80 (br s, 1H), 9.69 (t, J = 5.6 Hz, 1H), 8.06–8.02 (m, 2H), 7.26–7.13 (m, 3H), 6.68–6.56 (m, 3H), 4.57 (d, J = 3.6 Hz, 2H); 13C NMR (101 MHz, DMSO-d6) δ 162.4 (d, J = 242.4 Hz), 157.4 (d, J = 11.0 Hz), 154.8, 147.0, 144.7, 133.4, 130.9 (d, J = 10.2 Hz), 128.0, 123.3 (d, J = 2.7 Hz), 118.0, 111.5, 108.8, 105.7 (d, J = 21.1 Hz), 103.1 (d, J = 23.5 Hz), 39.8. LC-MS Calcd: 284.11, found: 285.2 [M+H]+. [0336] Synthesis of 2-(((3-(1H-imidazol-4-yl)pyridin-2-yl)amino)methyl)-5-fluorophenol (compound 8)
Figure imgf000110_0001
[0337] g, , mg, 1.36 mmol), Pd(dppf)Cl2 (85 mg, 0.116 mmol), K2CO3 (193 mg, 1.395 mmol) in dioxane (5 mL) and H2O (0.5 mL) was stirred at 100 oC for 2 hours. The crude product was purified by silica gel chromatography (EtOAc in PE = 25%) to provide the 130 mg product in 81% yield. The product was further purified using prep-HPLC to give product as a white solid (compound 8, 70 mg). 1H NMR (400 MHz, DMSO) δ 11.92 ( br s, 1H), 9.30 (s, 1H), 7.90 (dd, J = 5.0, 1.7 Hz, 1H), 7.85 – 7.83 (m, 2H), 7.72 (d, J = 1.0 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 6.60 – 6.50 (m, 3H), 4.51 (s, 2H). MS (ESI+, m/z): Calcd for C15H13FN4O: 284.1; found 285.2 [M+H]+. [0338] Synthesis of 5-fluoro-2-(((3-(thiazol-4-yl)pyridin-2-yl)amino)methyl)phenol (compound 14) [0339] To a
Figure imgf000111_0001
1.26 mmol) and K2CO3 (350 mg, 2.53 mmol) in dioxane (5 mL) and H2O (0.5 mL) was added Pd(dppf)Cl2 (91 mg, 0.127 mmol) under nitrogen atmosphere. The reaction was stirred at 110 oC with microwave for 2 hours. The mixture was partitioned between DCM (10 mL) and water (10 mL). The organic layer was separated. The aqueous layer was extracted with DCM (2×10 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography using a mixture of petroleum ether-ethyl acetate (100:0 to 75:25 v/v) as eluent to afford compound 14 (198 mg, yield: 52%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.82 (s, 1H), 9.31 (d, J = 4.0 Hz, 1H), 8.20–8.19 (m, 1H), 8.07–8.05 (m, 1H), 8.00–7.98 (m, 2H), 7.23 (t, J = 8.0 Hz, 1H), 6.69–6.66 (m, 1H), 6.60–6.53 (m, 2H), 4.53 (d, J = 8.0 Hz, 2H).13C NMR (101 MHz, DMSO-d6) δ 162.6 (d, J = 242.4 Hz), 157.4 (d, J = 11.4 Hz), 155.0, 154.7, 153.5, 147.4, 136.6, 131.0 (d, J = 10.3 Hz), 123.3 (d, J = 2.8 Hz), 116.5, 113.4, 112.4, 105.7 (d, J = 21.1 Hz), 103.2 (d, J = 23.6 Hz), 40.1. MS Calcd for C15H12FN3OS: 301.07; MS Found: 302.0 [M+H]+. [0340] Synthesis of 5-fluoro-2-(((3-(isothiazol-5-yl)pyridin-2-yl)amino)methyl)phenol (compound 16)
[0341] A solution of S4 (1.3 g, 3.02 mmol), 7 (450 mg, 2.74 mmol), Pd(dppf)Cl2 (200 mg, 0.274 mmol), K2CO3 (756 mg, 5.486 mmol) in dioxane (5 mL) and H2O (0.5 mL) was stirred for 2 hours at 110 oC. The crude product was purified by silica gel chromatography to provide the product (compound 16, 264 mg, yield: 32%). 1H NMR (400 MHz, DMSO) δ 10.67 (s, 1H), 8.66 (d, J = 1.7 Hz, 1H), 8.10 (dd, J = 5.0, 1.8 Hz, 1H), 7.65 (d, J = 1.8 Hz, 1H), 7.61 (dd, J = 7.4, 1.7 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 6.71 (dd, J = 7.4, 5.0 Hz, 1H), 6.63 (t, J = 5.8 Hz, 1H), 6.60 – 6.51 (m, 2H), 4.42 (d, J = 5.6 Hz, 2H). MS (ESI+, m/z): Calcd for C15H12FN3OS: 301.1; found 302.2 [M+H]+. [0342] Synthesis of 5-fluoro-2-(((3-(thiazol-2-yl)pyridin-2-yl)amino)methyl)phenol (compound 17) [0343] To
Figure imgf000112_0001
, 1.26 mmol) and K2CO3 (350 mg, 2.53 mmol) in dioxane (5 mL) and H2O (0.5 mL) was added Pd(dppf)Cl2 (91 mg, 0.127 mmol) under nitrogen atmosphere. The reaction was stirred at 110 oC with microwave for 2 hours. The mixture was partitioned between DCM (10 mL) and water (10 mL). The organic layer was separated. The aqueous layer was extracted with DCM (2×10 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography using a mixture of petroleum ether-ethyl acetate (100:0 to 75:25 v/v) as eluent to afford compound 17 (88 mg, yield: 23%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 9.29 (t, J = 4.0 Hz, 1H), 8.17–8.16 (m, 1H), 8.05–8.03 (m, 1H), 7.94–7.93 (m, 1H), 7.79 (d, J = 4.0 Hz, 1H), 7.22–7.20 (m, 1H), 6.71–6.68 (m, 1H), 6.62–6.54 (m, 2H), 4.53 (d, J = 8.0 Hz, 2H).13C NMR (101 MHz, DMSO-d6) δ 167.5, 162.3 (d, J = 242.6 Hz), 157.2 (d, J = 11.2 Hz), 154.3, 149.8, 142.3, 137.4, 130.6 (d, J = 10.3 Hz), 123.1, 122.9 (d, J = 2.8 Hz), 112.2, 111.1, 105.7 (d, J = 21.1 Hz), 102.9 (d, J = 23.8 Hz), 39.8. MS Calcd for C15H12FN3OS: 301.07; MS Found: 302.0 [M+H]+. [0344] Synthesis of 5-fluoro-2-(((3-(1-methyl-1H-imidazol-4-yl)pyridin-2- yl)amino)methyl)phenol (compound 18) [0345] ol), 7- fluoro-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-3,4-dihydro-2H- benzo[e][1,3]oxazin-2-one (S4)(60.0 mg, 0.160 mmol), Pd(dppf)Cl2 (12.0 mg, 16.0 µmol) and K2CO3 (27 mg, 0.190 mmol) in 0.690 mL of mixed solvent (dioxane/H2O = 7/1) was stirred at 100 °C for 2 hours using microwave irradiation. Subsequently, the mixture was extracted with EtOAc and this crude compound was purified by silica gel chromatography (MeOH in DCM = 0 ~ 5%) and by prep-HPLC to provide 5-fluoro-2-(((3-(1-methyl-1H- imidazol-4-yl)pyridin-2-yl)amino)methyl)phenol (compound 18, 11.5 mg, 24%). 1H NMR (400 MHz, DMSO-d6) δ 11.27 (broad s, 1H), 9.19 (t, J = 6.1 Hz, 1H), 7.91 (dd, J = 5.0, 1.8 Hz, 1H), 7.77 (dd, J = 7.5, 1.6 Hz, 2H), 7.71 (d, J = 1.3 Hz, 1H), 7.26 (dd, J = 8.3, 7.1 Hz, 1H), 6.62 – 6.53 (m, 3H), 4.51 (d, J = 6.0 Hz, 2H), 3.73 (s, 3H).13C NMR (100 MHz, DMSO) δ 162.46 (d, J = 241.4 Hz), 157.65, 157.53, 154.75, 144.92, 139.15, 137.56, 133.50, 131.22 (d, J = 10.3 Hz), 123.70 (d, J = 2.8 Hz), 118.44, 113.33, 112.03, 105.70 (d, J = 21.0 Hz), 103.38 (d, J = 23.2 Hz), 33.76. MS Calcd for C16H15FN4O: 298.12; MS Found: 299.19 [M+H]+. [0346] Synthesis of 5-fluoro-2-(((3-(isothiazol-3-yl)pyridin-2-yl)amino)methyl)phenol (compound 19)
Figure imgf000113_0001
[0347] To a solution of S4 (1.3 g, 3.02 mmol), 3-bromoisothiazole (450 mg, 2.74 mmol) and K2CO3 (756 mg, 5.49 mmol) in dioxane (5 mL) and H2O (0.5 mL) was added Pd(dppf)Cl2 (198 mg, 0.274 mmol) under nitrogen atmosphere. The reaction was stirred at 110 oC with microwave for 2 hours. The mixture was partitioned between DCM (10 mL) and water (10 mL). The organic layer was separated. The aqueous layer was extracted with DCM (2×10 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography using a mixture of petroleum ether-ethyl acetate (100:0 to 75:25 v/v) as eluent to afford compound 19 (100 mg, yield: 12%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.70 (br s, 1H), 9.22–9.15 (m, 2H), 8.23–8.20 (m, 1H), 8.13–8.12 (m, 1H), 8.05 (d, J = 4.0 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 6.71–6.68 (m, 1H), 6.61–6.54 (m, 2H), 4.61 (d, J = 4.0 Hz, 2H).13C NMR (101 MHz, DMSO-d6) δ 166.6, 162.4 (d, J = 242.5 Hz), 157.4 (d, J = 11.3 Hz), 155.6, 150.0, 148.6, 138.0, 130.9 (d, J = 10.3 Hz), 123.1, 123.0 (d, J = 3.5 Hz), 112.7, 111.9, 105.7 (d, J = 21.1 Hz), 103.1 (d, J = 23.7 Hz), 40.0. MS Calcd for C15H12FN3OS: 301.07; MS Found: 302.1 [M+H]+. [0348] Synthesis of 2-(((3-(1H-1,2,4-triazol-3-yl)pyridin-2-yl)amino)methyl)-5- fluorophenol (compound 20)
Figure imgf000114_0001
[0349] To a mg, was NaH (130 mg, 3.24 mmol) at 0 oC under nitrogen atmosphere. The mixture was stirred at 0 oC for 10 min, followed by addition of SEMCl (540 mg, 3.24 mmol). The reaction was stirred at room temperature for 2 h, and then quenched with saturated NH4Cl. The mixture was extracted with EtOAc (3×20 mL), the combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford 20b (450 mg, yield: 60%). The crude product was used directly without further purification. [0350] To a solution of 20b (400 mg, 1.162 mmol), S4 (388 mg, 1.395 mmol) and K2CO3 (95 mg, 1.395 mmol) in dioxane (5 mL) and H2O (0.5 mL) was added Pd(dppf)Cl2 (85 mg, 0.116 mmol) under nitrogen atmosphere. The reaction was stirred at 100 oC for 2 hours. The mixture was partitioned between EtOAc (10 mL) and water (10 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography using a mixture of petroleum ether-ethyl acetate (75:15 v/v) as eluent to afford 20c (250 mg, yield: 52%). [0351] To a solution of 20c (200 mg, 0.482 mmol) in CH2Cl2 (2 mL) was added TFA (8 mL) at 0 oC. The reaction was allowed to stir at room temperature for 4 h. Aqueous Na2CO3 was added until pH to 8. The mixture was extracted with EtOAc. The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by prep-HPLC to afford compound 20 (30 mg, yield: 22%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.73 (s, 1H), 8.52 (s, 1H), 8.25 (dd, J = 7.6, 1.6 Hz, 1H), 8.11 (dd, J = 5.2, 2.0 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 6.71–6.68 (m, 1H), 6.62– 6.54 (m, 2H), 4.59 (d, J = 4.4 Hz, 2H).13C NMR (101 MHz, DMSO-d6) δ 162.4 (d, J = 241.6 Hz), 157.9, 157.5 (d, J = 11.3 Hz), 155.1, 148.4, 146.2, 135.8, 130.9 (d, J = 10.3 Hz), 123.2 (d, J = 2.8 Hz), 112.0, 108.9, 105.6 (d, J = 21.0 Hz), 103.1 (d, J = 23.4 Hz), 40.6. MS Calcd for C14H12FN5O: 285.10; MS Found: 286.2 [M+H]+. [0352] Synthesis of 5-fluoro-2-(((3-(1-methyl-1H-1,2,3-triazol-4-yl)pyridin-2- yl)amino)methyl)phenol (compound 24)
Figure imgf000115_0001
[0353] A mixture of 4-bromo-1-methyl-1H-1,2,3-triazole (32.0 mg, 0.190 mmol), 7-fluoro- 3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-3,4-dihydro-2H- benzo[e][1,3]oxazin-2-one (S4)(60.0 mg, 0.160 mmol), Pd(dppf)Cl2 (12.0 mg, 16.0 µmol) and K2CO3 (27 mg, 0.190 mmol) in 0.690 mL of mixed solvent (dioxane/H2O = 7/1) was stirred at 100 °C for 2 hours using microwave irradiation. Subsequently, the mixture was extracted with EtOAc and this crude compound was purified by silica gel chromatography (MeOH in DCM = 0 ~ 5%) to provide compound 24 (5.3 mg, 11%). 1H NMR (400 MHz, DMSO-d6) δ 10.87 (s, 1H), 8.64 (s, 1H), 8.47 (t, J = 5.9 Hz, 1H), 8.05 (dd, J = 5.0, 1.8 Hz, 1H), 7.86 (dd, J = 7.4, 1.8 Hz, 1H), 7.27 (dd, J = 8.4, 7.0 Hz, 1H), 6.68 (dd, J = 7.4, 4.9 Hz, 1H), 6.64 – 6.53 (m, 2H), 4.59 (d, J = 5.8 Hz, 2H), 4.13 (s, 3H). 13C NMR (100 MHz, DMSO-d6) δ 162.40 (d, J = 241.6 Hz), 157.44 (d, J = 11.4 Hz), 154.61, 146.96, 145.63, 135.45, 131.07, 130.96, 123.79, 123.26 (d, J = 2.9 Hz), 112.15, 109.62, 105.66 (d, J = 21.0 Hz), 103.12 (d, J = 23.5 Hz), 37.13. MS Calcd for C15H14FN5O: 299.12; MS Found: 300.19 [M+H]+. [0354] Synthesis of 2-(((3-(1,2,4-triazin-3-yl)pyridin-2-yl)amino)methyl)-5-fluorophenol (compound 25).
Figure imgf000116_0001
Figure imgf000116_0002
[0355] To a solution of 5‐fluoro‐2‐({[3‐
Figure imgf000116_0003
yl)pyridin‐2‐yl]amino}methyl)phenol (400 mg, 1.16 mmol), 3-(methylthio)-1,2,4-triazine (74 mg, 0.58 mmol) and Copper(I) 3-methylsalicylate (124 mg, 0.58 mmol) in dioxane (5 mL) was added Pd(PPh3)4 (85 mg, 0.116 mmol) under nitrogen atmosphere. The reaction was stirred at 80 oC for 4 hours. The mixture was partitioned between EtOAc (10 mL) and water (10 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (2×10 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by prep-HPLC to afford compound 25 (12 mg, yield: 7%) as a green solid. 1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 9.49 (t, J = 6.0 Hz, 1H), 9.33 (d, J = 2.0 Hz, 1H), 8.96 (d, J = 1.6 Hz, 1H), 8.72–8.70 (m, 1H), 8.31–8.30 (m, 1H), 7.26 (t, J = 8.0 Hz, 1H), 6.81–6.78 (m, 1H), 6.63–6.54 (m, 2H), 4.68 (d, J = 6.0 Hz, 2H). MS Calcd for C15H12FN5O: 297.10; MS Found: 298.2 [M+H]+. [0356] Synthesis of 5-fluoro-2-(((3-(1-methyl-1H-imidazol-4-yl)pyridin-2- yl)amino)methyl)phenol (28) [0357] A
Figure imgf000117_0001
7-fluoro-3-(3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)-3,4-dihydro-2H- benzo[e][1,3]oxazin-2-one (S4) (60.0 mg, 0.160 mmol), Pd(dppf)Cl2 (12.0 mg, 16.0 µmol) and K2CO3 (27 mg, 0.190 mmol) in 0.690 mL of mixed solvent (dioxane/H2O = 7/1) was stirred at 100 °C for 2 hours using microwave irradiation. Subsequently, the mixture was extracted with EtOAc and this crude compound was purified by silica gel chromatography (EtOAc in hexane = 0 ~ 50%) and by prep.HPLC to provide 5-fluoro-2-(((3-(1-methyl-1H- imidazol-4-yl)pyridin-2-yl)amino)methyl)phenol (19.8 mg, 37%). 1H NMR (400 MHz, CDCl3) δ 9.67 (brs, 1H), 8.12 (dt, J = 6.8, 1.3 Hz, 1H), 8.04 (dd, J = 5.4, 1.7 Hz, 1H), 7.81 (s, 1H), 7.75 (dd, J = 7.5, 1.7 Hz, 1H), 7.63 (dd, J = 9.1, 1.0 Hz, 1H), 7.27-7.20 (m, 2H), 6.84 (ddd, J = 6.8, 6.8, 1.2 Hz, 1H), 6.65-6.60 (m, 2H), 6.53 (ddd, J = 8.4, 8.4, 2.6 Hz, 1H), 4.58 (d, J = 5.4 Hz, 2H); 13C NMR (100 MHz, acetone-d6) δ 163.3 (d, J = 242 Hz), 158.6 (d, J = 13.5 Hz), 155.1, 145.1, 144.1, 143.2, 135.4, 132.4 (d, J = 10.5 Hz), 126.4, 125.1, 123.5 (d, J = 3.1 Hz), 116.7, 113.0, 111.7, 109.6, 105.6 (d, J = 21.5 Hz), 104.1 (d, J = 23.1 Hz), 40.6. LRMS (ESI+) calcd for C19H16FN4O ([M+H]+): 335.13; found: 335.25. [0358] Synthesis of 2-(((3-(benzo[d]thiazol-2-yl)pyridin-2-yl)amino)methyl)-5- fluorophenol (compound 29)
[0359] A mixture of 7-fluoro-3-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2- yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one (S4)(45 mg, 0.12 mmol), 2- bromobenzo[d]thiazole (13 mg, 60.7 µmol), Pd(dppf)Cl2 (1.11 mg, 1.52 µmol) and Cs2CO3 (82 mg, 0.25 mmol) in 0.23 mL of mixed solvent (dioxane/H2O = 10/1) was stirred at 130 °C for 1 hour using microwave irradiation. Subsequently, the mixture was extracted with EtOAc and this crude compound was purified by silica gel chromatography (EtOAc in hexane = 20 ~ 40%) to provide compound 29 as off-white solid (6.5 mg, 30%). 1H NMR (400 MHz, Methylene Chloride-d2 and Methanol-d4, 3:1) δ 8.28 – 8.19 (m, 1H), 8.18 – 8.12 (m, 1H), 8.09 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 7.9 Hz, 0H), 7.59 – 7.53 (m, 1H), 7.51 – 7.44 (m, 1H), 7.38 (dd, J = 8.1, 6.8 Hz, 1H), 6.82 (dd, J = 7.6, 5.4 Hz, 1H), 6.68 – 6.57 (m, 2H), 4.73 (s, 1H).13C NMR (100 MHz, Methylene Chloride-d2 and Methanol-d4, 3:1) δ 152.89, 139.90, 133.26, 131.80 (d, J = 10.0 Hz), 126.65, 125.96, 122.81, 121.41, 113.06, 111.74, 106.41 (d, J = 21.6 Hz), 104.19 (d, J = 23.7 Hz), 41.13. LC-MS (ESI) calculated for C19H14FN3OS m/z [M+H]+ =352.4, found 352.08. [0360] Synthesis of 2-(((3-(1H-benzo[d]imidazol-2-yl)pyridin-2-yl)amino)methyl)-5- fluorophenol (compound 30)
Figure imgf000118_0001
2- yl)-3,4-dihydro-2H-benzo[e][1,3]oxazin-2-one (S4) (84.5 mg, 0.23 mmol), 2-bromo-1H- benzo[d]imidazole (30 mg, 0.15 mmol), Pd(dppf)Cl2 (11.1 mg, 15.2 µmol) and Cs2CO3 (124 mg, 0.38 mmol) in 0.46 mL of mixed solvent (dioxane/H2O = 10/1) was stirred at 130 °C for 1 hour using microwave irradiation. Subsequently, the mixture was extracted with 1% MeOH in DCM and this crude compound was purified by reversed phase chromatography (Acetonitrile (0.1 % Formic acid) in water = 0 ~ 50%) to provide 2-(((3-(1H- benzo[d]imidazol-2-yl)pyridin-2-yl)amino)methyl)-5-fluorophenol as white solid (15 mg, 30%). 1H NMR (400 MHz, Methylene Chloride-d2 and Methanol-d4, 3:1) δ 8.17 – 8.10 (m, 1H), 7.66 (s, 1H), 7.36 (td, J = 7.4, 6.7, 2.1 Hz, 1H), 7.32 – 7.26 (m, 1H), 6.75 (dd, J = 7.5, 5.1 Hz, 1H), 6.62 – 6.56 (m, 1H), 4.64 (s, 1H). 13C NMR (100 MHz, Methylene Chloride-d2 and Methanol-d4, 3:1) δ 163.40 (d, J = 243.7 Hz), 157.65 (d, J = 12.2 Hz), 155.29, 149.97, 146.91, 135.72, 132.19 (d, J = 10.3 Hz), 122.81 (d, J = 3.1 Hz), 111.39, 108.93, 106.32 (d, J = 21.5 Hz), 104.47 (d, J = 23.1 Hz), 40.86. LC-MS (ESI) calculated for C19H15FN4O m/z [M+H]+ =335.35, found 335.18. [0362] Synthesis using alternative routes, for compound 3, 10, 11, 21-23, 27 [0363] The synthesis of 5-fluoro-2-(((3-(pyrimidin-4-yl)pyridin-2-yl)amino)methyl)phenol (compound 3)
Figure imgf000119_0001
, mmol) and K2CO3 (3.46 g, 25.07 mmol) in THF (80 mL) and water (40 mL) was added Pd(PPh3)4 (0.75 g, 1.03 mmol) under nitrogen atmosphere. The reaction was stirred at 85 oC for 2 hours. The mixture was concentrated and extracted with EA (80 mL) and water (30 mL). The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography using a mixture of petroleum ether-ethyl acetate (1:10 v/v) as eluent to afford 3b (900 mg, yield: 29.4%). [0365] The mixture of 3b (840 mg, 2.75 mmol), ammonium formate (1.74 g, 27.59 mmol) and Pd/C (800 mg) in MeOH (80 mL) was stirred at room temperature overnight. The mixture was filtered by silica, washed with EA (90 mL). The filtrate was concentrated and purified by silica gel chromatography using a mixture of petroleum ether-ethyl acetate (1:10 v/v) as eluent to afford 3c (533 mg, yield: 71.3%). [0366] The solution of 3c (533 mg, 1.96 mmol) and TFA (6 mL) in DCM (6 mL) was stirred at room temperature for 1h. The mixture was concentrated to give 533 mg crude product which was used for next step without purification. [0367] To a solution of 3d (350 mg, 2.03 mmol), 4-fluoro-2-hydroxybenzaldehyde (1.4 g, 9.99 mmol) in MeOH (40 mL) was added AcOH (0.1 mL). The mixture was stirred at room temperature for 4 hours. Sodium triacetoxyborohydride (2.97 g, 14.01 mmol) was added at 0oC. The mixture was stirred at room temperature overnight. Water (3.0 mL) was added. The mixture was concentrated and extracted with DCM (2×50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography using a mixture of petroleum ether-ethyl acetate (1/1 v/v) as eluent to afford compound 3 (159.5 mg, yield: 26.9%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.56 (br s, 1H), 9.73 (t, J = 5.6 Hz, 1H), 9.21 (s, 1H), 8.84 (d, J = 5.6 Hz, 1H), 8.29 (dd, J = 7.6, 2.0 Hz, 1H), 8.22 (dd, J = 4.8, 1.6 Hz, 1H), 8.11 (dd, J = 5.6, 2.0 Hz, 1H), 7.22 (dd, J = 8.4, 7.2 Hz, 1H), 6.74-6.71 (m, 1H), 6.62-6.53 (m, 2H), 4.62 (d, J = 6.0 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 163.4, 162.3 (d, J = 242.4 Hz), 157.8, 157.5, 157.2 (d, J = 11.1 Hz), 156.8, 151.2, 138.4, 130.5 (d, J = 10.3 Hz), 123.0 (d, J = 2.8 Hz), 118.3, 112.6, 112.2, 105.6 (d, J = 21.2 Hz), 103.0 (d, J = 24.2 Hz), 39.9. MS Calcd for C16H13FN4O: 296.11; MS Found: 297.2 [M+H]+. [0368] Synthesis of 5-fluoro-2-(((3-(oxazol-4-yl)pyridin-2-yl)amino)methyl)phenol (compound 10)
[0369] To a solution of 10a (10 g, 30.95 mmol) and tributyl(1-ethoxyvinyl)stannane (10.2 g, 28.1 mmol) in toluene (80 mL) and was added Pd(PPh3)4 (3.6 g, 3.10 mmol) under nitrogen atmosphere. The reaction was stirred at 110 oC for 16 hours. The mixture was cooled to rt. Saturated KF solution (100 mL) was added. The mixture was stirred at room temperature overnight and extracted with EtOAc (200 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography using a mixture of petroleum ether- ethyl acetate (1:1 v/v) as eluent to afford 10a (10 g, yield: 91%). [0370] To a solution of 10b (4.5 g, 14.33 mmol) in dioxane/H2O (50 mL/15 mL) was added NBS (3.06 g, 17.2 mmol) at 0 oC. The mixture was stirred at room temperature for 2 hours. The mixture was extracted with EtOAc (90 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography using a mixture of petroleum ether-ethyl acetate (3:1 v/v) as eluent to afford 10c (1.5 g, yield: 28.8%). [0371] The mixture of 10c (400 mg, 1.10 mmol) and formamide (10 mL) was stirred was stirred at 110 oC in microwave for 4 hours under N2. The mixture was extracted with EtOAc (60 mL). The organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography using a mixture of petroleum ether-ethyl acetate (5:1 v/v) as eluent to afford compound 10 (33 mg, yield: 28.8%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.75 (br s, 1H), 8.66 (s, 1H), 8.62 (s, 1H), 8.04 (dd, J = 5.2, 2.0 Hz, 1H), 7.87-7.84 (m, 2H), 7.23 (t, J = 8.0Hz, 1H), 6.67-6.64 (m, 1H), 6.61-6.53 (m, 2H), 4.52 (d, J = 6.0 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 162.4 (d, J = 242.2 Hz), 157.4 (d, J = 11.7 Hz), 155.8, 152.6, 147.4, 137.4, 136.7, 135.7, 131.0 (d, J = 10.3 Hz), 123.2 (d, J = 2.1 Hz), 112.3, 109.9, 105.7 (d, J = 21.2 Hz), 103.1 (d, J = 23.7 Hz), 40.0. MS Calcd for C15H12FN3O2: 285.09; MS Found: 286.2 [M+H]+. [0372] Synthesis of 5-fluoro-2-(((3-(isoxazol-3-yl)pyridin-2-yl)amino)methyl)phenol (compound 11)
78 mmol) in EtOH/H2O (70 mL/70 mL) was added the solution of NaOH (6.8 g, 170 mmol) in H2O (70 mL) under nitrogen atmosphere at 0 oC. After 10 min, the reaction was allowed to warm to room temperature and keep stirring for 1 h. The mixture was neutralized to pH = 7 with 6N aqueous HCl. The product 11b (9.7 g, yield: 87%) was obtained by filtration, washed with water and dried in vacuo. [0374] To a solution of 11b (5 g, 31.8 mmol) and ethynyltrimethylsilane (31.2 g, 318 mmol) in CH3CN (100 mL) was added CrO3 (26.7 g, 318 mmol) under nitrogen atmosphere. The reaction was stirred at 80 oC for 48 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo, and the crude product was purified by silica gel chromatography using a mixture of petroleum ether-ethyl acetate (95:5 v/v) as eluent to afford 11c (3.43 g, yield: 43%). [0375] To a solution of 11c (3.4 g, 13.43 mmol) in MeOH (100 mL) was added K2CO3 (5.56 g, 40.3 mmol) under nitrogen atmosphere. The reaction was stirred for 1 h at room temperature. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography using a mixture of petroleum ether-ethyl acetate (95:5 v/v) as eluent to afford 11d (1.40 g, yield: 58%). [0376] A mixture of 11d (400 mg, 2.2 mmol) and BnNH2 (7.2 mL) was stirred at 180 oC for 2 h under nitrogen atmosphere in a sealed tube. EtOAc (200 mL) was added to the mixture, and then was removed under reduced pressure. The residue was purified by silica gel chromatography using a mixture of petroleum ether-ethyl acetate (92:8 v/v) as eluent to afford 11e (500 mg, yield: 68%). [0377] To a solution 11e (1 g, 3.97 mmol) in CH3CN (30 mL) and H2O (6 mL) was added diammonium cerium(IV) nitrate (4.34 g, 7.94 mmol) at 0 oC under nitrogen atmosphere. The reaction was stirred at room temperature for 16 h and quenched with aqueous Na2CO3. The mixture was extracted with EtOAc (3×50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography using a mixture of petroleum ether-ethyl acetate (75:25 v/v) as eluent to afford 11f (590 mg, yield: 92%). [0378] To a solution of 11f (200 mg, 1.24 mmol) and 4-fluoro-2-hydroxybenzaldehyde (1.04 g, 7.45 mmol) in EtOH (20 mL) was added AcOH (2 drops) under nitrogen atmosphere. The mixture was stirred at 60 oC for 16 h. Subsequently, the mixture was cooled to 0 oC, and NaBH3CN (547 mg, 8.68 mmol) was added. After stirring for 10 min, the reaction was heated to 60 oC and stirred for 4 h. After addition of aqueous K2CO3 (15 mL), the mixture was extracted with EtOAc by three times. The organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography using a mixture of petroleum ether-ethyl acetate (92:8 v/v) as eluent to afford crude product. Further purification was carried out in the means of silica gel chromatography using a mixture of petroleum ether-CH2Cl2 (66:34 v/v) as eluent to afford ELG-000027 (100 mg, yield: 28%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 10.53 (s, 1H), 9.03 (s, 1H), 8.20–8.18 (m, 1H), 8.12–8.10 (m, 1H), 7.91–7.88 (m, 1H), 7.31 (d, J = 4.0 Hz, 1H), 7.26–7.22 (m, 1H), 6.75 (dd, J = 8.0, 4.0 Hz, 1H), 6.62–6.53 (m, 2H), 4.62 (d, J = 4.0 Hz, 1H13C NMR (101 MHz, DMSO-d6) δ 162.4 (d, J = 242.4 Hz), 161.2, 160.7, 159.9, 157.3 (d, J = 10.1 Hz), 155.0, 149.6, 138.5, 131.0 (d, J = 10.3 Hz), 122.8 (d, J = 2.8 Hz), 112.2, 107.0, 105.7 (d, J = 21.2 Hz), 103.0 (d, J = 24.2 Hz), 102.8, 40.2. MS Calcd for C15H12FN3O2: 285.09. MS Found: 286.2 [M+H]+. [0379] Synthesis of 2-(((3-(1,2,4-oxadiazol-3-yl)pyridin-2-yl)amino)methyl)-5- fluorophenol (compound 21)
[0380] . , . , 2- aminonicotinonitrile (5.3 g, 37.8 mmol) in toluene (100 mL) was added camphor-10-sulfonic acid (0.9 g, 3.78 mmol). A Dean–Stark apparatus was equipped, and mixture was refluxed until LCMS showed 3-bromopyridin-2-amine was consumed completely. After the water was removed completely, the reaction mixture was cooled to 0 oC and NaBH4 (3.39 g, 89.3 mmol) was added in portions. Subsequently, the reaction was allowed to stir at room temperature overnight. Water (100 mL) was added and the mixture was extracted with DCM (200 mL). The organic layer was separated. The aqueous layer was extracted with DCM (2×50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography using a mixture of petroleum ether-ethyl acetate (90:10 to 80:20 v/v) as eluent to afford 21a (4.00 g, yield: 65%). [0381] To a solution of 21a (400 mg, 1.65 mmol) and Na2CO3 (520 mg, 4.95 mmol) in EtOH (10 mL) was added hydroxylamine hydrochloride (34.2 mg, 4.95 mmol). The reaction was stirred at 80 oC for 2 hour. The reaction was concentrated in vacuo, and the residual was purified by silica gel chromatography using a mixture of petroleum ether-ethyl acetate (90:10 to 80:20 v/v) as eluent to afford 21b (280 mg, yield: 62%). [0382] To a solution of 21b (276 mg, 1.0 mmol) in triethyl orthoformate (10 mL) was added TEA (0.1 mL). The reaction mixture was stirred at 80 oC for 4 h. The reaction mixture was purified by silica gel chromatography using a mixture of petroleum ether-ethyl acetate (100:0 to 75:25 v/v) as eluent to afford crude product, and further purification by using prep- HPLC gave compound 21 (60 mg, yield: 21%) as a white solid. 1H NMR (400 MHz, DMSO- d6) δ 10.44 (s, 1H), 9.75 (s, 1H), 8.32–8.29 (m, 2H), 7.58–7.56 (m, 1H), 7.25–7.23 (m, 1H), 6.81–6.78 (m, 1H), 6.64–6.56 (m, 2H), 4.65 (d, J = 4.0 Hz, 2H). 13C NMR (101 MHz, DMSO-d6) δ 166.6, 165.8, 162.4 (d, J = 242.8 Hz), 157.3 (d, J = 11.1 Hz), 155.3, 151.5, 138.7, 130.8 (d, J = 10.3 Hz), 122.5 (d, J = 2.8 Hz), 112.5, 105.7 (d, J = 21.1 Hz), 104.6, 102.9 (d, J = 23.7 Hz), 40.3. MS Calcd for C14H11FN4O2: 286.09; MS Found: 287.1 [M+H]+. [0383] Synthesis of 2-(((3-ethynylpyridin-2-yl)((2- (trimethylsilyl)ethoxy)methyl)amino)methyl)-5-fluorophenol (compound 22)
Figure imgf000125_0001
, mmol) and Et3N (470 mg, 4.65 mmol) in dry DMA (5 mL) was added Pd(dppf)Cl2 (113 mg, 0.155 mmol) under nitrogen atmosphere. The reaction was stirred at 100 oC with microwave for 1 hour. The mixture was added K2CO3 and MeOH (10 mL) and then stirred at room temperature for 1 hour. The reaction was quenched with water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography using a mixture of petroleum ether-ethyl acetate (90:10 to 85:15 v/v) as eluent to afford 22a. [0385] To a solution of 22a (800 mg, 3.3 mmol) in dry THF (10 mL) was added NaH (422 mg, 10.56 mmol) at 0 oC under nitrogen atmosphere. After 5 min, SEMCl (823 mg, 4.96 mmol) was added. The reaction was stirred for 30 min at room temperature. The mixture was quenched with saturated NH4Cl and extracted with EtOAc (3×20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography using a mixture of petroleum ether-ethyl acetate (90:10 v/v) as eluent to afford 22b (220 mg, yield: 18%). [0386] To a solution of 22b (200 mg, 0.54 mmol) and NaN3 (70.2 mg, 10.8 mmol) in DMA (5 mL) was added CuI (10 mg, 0.054 mmol) under nitrogen atmosphere. The reaction was stirred for 3 hours at 100 oC with microwave. After cooling to room temperature, the mixture was concentrated to dryness in vacuo. The residue was purified by silica gel chromatography using a mixture of petroleum ether-ethyl acetate (75:25 v/v) as eluent to afford 22c (200 mg, yield: 89%). [0387] To a solution of 22c (180 mg, 0.434 mmol) in EtOH (80%) was added conc. HCl (2 mL). The reaction was stirred at 80 oC for 16 hours. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc (3×30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was obtained through purification by using silica gel chromatography with a mixture of petroleum ether-ethyl acetate (75:25 v/v) as eluent. Further purification was carried out in the means of prep-HPLC to afford compound 22 (12 mg, yield: 9.7%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (br s, 1H), 8.06–8.05 (m, 2H), 7.26–7.23 (m, 1H), 6.69 (dd, J = 8.0, 4.0 Hz, 1H), 6.61–6.53 (m, 2H), 4.56 (s, 2H). MS Calcd for C14H12FN5O: 285.10; MS Found: 286.2 [M+H]+. [0388] Synthesis of 2-(((3-(2H-tetrazol-5-yl)pyridin-2-yl)amino)methyl)-5-fluorophenol (compound 23)
Figure imgf000126_0001
[0389] NaN3 mg, was to mg, 1.65 mmol) in DMF. The reaction was stirred at 120 oC for 16 hours. Saturated NaHCO3 was added and the mixture was extracted with EtOAc (10 mL×3). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo, the crude product was purified by silica gel chromatography (EtOAc in PE = 25 - 100%) to provide product (compound 23, 52 mg, yield: 11%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.5 (br, 1H), 8.26 (dd, J = 8.0, 4.0 Hz, 1H), 8.18 (d, J = 4.0 Hz, 1H), 7.26 (t, J = 8.0 Hz, 1H), 6.81 (dd, J = 8.0, 4.0 Hz, 1H), 6.82 - 6.57 (m, 2H), 4.64 (s, 2H). MS (ESI+, m/z): Calcd for C13H11FN6O: 286.1; found 287.3 [M+H]+. [0390] Synthesis of 5-fluoro-2-(((3-(furan-2-yl)pyridin-2-yl)amino)methyl)phenol (compound 27)
Figure imgf000127_0001
4,4,5,5-tetramethyl-1,3,2-dioxaborolane (500 mg, 2.58 mmol) and K2CO3 (712 mg, 5.16 mmol) in dioxane (5 mL) and H2O (0.5 mL) was added Pd(dppf)Cl2 (189 mg, 0.258 mmol) under nitrogen atmosphere. The reaction was stirred at 120 oC with microwave for 1 hours. The mixture was partitioned between DCM (10 mL) and water (10 mL). The organic layer was separated. The aqueous layer was extracted with DCM (2×10 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography using a mixture of petroleum ether-ethyl acetate (100:0 to 90:10 v/v) as eluent to afford 27a (400 mg, yield: 97%). [0392] To a solution of 27a (288 mg, 2.06 mmol), 4-fluoro-2-hydroxybenzaldehyde (220 mg, 1.37 mmol) and AcOH (107 mg, 1.79 mmol) in MeOH (10 mL) was added borane 2- methylpyridine (190 mg, 1.79 mmol) under nitrogen atmosphere. The reaction was stirred at 60 oC overnight. The reaction mixture was quenched with saturated NaHCO3 (10 mL), and the mixture was extracted with EtOAc (3×15 mL). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography using a mixture of petroleum ether-ethyl acetate (100:0 to 90:10 v/v) as eluent to afford crude product. Further purification was performed by using prep-HPLC to afford compound 27 (60 mg, 15%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.30 (s, 1H), 8.06–8.05 (m, 1H), 7.67–8.05 (m, 1H), 7.55– 7.54 (m, 1H), 7.19–7.15 (m, 1H), 6.70–6.52 (m, 6H), 4.51 (d, J = 4.0 Hz, 2H).13C NMR (101 MHz, DMSO-d6) δ 162.4 (d, J = 242.3 Hz), 157.4 (d, J = 11.4 Hz), 153.7, 150.5, 146.8, 143.2, 135.4, 130.9 (d, J = 10.3 Hz), 123.3 (d, J = 2.7 Hz), 112.7, 112.3, 111.3, 108.3, 105.6 (d, J = 21.0 Hz), 103.2 (d, J = 23.5 Hz), 40.5. MS Calcd for C16H13FN2O2: 284.10; MS Found: 285.2 [M+H]+. Example 3: Biophysical data [0393] Table 1. Measured and predicted binding affinities of compounds 1-30 for procaspase-6.
Figure imgf000128_0001
Compound ID Ring A ΔG E_int M SD l)
Figure imgf000128_0002
Compound ID Ring A Average KD ΔG E_int (µM) SD (kcal/mol) (kcal/mol)
Figure imgf000129_0001
Compound ID Ring A Average KD ΔG E_int (µM) SD (kcal/mol) (kcal/mol)
Figure imgf000130_0001
REFERENCES [0394] 1. Murray, J.; Giannetti, A. M.; Steffek, M.; Gibbons, P.; Hearn, B. R.; Cohen, F.; Tam, C.; Pozniak, C.; Bravo, B.; Lewcock, J.; Jaishankar, P.; Ly, C. Q.; Zhao, X.; Tang, Y.; Chugha, P.; Arkin, M. R.; Flygare, J.; Renslo, A. R. ChemMedChem 2014, 9, 73-77. 2. Ehrnhoefer, D. E. et al. Cell Chem. Biol.2019, 26, 1295-1305. 3. Zhao, P. et al. Science 2020, 367, 652-660. 4. Chu, H. et al. Nature 2022, 609, 785-792.

Claims

WHAT IS CLAIMED IS: 1. A compound, or a pharmaceutically acceptable salt thereof, having the formula: ;
Figure imgf000132_0001
a or unsubstituted 5 to 6 membered heteroaryl or substituted or unsubstituted 8 to 10 membered fused ring heteroaryl; L1 is a bond or substituted or unsubstituted C1-C3 alkylene; R1 is independently halogen, -CX1 3, -CHX1 2, -CH2X1, -OCX1 3, -OCH2X1, -OCHX12, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -B(OR1C)(OR1D), -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A, R1B, R1C, and R1D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -
Figure imgf000132_0002
-CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1 is independently –F, -Cl, -Br, or –I; n1 is an integer from 0 to 4; m1 and v1 are independently 1 or 2; and z1 is an integer from 0 to 5; wherein Ring A is not a substituted or unsubstituted pyrimidinyl. 2. The compound of claim 1, wherein Ring A is a substituted or unsubstituted nitrogen-containing 5 to 6 membered heteroaryl or substituted or unsubstituted nitrogen-containing 8 to 10 membered fused ring heteroaryl. 3. The compound of claim 1, wherein Ring A is substituted or unsubstituted pyridyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted triazinyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isoxazolyl, substituted or unsubstituted furanyl, substituted or unsubstituted thienyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted isothiazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted tetrazolyl, substituted or unsubstituted imidazopyridinyl, substituted or unsubstituted benzothiazolyl, or substituted or unsubstituted benzoimidazolyl. 4. The compound of claim 1, wherein Ring A is N N N H, -NHC(O)OH, -NHOH, -OCCl3, -OCBr3, -OCF3, -OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and z2 is an integer from 0 to 5. 5. The compound of claim 4, wherein R2 is independently unsubstituted C1-C4 alkyl. 6. The compound of claim 4, wherein R2 is independently unsubstituted methyl. 7. The compound of claim 4, wherein z2 is 0. 8. The compound of claim 4, wherein z2 is 1. 9. The compound of claim 1, wherein Ring A is ,
-OCI3, -OCH2Cl, -OCH2Br, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -B(OH)2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 11. The compound of claim 1, wherein R1 is independently halogen or -OR1D. 12. The compound of claim 11, wherein R1D is independently hydrogen or unsubstituted C1-C4 alkyl. 13. The compound of claim 11, wherein R1D is hydrogen. 14. The compound of claim 1, wherein R1 is independently –F or -OH. 15. The compound of claim 1, wherein z1 is 1. 16. The compound of claim 1, wherein z1 is 2. 17. A compound, or a pharmaceutically acceptable salt thereof, having the formula: ;
Figure imgf000135_0001
Ring B is a substituted or unsubstituted pyrimidinyl; L1 is a bond or substituted or unsubstituted C1-C3 alkylene; R1.1, R1.2, R1.3, R1.4, and R1.5 are independently hydrogen, halogen, -CX13, -CHX1 2, -CH2X1, -OCX1 3, -OCH2X1, -OCHX1 2, -CN, -SOn1R1D, -SOv1NR1AR1B, ^NR1CNR1AR1B, ^ONR1AR1B, -NR1CC(O)NR1AR1B, -N(O)m1, -NR1AR1B, -C(O)R1C, -C(O)OR1C, -OC(O)R1C, -OC(O)OR1C, -C(O)NR1AR1B, -OC(O)NR1AR1B, -OR1D, -SR1D, -NR1ASO2R1D, -NR1AC(O)R1C, -NR1AC(O)OR1C, -NR1AOR1C, -B(OR1C)(OR1D), -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each R1A, R1B, R1C, and R1D are independently hydrogen, -CCl3, -CBr3, -CF3, -CI3, -CHCl2, -CHBr2, -CHF2, -CHI2, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CN, -OH, -NH2, -COOH, -CONH2, -OCCl3, -OCF3, -OCBr3, -OCI3, -OCHCl2, -OCHBr2, -OCHI2, -OCHF2, -OCH2Cl, -OCH2Br, -OCH2I, -OCH2F, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R1A and R1B substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; each X1 is independently –F, -Cl, -Br, or –I; each n1 is an integer from 0 to 4; and each m1 and v1 are independently 1 or 2; wherein: (i) R1.1 and R1.5 are not –OH; or (ii) wherein if R1.1 or R1.5 is –OH, then Ring B is not substituted or unsubstituted 2-pyrimidinyl or unsubstituted 5-pyrimidinyl; or (iii) wherein if Ring B is 5-pyrimidinyl, then the Ring B 5-pyrimidinyl is substituted. 18. The compound of claim 17, wherein Ring B is N (R 2 )z2 ; wherein
Figure imgf000136_0001
-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, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; and z2 is an integer from 0 to 3.
19. The compound of claim 18, wherein R2 is independently –NH2 or unsubstituted C1-C4 alkyl. 20. The compound of claim 18, wherein R2 is independently –NH2 or unsubstituted methyl. 21. The compound of claim 18, wherein z2 is 0. 22. The compound of claim 18, wherein z2 is 1. 23. The compound of claim 17, wherein Ring B is or
Figure imgf000137_0001
and R1.5 are independently hydrogen, halogen, -CCl3, -CBr3, -CF3, -CI3, -CH2Cl, -CH2Br, -CH2F, -CH2I, -CHCl2, -CHBr2, -CHF2, -CHI2, -CN, -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, -OCH2F, -OCH2I, -OCHCl2, -OCHBr2, -OCHF2, -OCHI2, -B(OH)2, -SF5, -N3, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 25. The compound of claim 17, wherein R1.1 is -OH. 26. The compound of claim 17, wherein R1.3 is halogen. 27. The compound of claim 17, wherein R1.3 is -F. 28. The compound of claim 17, wherein R1.2, R1.4, and R1.5 are hydrogen. 29. The compound of claim 1, wherein L1 is unsubstituted C1-C3 alkylene.
30. The compound of claim 1, wherein L1 is unsubstituted methylene. 31. A pharmaceutical composition comprising a compound of one of claims 1 to 30, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 32. A method of treating a neurodegenerative disease in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of claims 1 to 30, or a pharmaceutically acceptable salt thereof. 33. The method of claim 32, wherein the neurodegenerative disease is a tauopathy. 34. The method of claim 32, wherein the neurodegenerative disease is Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, Lewy body disease, progressive supranuclear palsy, or Parkinson’s disease. 35. The method of claim 32, wherein the neurodegenerative disease is Alzheimer’s disease. 36. A method of treating a liver disease in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of claims 1 to 30, or a pharmaceutically acceptable salt thereof. 37. The method of claim 36, wherein the liver disease is nonalcoholic steatohepatitis. 38. A method of treating a fibrotic disease in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of claims 1 to 30, or a pharmaceutically acceptable salt thereof. 39. A method of treating a coronavirus infection in a subject in need thereof, said method comprising administering to the subject in need thereof a therapeutically effective amount of a compound of one of claims 1 to 30, or a pharmaceutically acceptable salt thereof.
40. A method of reducing the level of activity of caspase-6 protein in a cell, said method comprising contacting the cell with an effective amount of a compound of one of claims 1 to 30, or a pharmaceutically acceptable salt thereof. 41. A method of reducing the level of activation of procaspase-6 protein in a cell, said method comprising contacting the cell with an effective amount of a compound of one of claims 1 to 30, or a pharmaceutically acceptable salt thereof.
PCT/US2023/083886 2022-12-14 2023-12-13 Inhibitors of procaspase-6 activation and uses thereof WO2024129892A2 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202263432557P 2022-12-14 2022-12-14
US63/432,557 2022-12-14

Publications (1)

Publication Number Publication Date
WO2024129892A2 true WO2024129892A2 (en) 2024-06-20

Family

ID=91485834

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2023/083886 WO2024129892A2 (en) 2022-12-14 2023-12-13 Inhibitors of procaspase-6 activation and uses thereof

Country Status (1)

Country Link
WO (1) WO2024129892A2 (en)

Similar Documents

Publication Publication Date Title
EP3534899B1 (en) Compounds and methods for modulating interleukin-2-inducible t-cell kinase
EP3426637B1 (en) Compounds and methods for modulating bruton's tyrosine kinase
US10980755B2 (en) LRH-1 modulators
EP3055290B1 (en) Inhibitors of kras g12c
KR20150014452A (en) Compounds and compositions for inhibiting the activity of abl1, abl2 and bcr-abl1
US11124483B2 (en) HER3 ligands and uses thereof
WO2017091616A1 (en) Platinum anticancer agents
AU2012335409A1 (en) 5-(pyridin-2-yl-amino)-pyrazine-2-carbonitrile compounds and their therapeutic use
US20200345804A1 (en) Novel agents targeting inhibitor of apoptosis proteins
WO2024129892A2 (en) Inhibitors of procaspase-6 activation and uses thereof
WO2016022839A1 (en) Modulators of ire1
WO2024129896A1 (en) Inhibitors of procaspase-6 activation and uses thereof
US11046670B2 (en) Piperazinyl norbenzomorphan compounds and methods for using the same
WO2024016000A2 (en) Eif4a inhibitors and uses thereof
WO2023023156A1 (en) Acid ceramidase inhibitors and uses thereof
WO2023114759A2 (en) Abl inhibitors and uses thereof
WO2024076635A2 (en) Suppressors of site iq electron leak and uses thereof
WO2023060039A1 (en) Inhibitors of alpha-5 beta-1 integrin and uses thereof
WO2019040511A1 (en) Dual inhibitors of the bcl-2 and hdm2 families through co-mimicry of the bh3 and p53-alpha-helices
WO2017210559A1 (en) Compounds and methods for treating fibrosis or cancer
WO2023141635A2 (en) Her3 ligands and uses thereof
US11786528B2 (en) Pyrazolopyrimidine compounds as adenosine receptor antagonists
EP4380560A1 (en) Lpar1 antagonists and uses thereof
WO2023014907A1 (en) Lpar1 antagonists and uses thereof
EP4308110A1 (en) Compounds targeting fibroblast-activation protein and methods of use thereof