WO2025188508A1 - E3 ligase and bex inhibitors and methods of use thereof - Google Patents

E3 ligase and bex inhibitors and methods of use thereof

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Publication number
WO2025188508A1
WO2025188508A1 PCT/US2025/017209 US2025017209W WO2025188508A1 WO 2025188508 A1 WO2025188508 A1 WO 2025188508A1 US 2025017209 W US2025017209 W US 2025017209W WO 2025188508 A1 WO2025188508 A1 WO 2025188508A1
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WIPO (PCT)
Prior art keywords
substituted
alkyl
heteroaryl
heterocycloalkyl
cycloalkyl
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
PCT/US2025/017209
Other languages
French (fr)
Other versions
WO2025188508A8 (en
Inventor
Julia S. SCHALETZKY
Michael RAPE
Andrew G. MANFORD
Edward E. WEHRI
Srividya CHANDRASEKHAR
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of California Berkeley
University of California San Diego UCSD
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University of California Berkeley
University of California San Diego UCSD
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Application filed by University of California Berkeley, University of California San Diego UCSD filed Critical University of California Berkeley
Publication of WO2025188508A1 publication Critical patent/WO2025188508A1/en
Publication of WO2025188508A8 publication Critical patent/WO2025188508A8/en
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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    • C07D513/14—Ortho-condensed systems

Definitions

  • E3 ubiquitin ligases are a family of enzymes that play an essential role in ubiquitination of various substrates. E3 ligases confer substrate specificity for ubiquitination, and thus are attractive therapeutic targets due to their specificity for certain protein substrates.
  • Femlb is an E3 ligase implicated in the regulation of mitochondrial function and is involved in the system that senses redox balance within the cell. Femlb is sequestered and inhibited by a pseudosubstrate inhibitor Bex (brain expressed and X-linked protein). In the absence of the pseudosubstrate inhibitor Bex, Femlb can bind to and degrade the substrate Fnipl. Degradation of Fnipl leads to increased import of factors for oxidative phosphorylation into the mitochondria, thus leading to further downstream effects such as altering mitochondrial function.
  • Bex a pseudosubstrate inhibitor
  • compositions and drug delivery devices comprising a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a compound depicted in Fig. 1.
  • Methods are provided for inhibiting the binding of Bex to an E3 ligase in a cell, involving contacting the cell with a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a compound depicted in Fig. 1 to inhibit the binding of Bex to an E3 ligase.
  • the present disclosure provides various treatment methods involving administration of such compounds.
  • Aspects of the present disclosure include compositions comprising: al) a compound of formula (I): wherein:
  • R 1 , R 2 , R 3 , R 4 , R s , R 6 , R 7 and R 8 are each independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and bl) a pharmaceutically acceptable excipient; or a2) a compound depicted in FIG. 1; and b2) a pharmaceutically acceptable excipient.
  • R 1 , R 2 , R 3 , R 4 and R 5 of the compound of formula (I) are independently selected from H, alkyl, alkoxy and halo.
  • R 8 of the compound of formula (I) is H.
  • R 6 and R 7 of the compound of formula (I) are independently selected from H, alkyl, substituted alkyl, amino, substituted amino, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl.
  • R 6 and R 7 of the compound of formula (I) are independently selected from H and -NR 9 R 10 , wherein R 9 and R 10 are independently selected from H, alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl, or R 9 and R 10 together with the N to which they are attached form a cycloalkyl or substituted cycloalkyl.
  • the compound is selected from:
  • compositions comprising: a compound of formula (II): wherein:
  • R a is selected from H, alkyl, and substituted alkyl
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
  • R 1 , R 2 , R 3 , R 4 and R 5 of the compound of formula (II) are each independently selected from H, halo and alkyl.
  • the compound is selected from:
  • compositions comprising: a compound of formula (III): wherein:
  • R a is selected from H, halo, alkyl, and substituted alkyl
  • R 6 , R 7 and R 8 are each independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
  • the compound is:
  • compositions comprising: a compound of formula (IV): wherein:
  • R 1 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
  • R 2 and R 3 are each independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl and substituted alkenyl; and a pharmaceutically acceptable excipient.
  • R 2 of the compound of formula (IV) is nitro or halo.
  • R 3 of the compound of formula (IV) is halo.
  • the compound is selected from: [0017] Aspects of the present disclosure include compositions comprising: a compound of formula (V): wherein:
  • R 1 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
  • R 2 and R 3 are each independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R 2 and R 3 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl; and a pharmaceutically acceptable excipient.
  • R 1 of the compound of formula (V) is selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl and substituted heterocycloalkyl.
  • R 2 and R 3 of the compound of formula (V) are independently selected from H, alkyl and substituted alkyl.
  • R 2 and R 3 of the compound of formula (V) together with the N to which they are attached form a heterocycloalkyl or substituted heterocycloalkyl.
  • the compound is selected from:
  • compositions comprising: a compound of formula (VI): wherein:
  • R 1 and R 2 are independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
  • the compound is selected from:
  • compositions comprising: a compound of formula (VII): wherein:
  • R 1 and R 2 are each independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R 1 and R 2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl; and a pharmaceutically acceptable excipient.
  • the compound is selected from:
  • compositions comprising: a compound of formula (VIII): wherein:
  • R 1 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
  • the compound is:
  • compositions comprising: a compound of formula (IX): wherein:
  • R 1 and R 2 are each independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R 1 and R 2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl; and a pharmaceutically acceptable excipient.
  • the compound is:
  • compositions comprising: a compound of formula (X):
  • R 1 and R 2 are each independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R 1 and R 2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl;
  • R 3 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
  • the compound is:
  • compositions wherein the composition is sterile.
  • aspects of the present disclosure include a drug delivery device comprising the composition.
  • the drug delivery device comprises a syringe comprising the composition.
  • the drug delivery device comprises a pump.
  • aspects of the present disclosure include a method of inhibiting the binding of
  • Bex to an E3 ligase a cell comprising contacting the cell with the compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a compound depicted in Fig. 1 to inhibit the binding of Bex to an E3 ligase.
  • the contacting causes activation of the E3 ligase.
  • the E3 ligase is Femlb.
  • aspects of the present disclosure include a method for treating mitochondrial dysfunction in a subject, the method comprising: administering an effective amount of a composition of the present disclosure to treat the subject for mitochondrial dysfunction.
  • the administering causes mitochondrial activation.
  • the compound is administered orally, intraperitoneally, intramuscularly, or intravenously.
  • the subject has a neurodegenerative disease.
  • the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, amytrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, and neuronopathic Gaucher's disease.
  • the subject has a cardiovascular disease.
  • the cardiovascular disease is selected from the group consisting of atherosclerosis, cardiac ischemia reperfusion, stroke, and hypertrophic cardiomyopathy.
  • the subject has a metabolic disease.
  • the metabolic disease is diabetes.
  • the metabolic disease is type 2 diabetes.
  • the subject has a body mass index greater than 30 kg/m 2 .
  • FIG. 1 provides the structures of exemplary compounds, according to embodiments of the present disclosure.
  • FIG. 2 provides the structures of exemplary compounds and EC50 values for the compounds, according to embodiments of the present disclosure.
  • C7-C12 alkyl describes an alkyl group, as defined below, having a total of 7 to 12 carbon atoms
  • C4-C12 cycloalkylalkyl describes a cycloalkylalkyl group, as defined below, having a total of 4 to 12 carbon atoms.
  • the total number of carbons in the shorthand notation does not include carbons that may exist in substituents of the group described.
  • Amino refers to the — NH2 radical.
  • Cyano refers to the — CN radical.
  • Niro refers to the — NO2 radical.
  • Trifluoromethyl refers to the — CF3 radical.
  • Alkyl refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and such as 1 to 6 carbon atoms, or 1 to 5, or 1 to 4, or 1 to 3 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CHshCH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH 3 ) 2 CHCH2-), sec-butyl ((CH 3 )(CH 3 CH2)CH-), t-butyl ((CH 3 ) 3 C-), n- pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH 3 ) 3 CCH 2 -).
  • substituted alkyl refers to an alkyl group as defined herein wherein one or more carbon atoms in the alkyl chain (except the Ci carbon atom) have been optionally replaced with a heteroatom such as -O-, -N-, -S(O) n - (where n is 0 to 2), -NR- (where R is hydrogen or alkyl) and having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy
  • Alkylene refers to divalent aliphatic hydrocarbyl groups preferably having from 1 to 6 and more preferably 1 to 3 carbon atoms that are either straight-chained or branched, and which are optionally interrupted with one or more groups selected from -O-, - NR 10 -, -NR 10 C(O)-, -C(O)NR 10 - and the like.
  • This term includes, by way of example, methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), iso-propylene (-CH2CH(CH3)-), (-C(CH 3 ) 2 CH 2 CH 2 -), (-C(CH 3 ) 2 CH 2 C(O)-), (-C(CH 3 ) 2 CH 2 C(O)NH-), (-CH(CH 3 )CH 2 -), and the like.
  • “Substituted alkylene” refers to an alkylene group having from 1 to 3 hydrogens replaced with substituents as described for carbons in the definition of "substituted” below.
  • alkane refers to alkyl group and alkylene group, as defined herein.
  • alkylaminoalkyl refers to the groups R'NHR"- where R' is alkyl group as defined herein and R" is alkylene, alkenylene or alkynylene group as defined herein.
  • alkaryl or "aralkyl” refers to the groups -alkylene-aryl and -substituted alkylene-aryl where alkylene, substituted alkylene and aryl are defined herein.
  • Alkoxy refers to the group -O-alkyl, wherein alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, secbutoxy, n-pentoxy, and the like.
  • alkoxy also refers to the groups alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and alkynyl-O-, where alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein.
  • substituted alkoxy refers to the groups substituted alkyl-O-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O- where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl are as defined herein.
  • alkoxyamino refers to the group -NH-alkoxy, wherein alkoxy is defined herein.
  • haloalkoxy refers to the groups alkyl-O- wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group and include, by way of examples, groups such as trifluoromethoxy, and the like.
  • haloalkyl refers to a substituted alkyl group as described above, wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group.
  • groups include, without limitation, fluoroalkyl groups, such as trifluoromethyl, difluoromethyl, trifluoroethyl and the like.
  • alkylalkoxy refers to the groups -alkylene-O-alkyl, alkylene-O- substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene-O-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.
  • alkylthioalkoxy refers to the group -a Iky lene-S-a I kyl, alkylene-S- substituted alkyl, substituted a Ikylene-S-a Ikyl and substituted alkylene-S-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.
  • Alkenyl refers to straight chain or branched hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and having at least 1 and preferably from 1 to 2 sites of double bond unsaturation. This term includes, by way of example, bi-vinyl, allyl, and but-3-en-l-yl. Included within this term are the cis and trans isomers or mixtures of these isomers.
  • substituted alkenyl refers to an alkenyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxy
  • Alkynyl refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of triple bond unsaturation. Examples of such alkynyl groups include acetylenyl (-C CH), and propargyl (-CH2C CH).
  • substituted alkynyl refers to an alkynyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, al
  • Alkynyloxy refers to the group -O-alkynyl, wherein alkynyl is as defined herein. Alkynyloxy includes, by way of example, ethynyloxy, propynyloxy, and the like.
  • Acyl refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl- C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclyl-C(O)-, and substituted heterocyclyl-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkenyl-C
  • Acylamino refers to the groups -NR 20 C(O)alkyl, -NR 20 C(O)substituted alkyl, N R 20 C(O)cycloalkyl, -NR 20 C(O)substituted cycloalkyl, -NR 20 C(O)cycloalkenyl, -NR 20 C(O)substituted cycloalkenyl, -NR 20 C(O)alkenyl, -NR 20 C(O)substituted alkenyl, -NR 20 C(O)alkynyl, - NR 20 C(O)substituted alkynyl, -NR 20 C(O)aryl, -NR 20 C(O)substituted aryl, -NR 20 C(O)heteroaryl, -NR 20 C(O)substituted heteroaryl, -NR 20 C(O)heterocyclic, and
  • Aminocarbonyl or the term “aminoacyl” refers to the group -C(O)NR 21 R 22 , wherein R 21 and R 22 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 21 and R 22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted
  • Aminocarbonylamino refers to the group -NR 21 C(O)NR 22 R 23 where R 21 , R 22 , and R 23 are independently selected from hydrogen, alkyl, aryl or cycloalkyl, or where two R groups are joined to form a heterocyclyl group.
  • alkoxycarbonylamino refers to the group -NRC(O)OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclyl wherein alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.
  • acyloxy refers to the groups alkyl-C(O)O-, substituted a I ky l-C(O)O- classroom cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, aryl-C(O)O-, heteroaryl-C(O)O-, and heterocyclyl-C(O)O- wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.
  • Aminosulfonyl refers to the group -SC>2NR 21 R 22 , wherein R 21 and R 22 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where R 21 and R 22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,
  • Sulfonylamino refers to the group -NR 21 SO2R 22 , wherein R 21 and R 22 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 21 and R 22 are optionally joined together with the atoms bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, substituted cyclo
  • Aryl or “Ar” refers to a monovalent aromatic carbocyclic group of from 6 to 18 carbon atoms having a single ring (such as is present in a phenyl group) or a ring system having multiple condensed rings (examples of such aromatic ring systems include naphthyl, anthryl and indanyl) which condensed rings may or may not be aromatic, provided that the point of attachment is through an atom of an aromatic ring. This term includes, by way of example, phenyl and naphthyl.
  • such aryl groups can optionally be substituted with from 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryl oxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy,
  • Aryloxy refers to the group -O-aryl, wherein aryl is as defined herein, including, by way of example, phenoxy, naphthoxy, and the like, including optionally substituted aryl groups as also defined herein.
  • Amino refers to the group -NH2.
  • substituted amino refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclyl provided that at least one R is not hydrogen.
  • Carboxyl refers to -CO2H or salts thereof.
  • Carboxyl ester or “carboxy ester” or the terms “carboxyalkyl” or “carboxylalkyl” refers to the groups -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-cycloalkenyl, -C(O)
  • (Carboxyl ester)oxy refers to the groups -O-C(O)O-alkyl, -O-C(O)O-substituted alkyl, -O-C(O)O-alkenyl, -O-C(O)O-substituted alkenyl, -O-C(O)O-alkynyl, -O-C(O)O-substituted alkynyl, -O-C(O)O-aryl, -O-C(O)O-substituted aryl, -O-C(O)O-cycloalkyl, -O-C(O)O-substituted cycloalkyl, -O-C(O)O-cycloalkenyl, -O-C(O)O-substituted cycloalkenyl, -O-C(O)O-heteroaryl
  • Cycloalkyl refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems.
  • suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like.
  • Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
  • substituted cycloalkyl refers to cycloalkyl groups having from 1 to 5 substituents, or from I to 3 substituents, selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryl oxy, heterocyclyl, heterocyclooxy, substituted thioalkoxy,
  • Cycloalkenyl refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple rings and having at least one double bond and preferably from 1 to 2 double bonds.
  • substituted cycloalkenyl refers to cycloalkenyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamin
  • Cycloalkynyl refers to non-aromatic cycloalkyl groups of from 5 to 10 carbon atoms having single or multiple rings and having at least one triple bond.
  • Cycloalkoxy refers to -O-cycloalkyl
  • Cycloalkenyloxy refers to -O-cycloalkenyl.
  • Halo or "halogen” refers to fluoro, chloro, bromo, and iodo.
  • Heteroaryl refers to an aromatic group of from 1 to 15 carbon atoms, such as from 1 to 10 carbon atoms and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring.
  • Such heteroaryl groups can have a single ring (such as, pyridinyl, imidazolyl or furyl) or multiple condensed rings in a ring system (for example as in groups such as, indolizinyl, quinolinyl, benzofuran, benzimidazolyl or benzothienyl), wherein at least one ring within the ring system is aromatic.
  • any heteroatoms in such heteroaryl rings may or may not be bonded to H or a substituent group, e.g., an alkyl group or other substituent as described herein.
  • the nitrogen and/or sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N->0), sulfinyl, or sulfonyl moieties.
  • This term includes, by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.
  • heteroaryl groups can be optionally substituted with 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thio
  • heteroarylkyl refers to the groups -alkylene-heteroaryl where alkylene and heteroaryl are defined herein. This term includes, by way of example, pyridylmethyl, pyridylethyl, indolylmethyl, and the like.
  • Heteroaryl oxy refers to -O-heteroaryl.
  • Heterocycle refers to a saturated or unsaturated group having a single ring or multiple condensed rings, including fused bridged and spiro ring systems, and having from 3 to 20 ring atoms, including 1 to 10 hetero atoms. These ring atoms are selected from nitrogen, sulfur, or oxygen, where, in fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through the non-aromatic ring.
  • the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N- oxide, -S(O)-, or -SCh- moieties.
  • any heteroatoms in such heterocyclic rings may or may not be bonded to one or more H or one or more substituent group(s), e.g., an alkyl group or other substituent as described herein.
  • heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline,
  • heterocyclic groups can be optionally substituted with 1 to 5, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino,
  • Heterocyclyloxy refers to the group -O-heterocyclyl.
  • heterocyclylthio refers to the group heterocyclic-S-.
  • heterocyclene refers to the diradical group formed from a heterocycle, as defined herein.
  • hydroxyamino refers to the group -NHOH.
  • Niro refers to the group -NO2.
  • Sulfonyl refers to the group -S02-alkyl, -SO2-substituted alkyl, -SO2-alkenyl, - S02-substituted alkenyl, -SO2-cycloalkyl, -S02-substituted cylcoalkyl, -SO2-cycloalkenyl, -SO2- substituted cylcoalkenyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic, and -S02-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloal
  • Sulfonyl includes, by way of example, methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-.
  • "Sulfonyloxy" refers to the group -OSOz-alkyl, -OSOz-substituted alkyl, -OSOz- alkenyl, -OSOz-substituted alkenyl, -OSOz-cycloalkyl, -OSOz-substituted cylcoalkyl, -OSO2- cycloalkenyl, -OSOz-substituted cylcoalkenyl, -OSOz-aryl, -OSOz-substituted aryl, -OSOz- heteroaryl, -OSOz-substituted heteroaryl, -OSOz-heterocyclic, and -OSOz-substituted heterocyclic, wherein alkyl
  • Sulfate or "sulfate ester” refers the group -O-SO2-OH, -O-SOz-O-alkyl, -O-SO2- O-substituted alkyl, -O-SOz-O-alkenyl, -O-SOz-O-substituted alkenyl, -O-SOz-O-cycloalkyl, -O- SOz-O-substituted cylcoalkyl, -O-SOz-O-cycloalkenyl, -O-SOz-O-substituted cylcoalkenyl, -O-SO2- O-aryl, -O-SOz-O-substituted aryl, -O-SOz-O-heteroaryl, -O-SOz-O-substituted heteroaryl, -O- SOz-O-heterocyclic, and -O-SO-SO2-OH,
  • aminocarbonyloxy refers to the group -OC(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
  • Thiol refers to the group -SH.
  • Alkylthio or the term “thioalkoxy” refers to the group -S-alkyl, wherein alkyl is as defined herein.
  • sulfur may be oxidized to -S(O)-.
  • the sulfoxide may exist as one or more stereoisomers.
  • substituted thioalkoxy refers to the group -S-substituted alkyl.
  • thioaryloxy refers to the group aryl-S- wherein the aryl group is as defined herein including optionally substituted aryl groups also defined herein.
  • heteroaryloxy refers to the group heteroaryl-S- wherein the heteroaryl group is as defined herein including optionally substituted aryl groups as also defined herein.
  • heterocyclooxy refers to the group heterocyclyl-S- wherein the heterocyclyl group is as defined herein including optionally substituted heterocyclyl groups as also defined herein.
  • substituted when used to modify a specified group or radical, can also mean that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent groups as defined below.
  • Each M + may independently be, for example, an alkali ion, such as K + , Na + , Li + ; an ammonium ion, such as + N(R 60 )4; or an alkaline earth ion, such as [Ca 2+ ]o.s, [Mg 2+ ]o.s, or [Ba 2+ ]o.s ("subscript 0.5 means that one of the counter ions for such divalent alkali earth ions can be an ionized form of a compound of the invention and the other a typical counter ion such as chloride, or two ionized compounds disclosed herein can serve as counter ions for such divalent alkali earth ions, or a doubly ionized compound of the invention can serve as the counter ion for such divalent alkali earth ions).
  • an alkali ion such as K + , Na + , Li +
  • an ammonium ion such as + N(R 60 )4
  • -NR 80 R 80 is meant to include -NH2, -N H-alkyl, /V-pyrrolidinyl, /V-piperazinyl, 4/V-methyl-piperazin-l-yl and A/-morpholinyl.
  • substituent groups for hydrogens on unsaturated carbon atoms in "substituted" alkene, alkyne, aryl and heteroaryl groups are, unless otherwise specified, -R 60 , halo, -O M + , -OR 70 , -SR 70 , -S _ M + , -NR 80 R 80 , trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO 2 , -N 3 , -SO 2 R 70 , -SO 3 M + , -SO3R 70 , -OSO2R 70 , -OSO3 M + , -OSO3R 70 , -PO 3 ’ 2 (M + ) 2 , -P(O)(OR 70 )O-M + , -P(O)(OR 70 ) 2 , -C(O)R 70 , -C(S)
  • substituent groups for hydrogens on nitrogen atoms in "substituted" heteroalkyl and cycloheteroalkyl groups are, unless otherwise specified, -R 60 , -O M + , -OR 70 , -SR 70 , -S M + , -NR8°R8°, trihalomethyl, -CF 3 , -CN, -NO, -NO 2 , -S(O) 2 R 70 , -S(O) 2 O’M + , -S(O) 2 OR 70 , -OS(O) 2 R 70 , -OS(O) 2 O M + , -OS(O) 2 OR 70 , -P(O)(Oj 2 (M + ) 2 , -P(O)(OR 70 )O M + , -P(O)(OR 70 )(OR 70 ), -C(O)R 70 ,
  • a group that is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.
  • substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment.
  • substituent "arylalkyloxycarbonyl” refers to the group (a ryl)-(a Ikyl)-O-C(O)-.
  • any of the groups disclosed herein which contain one or more substituents it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible.
  • the subject compounds include all stereochemical isomers arising from the substitution of these compounds.
  • Optional or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not.
  • optionally substituted aryl means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.
  • substituents on the functional group are also “optionally substituted” and so on, for the purposes of this disclosure, such iterations are limited to five, and in some cases, such iterations are limited to two.
  • “Pharmaceutically acceptable carrier, diluent or excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals.
  • pharmaceutically acceptable salt means a salt which is acceptable for administration to a patient, such as a mammal (salts with counterions having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.
  • “Pharmaceutically acceptable salt” refers to pharmaceutically
  • T1 acceptable salts of a compound which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, and the like.
  • “Pharmaceutically acceptable salt” includes both acid and base addition salts.
  • “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-l,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethan
  • “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Examples of suitable inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2- dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like.
  • suitable organic bases are isopropylamine
  • a "pharmaceutical composition” refers to a formulation of a compound and a medium generally accepted in the art for the delivery of the biologically active compound to a mammal, e.g., humans.
  • a medium can include a pharmaceutically acceptable carrier, diluent, or excipient.
  • “Therapeutically effective amount” refers to that amount of a compound which, when administered to a mammal, e.g., a human, is sufficient to effect treatment of the disease or condition of interest in a mammal, e.g., a human, having the disease or condition.
  • the amount of a compound which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease or condition and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
  • a compound as disclosed herein, or a pharmaceutically acceptable salt thereof may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids.
  • a compound as disclosed herein is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization.
  • solvent refers to a complex formed by combination of solvent molecules with molecules or ions of the solute.
  • the solvent can be an organic compound, an inorganic compound, or a mixture of both.
  • Some examples of solvents include, but are not limited to, methanol, N, A/-di methylformamide, tetra hydrofuran, dimethylsulfoxide, and water. When the solvent is water, the solvate formed is a hydrate.
  • a “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable.
  • the present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
  • pyrazoles imidazoles, benzimidazoles, triazoles, and tetrazoles.
  • compositions which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients.
  • Pharmaceutically acceptable carriers and other therapeutic ingredients may include one or more excipients and/or one or more vehicles.
  • the carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen.
  • compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, drageemaking, levigating, emulsifying, encapsulating, entrapping or compression processes.
  • drug delivery device shall be understood to encompass any type of device, system or apparatus designed to immediately dispense a drug to a human or nonhuman body.
  • immediate dispense is meant an absence of any necessary intermediate manipulation of the drug by a user between discharge of the drug from the drug delivery device and administration to the human or non-human body.
  • typical examples of drug delivery devices may be found in injection devices, inhalers, and stomach tube feeding systems.
  • exemplary injection devices may include, e.g., syringes, autoinjectors, injection pen devices and spinal injection systems.
  • a "ubiquitin ligase binding moiety” refers to a portion of a bifunctional compound that binds to a ubiquitin ligase (e.g., an E3 ligase).
  • a "protein targeting moiety” refers to a portion of a bifunctional compound that binds to a protein of interest.
  • the protein targeting moiety when in the presence of a ubiquitin ligase binding moiety, brings a protein of interest in close proximity of a ubiquitin ligase thereby leading to the ubiquitination and degradation of said protein of interest.
  • a “secondary treatment modality” refers to a secondary treatment (i.e. a second treatment following administration of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a compound depicted in Fig. 1) that is directed to the disease or disorder that is being treated by a composition of the present disclosure. Secondary treatment modalities are often used to supplement a treatment that is currently in use in order to improve the outcomes of individuals in need thereof relative to any single treatment.
  • treatment refers to obtaining a desired pharmacologic and/or physiologic effect.
  • the effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse effect attributable to the disease.
  • Treatment covers any treatment of a disease in a mammal, e.g., in a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease.
  • the terms "individual,” “subject,” “host,” and “patient,” used interchangeably herein, refer to an individual organism, e.g., a mammal, including, but not limited to, murines, simians, humans, non-human primates, mammalian farm animals, mammalian sport animals, and mammalian pets.
  • binding refers to a direct association between two molecules, due to, for example, covalent, electrostatic, hydrophobic, and ionic, and/or hydrogen-bond interactions, including interactions such as salt bridges and water bridges.
  • inhibitor refers to a compound having the ability to inhibit a biological function of a target protein or a target biological process. When inhibiting a target protein, an inhibitor can inhibit the activity of the target protein.
  • the terms "simultaneous” or “simultaneously” as applied to administering compounds to a subject refer to administering one or more compounds at the same time, or at two different time points that are separated by no more than 1 hour.
  • the term “sequentially” refers to administering more than one compound at two different time points that are separated by more than 1 hour, e.g., about 2 hours, about 5 hours, 8 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or even longer.
  • the present disclosure provides pharmaceutical compositions and drug delivery devices comprising a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a compound depicted in Fig. 1.
  • Methods are provided for inhibiting the binding of Bex to an E3 ligase in a cell, involving contacting the cell with a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a compound depicted in Fig. 1 to inhibit the binding of Bex to an E3 ligase.
  • the present disclosure provides methods of treatment of mitochondrial dysfunction, including methods of treatment of neurodegenerative disease, cardiovascular disease and metabolic disease.
  • compositions comprising: i) a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, or X; and ii) a pharmaceutical acceptable excipient.
  • compositions comprising: i) a compound depicted in FIG. 1; and ii) a pharmaceutical acceptable excipient.
  • a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, or X binds to an E3 ligase non-covalently.
  • the binding of a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, or X binds to an E3 ligase is non-covalent and is reversible.
  • a compound depicted in FIG. 1 binds to an E3 ligase non-covalently.
  • the binding of a compound depicted in FIG. 1 to an E3 ligase is non-covalent and is reversible.
  • a composition of the present disclosure can comprise, in addition to a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, or X of the present disclosure, or a compound depicted in FIG. 1, one or more of: a salt, e.g., NaCI, MgCh, KCI, MgSC , etc.; a buffering agent, e.g., a Tris buffer, N-(2-Hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), 2-(N- Morpholino)ethanesulfonic acid (MES), 2-(N-Morpholino)ethanesulfonic acid sodium salt (MES), 3-(N-Morpholino)propanesulfonic acid (MOPS), N- tris[Hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS), etc.; a solubilizing agent;
  • the pharmaceutical acceptable excipient is not dimethyl sulfoxide (DMSO).
  • a pharmaceutical composition can comprise: i) a compound comprising formula I, II, III, IV, V, VI, VII, VIII, IX, or X, or a compound depicted in FIG. 1; and ii) a pharmaceutically acceptable excipient.
  • a subject pharmaceutical composition will be suitable for administration to a subject, e.g., will be sterile.
  • a subject pharmaceutical composition will be suitable for administration to a human subject, e.g., where the composition is sterile and is free of detectable pyrogens and/or other toxins.
  • the protein compositions may comprise other components, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium, carbonate, and the like.
  • the compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, hydrochloride, sulfate salts, solvates (e.g., mixed ionic salts, water, organics), hydrates (e.g., water), and the like.
  • compositions may include aqueous solution, powder form, granules, tablets, pills, suppositories, capsules, suspensions, sprays, and the like.
  • the composition may be formulated according to the various routes of administration described below.
  • Suitable excipients include, e.g., croscarmellose sodium (disintegrant), microcrystalline cellulose (filler), magnesium stearate, (antiadherent, lubricant), povidone (disintegrant), sodium starch glycolate (disintegrant), silica, and colloidal anhydrous (glidant, lubricant).
  • Suitable excipients include, e.g., pyrazole-based heterocycle core excipient oral tablet formulation for cluster 47 compounds, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate (sodium dodecyl sulfate; SDS).
  • Suitable excipients include, e.g., oxazole core with sulfone moiety excipient oral tablet formulation for cluster 75 compounds, microcrystalline cellulose, docusate sodium, magnesium stearate, povidone, and sodium starch glycolate.
  • Suitable excipients include, e.g., sulfone-based excipient oral tablet formulation for cluster 75 compounds, including: croscarmellose sodium, docusate sodium, microcrystalline cellulose, povidone, sodium benzoate, sodium starch glycolate, and stearic acid.
  • Suitable excipients include, e.g., sodium chloride, poly(ethylene glycol) (PEG), benzyl alcohol, sorbitol, saccharin sodium, sodium citrate, citric acid anhydrous, methyl parahydroxybenzoate, propyl parahydroxybenzoate, propylene glycol, maltodextrin, lactic acid, and glyceryl triacetate.
  • compositions comprising: a compound of formula (I): wherein:
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are each independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
  • R 1 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 1 is H.
  • R 1 is halo (e.g., F, Cl, Br, I).
  • R 1 is hydroxyl.
  • R 1 is alkoxy.
  • R 1 is nitro. In certain embodiments, R 1 is amino or substituted amino. In certain embodiments, R 1 is carboxyl. In certain embodiments, R 1 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R 1 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 1 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 1 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C35 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 1 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 1 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a C& aryl or Ce substituted aryl.
  • R 1 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
  • R 1 is selected from H, alkyl, alkoxy and halo. In certain embodiments, R 1 is methyl.
  • R 1 is CL [00161]
  • R 2 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 2 is H.
  • R 2 is halo (e.g., F, Cl, Br, I).
  • R 2 is hydroxyl.
  • R 2 is alkoxy. In certain embodiments, R 2 is nitro. In certain embodiments, R 2 is amino or substituted amino. In certain embodiments, R 2 is carboxyl. In certain embodiments, R 2 is carboxylalkyl, such as C1-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R 2 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 2 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 2 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 2 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 2 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a C& aryl or Ce substituted aryl.
  • R 2 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
  • R 2 is selected from H, alkyl, alkoxy and halo.
  • R 2 is methyl.
  • R 2 is Cl.
  • R 2 is F.
  • R 3 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 3 is H.
  • R 3 is halo (e.g., F, Cl, Br, I).
  • R 3 is hydroxyl.
  • R 3 is alkoxy.
  • R 3 is nitro. In certain embodiments, R 3 is amino or substituted amino. In certain embodiments, R 3 is carboxyl. In certain embodiments, R 3 is carboxylalkyl, such as C1-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R 3 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 3 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 3 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 3 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 3 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl.
  • R 3 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a Cs heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
  • R 3 is selected from H, alkyl, alkoxy and halo.
  • R 3 is methoxy or ethoxy.
  • R 3 is methyl.
  • R 3 is tert-butyl.
  • R 3 is F.
  • R 3 is Br.
  • R 3 is Cl.
  • R 4 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 4 is H.
  • R 4 is halo (e.g., F, Cl, Br, I).
  • R 4 is hydroxyl.
  • R 4 is alkoxy.
  • R 4 is nitro. In certain embodiments, R 4 is amino or substituted amino. In certain embodiments, R 4 is carboxyl. In certain embodiments, R 4 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R 4 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 4 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 4 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 4 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 4 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a C& aryl or C& substituted aryl.
  • R 4 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a C& heteroaryl or CK substituted heteroaryl.
  • R 4 is selected from H, alkyl, alkoxy and halo.
  • R 4 is methyl.
  • R 4 is Cl.
  • R 4 is F.
  • R 5 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 5 is H.
  • R 5 is halo (e.g., F, Cl, Br, I).
  • R 5 is hydroxyl.
  • R 5 is alkoxy.
  • R 5 is nitro. In certain embodiments, R 5 is amino or substituted amino. In certain embodiments, R 5 is carboxyl. In certain embodiments, R 5 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R 5 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 5 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 5 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 5 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 5 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl.
  • R 5 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
  • R 5 is selected from H, alkyl, alkoxy and halo.
  • R 5 is methyl.
  • R 5 is CL
  • R 5 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 6 is H.
  • R 6 is halo (e.g., F, Cl, Br, I).
  • R 6 is hydroxyl.
  • R 6 is alkoxy.
  • R 6 is nitro. In certain embodiments, R 6 is amino or substituted amino. In certain embodiments, R 6 is carboxyl. In certain embodiments, R 6 is carboxylalkyl, such as C1-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R 6 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 6 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C23 substituted alkenyl.
  • R 6 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 6 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 6 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl.
  • R 6 is selected from H, alkyl, alkoxy and halo.
  • R 6 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
  • R 6 is selected from H, alkyl, substituted alkyl, amino, substituted amino, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl.
  • R 6 is selected from H and -NR 9 R 10 , wherein R 9 and R 10 are independently selected from H, alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl, or R 9 and R 10 together with the N to which they are attached form a cycloalkyl or substituted cycloalkyl.
  • R 6 is -NR 9 R 10 , wherein R 9 and R 10 together with the N to which they are attached form a substituted cyclohexyl ring, a cyclopentyl ring or a cycloheptyl ring.
  • R 6 is -NR 9 R 10 , wherein R 9 is propyl and R 10 is propyl. In certain embodiments, R 6 is -NR 9 R 10 , wherein R 9 is and R 10 is ethyl. In certain embodiments, R 6 is -NR 9 R 10 , wherein R 9 is methyl
  • R 7 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 7 is H.
  • R 7 is halo (e.g., F, Cl, Br, I).
  • R 7 is hydroxyl.
  • R 7 is alkoxy.
  • R 7 is nitro. In certain embodiments, R 7 is amino or substituted amino. In certain embodiments, R 7 is carboxyl. In certain embodiments, R 7 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R 7 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 7 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 7 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 7 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 7 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl.
  • R 7 is selected from H, alkyl, alkoxy and halo.
  • R 7 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
  • R 7 is selected from H, alkyl, substituted alkyl, amino, substituted amino, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl.
  • R 7 is selected from H and -NR 9 R 10 , wherein R 9 and R 10 are independently selected from H, alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl, or R 9 and R 10 together with the N to which they are attached form a cycloalkyl or substituted cycloalkyl.
  • R 7 is -NR 9 R 10 , wherein R 9 and R 10 together with the N to which they are attached form a substituted cyclohexyl ring or a cycloheptyl ring.
  • R 7 is -NR 9 R 10 , wherein R 9 is butyl and R 10 is phenyl.
  • R 8 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 8 is H.
  • R 8 is halo (e.g., F, Cl, Br, I).
  • R 8 is hydroxyl.
  • R 8 is alkoxy.
  • R 8 is nitro. In certain embodiments, R 8 is amino or substituted amino. In certain embodiments, R 8 is carboxyl. In certain embodiments, R 8 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R 8 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 8 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 8 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 8 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 8 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl.
  • R 8 is selected from H, alkyl, alkoxy and halo.
  • R 8 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
  • the compound is selected from:
  • compositions comprising: a compound of formula (II): wherein:
  • R a is selected from H, alkyl, and substituted alkyl
  • R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
  • R a is selected from H, alkyl, and substituted alkyl. In certain embodiments, R a is H. In certain embodiments, R a is alkyl. In certain embodiments, R a is substituted alkyl. In certain embodiments, R a is methyl. In certain embodiments, R a is ethyl.
  • R 1 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 1 is H.
  • R 1 is halo (e.g., F, Cl, Br, I).
  • R 1 is hydroxyl.
  • R 1 is alkoxy.
  • R 1 is nitro. In certain embodiments, R 1 is amino or substituted amino. In certain embodiments, R 1 is carboxyl. In certain embodiments, R 1 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R 1 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 1 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 1 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 1 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 1 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl.
  • R 1 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
  • R 1 is selected from H, alkyl and halo.
  • R 1 is Cl.
  • R 1 is Br.
  • R 2 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 2 is H.
  • R 2 is halo (e.g., F, Cl, Br, I).
  • R 2 is hydroxyl.
  • R 2 is alkoxy.
  • R 2 is nitro. In certain embodiments, R 2 is amino or substituted amino. In certain embodiments, R 2 is carboxyl. In certain embodiments, R 2 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R 2 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 2 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 2 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 2 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 2 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl.
  • R 2 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
  • R 2 is selected from H, alkyl, alkoxy and halo. In certain embodiments, R 2 is F.
  • R 3 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 3 is H.
  • R 3 is halo (e.g., F, Cl, Br, I).
  • R 3 is hydroxyl.
  • R 3 is alkoxy.
  • R 3 is nitro. In certain embodiments, R 3 is amino or substituted amino. In certain embodiments, R 3 is carboxyl. In certain embodiments, R 3 is carboxylalkyl, such as C1-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R 3 is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 3 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 3 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 3 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 3 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a C& aryl or Ce substituted aryl.
  • R 3 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
  • R 3 is selected from H, alkyl, alkoxy and halo.
  • R 3 is methoxy or ethoxy.
  • R 3 is methyl.
  • R 3 is Br.
  • R 4 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 4 is H.
  • R 4 is halo (e.g., F, Cl, Br, I).
  • R 4 is hydroxyl.
  • R 4 is alkoxy.
  • R 4 is nitro. In certain embodiments, R 4 is amino or substituted amino. In certain embodiments, R 4 is carboxyl. In certain embodiments, R 4 is carboxylalkyl, such as C1-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R 4 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 4 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 4 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C35 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 4 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C36 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 4 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a C& aryl or Ce substituted aryl.
  • R 4 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
  • R 4 is selected from H, alkyl, alkoxy and halo. In certain embodiments, R 4 is F.
  • R 5 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 5 is H.
  • R 5 is halo (e.g., F, Cl, Br, I).
  • R 5 is hydroxyl.
  • R 5 is alkoxy.
  • R 5 is nitro. In certain embodiments, R 5 is amino or substituted amino. In certain embodiments, R 5 is carboxyl. In certain embodiments, R 5 is carboxylalkyl, such as C1-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R 5 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 5 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 5 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 5 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 5 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl.
  • R 5 is heteroaryl or substituted heteroaryl, such as Cs s heteroaryl or Cs s substituted heteroaryl, such as a Cs heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
  • R 5 is selected from H, alkyl, alkoxy and halo.
  • R 5 is Br.
  • R s is Cl.
  • the compound is selected from:
  • compositions comprising: a compound of formula (III): wherein:
  • R a is selected from H, halo, alkyl, and substituted alkyl
  • R 6 , R 7 and R 8 are each independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
  • R a is selected from H, alkyl, and substituted alkyl. In certain embodiments, R a is H. In certain embodiments, R a is alkyl. In certain embodiments, R a is substituted alkyl. In certain embodiments, R a is methyl. In certain embodiments, R a is ethyl.
  • R e is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 6 is H.
  • R 6 is halo (e.g., F, Cl, Br, I).
  • R 6 is hydroxyl.
  • R 6 is alkoxy.
  • R 6 is nitro. In certain embodiments, R 6 is amino or substituted amino. In certain embodiments, R 6 is carboxyl. In certain embodiments, R 6 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R 6 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 6 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 6 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 6 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 6 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl.
  • R 6 is selected from H, alkyl, alkoxy and halo.
  • R 6 is heteroaryl or substituted heteroaryl, such as Cs s heteroaryl or Cs s substituted heteroaryl, such as a Cs heteroaryl or Cs substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
  • R 7 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 7 is H.
  • R 7 is halo (e.g., F, Cl, Br, I).
  • R 7 is hydroxyl.
  • R 7 is alkoxy.
  • R 7 is nitro. In certain embodiments, R 7 is amino or substituted amino. In certain embodiments, R 7 is carboxyl. In certain embodiments, R 7 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R 7 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 7 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 7 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 7 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 7 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl.
  • R 7 is selected from H, alkyl, alkoxy and halo.
  • R 7 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
  • R 7 is selected from H, alkyl, substituted alkyl, amino, substituted amino, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl.
  • R 7 is selected from H and -NR 9 R 10 , wherein R 9 and R 10 are independently selected from H, alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl, or R 9 and R 10 together with the N to which they are attached form a cycloalkyl or substituted cycloalkyl.
  • R 7 is -NR 9 R 10 , wherein R 9 and R 10 together with the N to which they are attached form a substituted cyclohexyl ring.
  • R 7 is -NR 9 R 10 , wherein R 9 is methyl and R 10
  • R 8 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 8 is H.
  • R 8 is halo (e.g., F, Cl, Br, I).
  • R 8 is hydroxyl.
  • R 8 is alkoxy.
  • R 8 is nitro. In certain embodiments, R 8 is amino or substituted amino. In certain embodiments, R 8 is carboxyl. In certain embodiments, R 8 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R 8 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 8 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 8 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 8 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 8 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a C& aryl or Ce substituted aryl.
  • R 8 is selected from H, alkyl, alkoxy and halo.
  • R 8 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
  • the compound is:
  • compositions comprising: a compound of formula (IV): wherein:
  • R 1 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
  • R 2 and R 3 are each independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl and substituted alkenyl; and a pharmaceutically acceptable excipient.
  • R 1 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 1 is H.
  • R 1 is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 1 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 1 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or Cs s substituted cycloalkyl.
  • R 1 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 1 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl.
  • R 1 is heteroaryl or substituted heteroaryl, such as C5- 8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
  • R 1 is benzyl.
  • R 1 is isobutyl.
  • R 1 is CH2CH2CI.
  • R 2 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 2 is H.
  • R 2 is halo (e.g., F, Cl, Br, I).
  • R 2 is hydroxyl.
  • R 2 is alkoxy.
  • R 2 is nitro. In certain embodiments, R 2 is amino or substituted amino. In certain embodiments, R 2 is carboxyl. In certain embodiments, R 2 is carboxylalkyl, such as C1-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R 2 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 2 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 2 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 2 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 2 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Cg aryl or Cg substituted aryl.
  • R 3 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 3 is H.
  • R 3 is halo (e.g., F, Cl, Br, I).
  • R 3 is hydroxyl.
  • R 3 is alkoxy.
  • R 3 is nitro. In certain embodiments, R 3 is amino or substituted amino. In certain embodiments, R 3 is carboxyl. In certain embodiments, R 3 is carboxylalkyl, such as C1-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R 3 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 3 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 3 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 3 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 3 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Cg aryl or C substituted aryl.
  • R 3 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Cg heteroaryl or C& substituted heteroaryl.
  • R 3 is Cl. In certain embodiments, R 3 is Br.
  • the compound is selected from:
  • compositions comprising: a compound of formula (V): wherein:
  • R 1 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
  • R 2 and R 3 are each independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R 2 and R 3 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl; and a pharmaceutically acceptable excipient.
  • R 1 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 1 is selected from H, halo, hydroxyl, amino, substituted aminoalkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl.
  • R 1 is H.
  • R 1 is halo (e.g., F, Cl, Br, I).
  • R 1 is hydroxyl.
  • R 1 is alkoxy.
  • R 1 is nitro.
  • R 1 is amino or substituted amino.
  • R 1 is carboxyl.
  • R 1 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl.
  • R 1 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 1 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 1 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 1 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 1 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a C& aryl or Ce substituted aryl.
  • R 1 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a C& heteroaryl or Ce substituted heteroaryl.
  • R 1 is Br.
  • R 1 is selected from -NR 9 R 10 , wherein R 9 and R 10 are independently selected from H, alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl, or R 9 and R 10 together with the N to which they are attached form a heterocycloalkyl or substituted heterocycloalkyl.
  • R 1 is -NR 9 R 10 , wherein R 9 and R 10 together with the N to which they are attached form a substituted cyclohexyl ring.
  • R 6 is -NR 9 R 10 , wherein R 9 is ethyl and R 10 is ethoxy.
  • R 2 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R 2 and R 3 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl.
  • R 2 is H.
  • R 2 is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-6 substituted alkyl, or Ci-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 3 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 2 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 2 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3- 6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 2 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or C& substituted aryl.
  • R 2 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
  • R 2 is selected from H, alkyl and substituted alkyl.
  • R 2 is CH2CH2OCH3.
  • R 2 is CH2CH2CH2COOH.
  • R 2 is CH2CH2OH.
  • R 2 is CH2CH 2 O(CO)CH 3 .
  • R 3 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R 2 and R 3 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl.
  • R 3 is H.
  • R 3 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 3 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 3 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C35 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 3 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3- 6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 3 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or C& substituted aryl.
  • R 3 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
  • R 3 is selected from H, alkyl and substituted alkyl.
  • R 3 is CH2CH2OCH3.
  • R 3 is CH2CH2CH2COOH.
  • R 3 is CH2CH2OH.
  • R 3 is CH 2 CH 2 O(CO)CH3.
  • R 2 and R 3 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl. In certain embodiments, R 2 and R 3 together with the N to which they are attached form a heterocycloalkyl or substituted heterocycloalkyl. In certain embodiments, R 2 and R 3 together with the N to which they are attached form a substituted cyclohexyl ring.
  • the compound is selected from:
  • compositions comprising: a compound of formula (VI): wherein:
  • R 1 and R 2 are independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
  • R 1 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 1 is H.
  • R 1 is halo (e.g., F, Cl, Br, I).
  • R 1 is hydroxyl.
  • R 1 is alkoxy.
  • R 1 is nitro. In certain embodiments, R 1 is amino or substituted amino. In certain embodiments, R 1 is carboxyl. In certain embodiments, R 1 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R 1 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 1 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 1 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 1 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 1 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a C& aryl or C& substituted aryl.
  • R 1 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a Cs heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R 1 is . In certain embodiments, R 1 is
  • R 2 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 2 is H.
  • R 2 is halo (e.g., F, Cl, Br, I).
  • R 2 is hydroxyl.
  • R 2 is alkoxy.
  • R 2 is nitro. In certain embodiments, R 2 is amino or substituted amino. In certain embodiments, R 2 is carboxyl. In certain embodiments, R 2 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R 2 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 2 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 2 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 2 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 2 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl.
  • R 2 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
  • the compound is selected from:
  • compositions comprising: a compound of formula (VII): wherein:
  • R 1 and R 2 are each independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R 1 and R 2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl; and a pharmaceutically acceptable excipient.
  • R 1 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R 1 and R 2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl.
  • R 1 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R 1 is H. In certain embodiments, R 1 is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 1 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 1 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 1 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 1 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a C& aryl or Ce substituted aryl.
  • R 1 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
  • R 1 is propyl. In certain embodiments, R 1
  • R 2 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R 1 and R 2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl.
  • R 2 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 2 is H.
  • R 2 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 2 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 2 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C35 cycloalkyl or C35 substituted cycloalkyl.
  • R 2 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 2 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a C& aryl or Ce substituted aryl.
  • R 2 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
  • R 2 is propyl. In certain embodiments, R 2
  • R 1 and R 2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl. In certain embodiments, R 1 and R 2 together with the N to which they are attached form a heterocyclohexyl ring or substituted heterocyclohexyl ring.
  • the compound is selected from: [00209] Aspects of the present disclosure include compositions comprising: a compound of formula (VIII): wherein:
  • R 1 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
  • R 1 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 1 is H.
  • R 1 is halo (e.g., F, Cl, Br, I).
  • R 1 is hydroxyl.
  • R 1 is alkoxy.
  • R 1 is nitro. In certain embodiments, R 1 is amino or substituted amino. In certain embodiments, R 1 is carboxyl. In certain embodiments, R 1 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R 1 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 1 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 1 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 1 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 1 is aryl or substituted aryl, such as C5-8 aryl or Cs s substituted aryl, such as a C5 aryl or C5 substituted aryl, or a C& aryl or Ce substituted aryl.
  • R 1 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or C& substituted heteroaryl.
  • the compound is:
  • compositions comprising: a compound of formula (IX): wherein:
  • R 1 and R 2 are each independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R 1 and R 2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl; and a pharmaceutically acceptable excipient.
  • R 1 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R 1 and R 2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl.
  • R 1 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R 1 is H. In certain embodiments, R 1 is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 1 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 1 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 1 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 1 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl.
  • R 1 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R 1 is methyl.
  • R 2 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R 1 and R 2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl.
  • R 2 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 2 is H.
  • R 2 is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 2 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 2 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 2 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 2 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or C& substituted aryl.
  • R 2 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R 2 is methyl.
  • R 1 and R 2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl. In certain embodiments, R 1 and R 2 together with the N to which they are attached form a heterocyclopentyl ring.
  • the compound is:
  • compositions comprising: a compound of formula (X): wherein:
  • R 1 and R 2 are each independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R 1 and R 2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl;
  • R 3 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
  • R 1 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R 1 and R 2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl.
  • R 1 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R 1 is H. In certain embodiments, R 1 is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 1 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 1 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 1 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 1 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Cg aryl or C& substituted aryl.
  • R 1 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Cg heteroaryl or Cg substituted heteroaryl. In certain embodiments, R 1 is
  • R 2 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R 1 and R 2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl.
  • R 2 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 2 is H.
  • R 2 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 2 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 2 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 2 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 2 is aryl or substituted aryl, such as Cs s aryl or Cs s substituted aryl, such as a Cs aryl or Cs substituted aryl, or a C& aryl or C& substituted aryl.
  • R 2 is heteroaryl or substituted heteroaryl, such as Cs s heteroaryl or Cs s substituted heteroaryl, such as a Cs heteroaryl or Cs substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R 2 is
  • R 1 and R 2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl. In certain embodiments, R 1 and R 2 together with the N to which they are attached form a substituted heterocyclohexyl ring.
  • R 3 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.
  • R 3 is H.
  • R 3 is halo (e.g., F, Cl, Br, I).
  • R 3 is hydroxyl.
  • R 3 is alkoxy.
  • R 3 is nitro. In certain embodiments, R 3 is amino or substituted amino. In certain embodiments, R 3 is carboxyl. In certain embodiments, R 3 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or Ci 3 carboxylalkyl. In certain embodiments, R 3 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.
  • R 3 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl.
  • R 3 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.
  • R 3 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.
  • R 3 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl.
  • R 3 is heteroaryl or substituted heteroaryl, such as Cs s heteroaryl or Cs s substituted heteroaryl, such as a Cs heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R 3 is Cl.
  • the compound is:
  • the present disclosure provides a drug delivery device comprising a composition of the present disclosure.
  • Suitable drug delivery devices include, without limitation, an injection device (e.g., syringe, pen injector, auto injector, large-volume device, pump, perfusion system, or other device configured for subcutaneous, intramuscular, or intravenous delivery; a skin patch (e.g., osmotic, chemical, micro-needle); an inhaler (e.g., nasal or pulmonary); an implantable device; and a feeding system for the gastro-intestinal tract.
  • an injection device e.g., syringe, pen injector, auto injector, large-volume device, pump, perfusion system, or other device configured for subcutaneous, intramuscular, or intravenous delivery
  • a skin patch e.g., osmotic, chemical, micro-needle
  • an inhaler e.g., nasal or pulmonary
  • the present disclosure provides methods of inhibiting the binding of Bex to an E3 ligase in a cell.
  • the methods comprise contacting the cell with a compound of the present disclosure to inhibit the binding of Bex to an E3 ligase.
  • the contacting of the cell with a compound of the present disclosure causes activation of the E3 ligase.
  • the activation of the E3 ligase is characterized by the ability of the E3 ligase to bind to a substrate peptide, such as Fnipl.
  • the E3 ligase is present in a cell in vitro.
  • the E3 ligase is present in a cell that is in a tissue, an organ, or an extracellular fluid in an individual.
  • An E3 ligase is a complex of polypeptides.
  • the E3 ligase is a Cullin- RING ligase.
  • the E3 ligase is a CULE2 ligase.
  • a compound of the present disclosure inhibits a FEM1B polypeptide.
  • the E3 ligase comprises a FEM1B polypeptide; for example, in some cases, the E3 ligase is composed of CUL2, EloB/C, RBX1, and FEM1B.
  • FEM1B is a component of an E3 ligase, and may act as a substrate recognition subunit.
  • the E3 ligase comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 1-627 of the following amino acid sequence of the following human Femlb amino acid sequence:
  • the E3 ligase comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 1-627 of the following amino acid sequence of the following mouse Femlb amino acid sequence:
  • Bex family proteins are comprised of five proteins including BEX1, BEX2, BEX3, BEX4, and BEX5.
  • the Bex protein is BEX3.
  • the BEX protein comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: RELQLRNCLRILMGELSNHHDHHDEFCLMP (SEQ ID NO:3).
  • a subject compound e.g., a compound of any one of Formulas I, II, III, IV, V, VI, VII, VIII, IX, X; a compound depicted in FIG. 1
  • a subject compound can inhibit the binding of Bex to an E3 ligase by greater than 10 % compared to the inhibition of the binding of E3 ligase and Bex not contacted with the compound.
  • a subject compound may inhibit the activity of an E3 ligase by 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40- 45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, 85-90%, 90-95%, or 95-100%, compared to the inhibition of the binding of Bex to an E3 ligase not contacted with the compound.
  • the compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, or the compound depicted in FIG. 1 is administered in an amount effective to selectively inhibit the binding of Bex to an E3 ligase in a subject.
  • subject compound inhibits the binding of Bex to an E3 ligase by 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, 85-90%, 90-95%, or 95-100%, compared to the inhibition of binding of Bex to an E3 ligase not contacted with the compound.
  • the E3 ligase is Femlb.
  • the E3 ligase and Bex are present in a cell in vitro. In some cases, the E3 ligase and Bex are present in a cell in vivo.
  • Whether a compound inhibits the binding of Bex to an E3 ligase in a cell can be determined using an assay such as those described in Example 1.
  • a Bex peptide comprising a fluorescent label can be used as the substrate and contacted with the E3 ligase in the presence or absence of a compound being tested for inhibitory activity toward the E3 ligase.
  • a degron reporter assay as described in Example 1 can be used to determine whether a compound inhibits an E3 ligase (e.g., a FEM1B polypeptide).
  • a reduction in the activity of the E3 ligase in the presence of the compound, compared to the activity of the E3 ligase in the absence of the compound indicates that the compound inhibits E3 ligase activity.
  • a compound of the present disclosure is useful for treating various diseases, disorders and dysfunctions.
  • the present disclosure provides a method of treating mitochondrial dysfunction in a subject, the method comprising administering an effective amount of a composition comprising: i) a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, or a compound depicted in FIG. 1; and ii) a pharmaceutically acceptable excipient to treat the subject for mitochondrial dysfunction.
  • Mitochondrial dysfunction is characterized by misregulation of ATP generation and oxidative/reductive stress. Mitochondrial dysfunction includes, but is not limited to, loss of efficiency in the electron transport chain, reduction in the synthesis of ATP, loss of maintenance of electrical and chemical transmembrane potentials of the inner mitochondrial membrane, reduction in the transport of metabolites into the mitochondria, and reduced efficiency of oxidative phosphorylation.
  • Mitochondrial dysfunction and mitochondrial disorders can also be caused by mutations (acquired or inherited), in mitochondrial DNA (mtDNA), or in nuclear genes that code for mitochondrial components. They may also be the result of acquired mitochondrial dysfunction due to adverse effects of drugs, infections, or other environmental causes. Oxalate may enter cells where it is known to cause mitochondrial dysfunction.
  • mitochondrial activation can serve to reverse and/or treat mitochondrial dysfunction.
  • mitochondrial activation is characterized by increased import of factors for oxidative phosphorylation into the mitochondria.
  • the administration of the composition comprising: i) a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, or a compound depicted in FIG. 1; and ii) a pharmaceutical acceptable excipient, causes mitochondrial activation.
  • subject compound increases mitochondrial activation by 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, 85-90%, 90-95%, or 95-100%, compared to mitochondrial activation when the compound is not administered.
  • a treatment method of the present disclosure comprises administering to an individual in need thereof a composition of the present disclosure. In some cases, a treatment method of the present disclosure comprises administering to an individual in need thereof a composition of the present disclosure in addition to a secondary treatment modality directed towards treating said condition.
  • the present disclosure provides methods for treating mitochondrial dysfunction.
  • the methods generally involve administering to an individual having mitochondrial dysfunction an effective amount of a compound of the present disclosure.
  • mitochondrial dysfunction can be treated in subjects with neurodegenerative diseases.
  • Neurodegenerative diseases can include, but are not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, amytrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, and neuronopathic Gaucher's disease.
  • mitochondrial dysfunction can be treated in subjects with cardiovascular diseases.
  • Cardiovascular diseases can include, but are not limited to, atherosclerosis, cardiac ischemia reperfusion, stroke, and hypertrophic cardiomyopathy.
  • mitochondrial dysfunction can be treated in subjects with metabolic diseases.
  • Metabolic diseases can include, but are not limited to, diabetes. In some cases, diabetes can be type 2 diabetes.
  • mitochondrial dysfunction can be treated in subjects with a body mass index greater than 30 kg/m2.
  • an "effective amount" of a composition is an amount that, when administered in one or more doses to an individual in need thereof, reduces adverse symptoms in the individual.
  • an "effective amount” of a composition of the present disclosure is an amount that, when administered in one or more doses to an individual in need thereof, reduces at least one adverse symptom of the dysfunction or disease in the individual by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%, compared to the symptoms in the individual before administration of the composition, or in the absence of administration with the composition.
  • an "effective amount" of a composition of the present disclosure is an amount that, when administered in one or more doses to an individual in need thereof, reduces adverse symptoms in the individual to undetectable levels.
  • an "effective amount” of a composition of the present disclosure is an amount that, when administered in one or more doses to an individual in need thereof, increases survival time of the individual by at least 1 month, at least 2 months, at least 3 months, from 3 months to 6 months, from 6 months to 1 year, from 1 year to 2 years, from 2 years to 5 years, from 5 years to 10 years, or more than 10 years, compared to the expected survival time of the individual in the absence of administration with the composition of the present disclosure.
  • a secondary treatment modality is used in addition to a composition of the present disclosure to treat a metabolic disorder in an individual in need thereof.
  • Secondary treatment modalities may be directed to the disease or disorder being treated.
  • Secondary treatment modalities that find use in the present disclosure include, without limitation, insulin, glucagon, a statin, a thiazolidinedione, sulfonylureas, glinides, metformin, starch blockers, incretin therapies, pramlintide, SGLT2 inhibitors, etc.
  • any suitable insulin may be used, including, without limitation, rapid-acting insulin, short-acting insulin, intermediate-acting insulin, long-acting insulin, etc.
  • the insulin administered is a combination of the insulins listed above.
  • any suitable statin may be used, including, without limitation, Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, etc.
  • any suitable thialzolidinedione may be used, including, without limitation, rosiglitazone, pioglitazone, etc.
  • a sulfonylureas are used as a secondary treatment modality, any suitable sulfonylurea may be used, including, without limitation, chlorpropamide, tolbutamide, glipizide, glyburide, glimepiride, etc.
  • any suitable glinides may be used, including, without limitation, repaglinide, nateglinide, mitiglinide, etc.
  • any suitable starch blocker may be used, including, without limitation, acarbose, miglitol, etc.
  • incretin therapies are used as a secondary treatment modality
  • any suitable incretin therapy may be used, including, without limitation, sitagliptin, saxagliptin, linagliptin, exenatide, liraglutide, etc.
  • SGLT2 inhibitors are used as a secondary treatment modality, any suitable SGLT2 inhibitor may be used, including, without limitation, canagliflozin, dapagliflozin, and empagliflozin, etc.
  • Subjects suitable for treatment with a method of the present disclosure include individuals who are in need of treatment for mitochondrial dysfunction.
  • Subjects suitable for treatment for mitochondrial dysfunction with a method of the present disclosure include individuals who have a neurodegenerative disease, including individuals who have been diagnosed as having a neurodegenerative disease, and individuals who have been treated for a neurodegenerative disease but who failed to respond to the treatment.
  • Subjects suitable for treatment for mitochondrial dysfunction with a method of the present disclosure include individuals who have a cardiovascular disease, including individuals who have been diagnosed as having a cardiovascular disease, and individuals who have been treated for a cardiovascular disease but who failed to respond to the treatment.
  • Subjects suitable for treatment for mitochondrial dysfunction with a method of the present disclosure include individuals who have a metabolic disease, including individuals who have been diagnosed as having a metabolic disease, and individuals who have been treated for a metabolic disease but who failed to respond to the treatment.
  • Subjects suitable for treatment for mitochondrial dysfunction with a method of the present disclosure include individuals who have a body mass index greater than 30 kg/m 2 or an obesity-related disorder, including individuals who have been diagnosed as having a body mass index greater than 30 kg/m 2 or an obesity-related disorder, and individuals who have been treated for an obesity-related disorder but who failed to respond to the treatment.
  • Suitable formulations are described above, where suitable formulations include a pharmaceutically acceptable excipient.
  • a suitable formulation comprises: a) a compound comprising Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a compound depicted in Fig. 1; and b) a pharmaceutically acceptable excipient.
  • Suitable pharmaceutically acceptable excipients are described above.
  • a suitable dosage can be determined by an attending physician or other qualified medical personnel, based on various clinical factors. As is well known in the medical arts, dosages for any one patient depend upon many factors, including the patient's size, body surface area, age, the particular compound to be administered, sex of the patient, time, and route of administration, general health, and other drugs being administered concurrently.
  • a composition of the present disclosure may be administered in amounts between 1 ng/kg body weight and 20 mg/kg body weight per dose, e.g. between 0.1 mg/kg body weight to 10 mg/kg body weight, e.g. between 0.5 mg/kg body weight to 5 mg/kg body weight; however, doses below or above this exemplary range are envisioned, especially considering the aforementioned factors.
  • a composition of the present disclosure can be administered in an amount of from about 1 mg/kg body weight to 50 mg/kg body weight, e.g., from about 1 mg/kg body weight to about 5 mg/kg body weight, from about 5 mg/kg body weight to about 10 mg/kg body weight, from about 10 mg/kg body weight to about 15 mg/kg body weight, from about 15 mg/kg body weight to about 20 mg/kg body weight, from about 20 mg/kg body weight to about 25 mg/kg body weight, from about 25 mg/kg body weight to about 30 mg/kg body weight, from about 30 mg/kg body weight to about 35 mg/kg body weight, from about 35 mg/kg body weight to about 40 mg/kg body weight, or from about 40 mg/kg body weight to about 50 mg/kg body weight.
  • a suitable dose of a composition of the present disclosure is from 0.01 pg to 100 g per kg of body weight, from 0.1 pg to 10 g per kg of body weight, from 1 pg to 1 g per kg of body weight, from 10 pg to 100 mg per kg of body weight, from 100 pg to 10 mg per kg of body weight, or from 100 pg to 1 mg per kg of body weight.
  • Persons of ordinary skill in the art can easily estimate repetition rates for dosing based on measured residence times and concentrations of the administered agent in bodily fluids or tissues.
  • a multimeric polypeptide of the present disclosure is administered in maintenance doses, ranging from 0.01 pg to 100 g per kg of body weight, from 0.1 pg to 10 g per kg of body weight, from 1 pg to 1 g per kg of body weight, from 10 pg to 100 mg per kg of body weight, from 100 pg to 10 mg per kg of body weight, or from 100 pg to 1 mg per kg of body weight.
  • dose levels can vary as a function of the specific composition of the present disclosure, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means.
  • a composition of the present disclosure is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (qid), or three times a day (tid).
  • composition of the present disclosure e.g., the period of time over which a composition of the present disclosure can vary, depending on any of a variety of factors, e.g., patient response, etc.
  • a composition of the present disclosure can be administered over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
  • An active agent (a composition or a compound of the present disclosure) is administered to an individual using any available method and route suitable for drug delivery, including in vivo and ex vivo methods, as well as systemic and localized routes of administration.
  • routes of administration include intratumoral, peritumoral, intramuscular, intratracheal, intracranial, subcutaneous, intradermal, topical application, intravenous, intraarterial, rectal, nasal, oral, and other enteral and parenteral routes of administration. Routes of administration may be combined, if desired, or adjusted depending upon the composition of the present disclosure and/or the desired effect.
  • a composition of the present disclosure can be administered in a single dose or in multiple doses.
  • a composition of the present disclosure is administered orally. In some cases, a composition of the present disclosure is administered intraperitoneally. In some cases, a composition of the present disclosure is administered intramuscularly. In some cases, a composition of the present disclosure is administered intravenously. In some cases, a composition of the present disclosure is administered locally. In some cases, a composition of the present disclosure is administered intratumorally. In some cases, a composition of the present disclosure is administered peritumorally. In some cases, a composition of the present disclosure is administered intracranially. In some cases, a composition of the present disclosure is administered subcutaneously.
  • a composition of the present disclosure can be administered to a host using any available conventional methods and routes suitable for delivery of conventional drugs, including systemic or localized routes.
  • routes of administration contemplated for use in a method of the present disclosure include, but are not necessarily limited to, enteral, parenteral, and inhalational routes.
  • Parenteral routes of administration other than inhalation administration include, but are not necessarily limited to, topical, transdermal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intratumoral, peritumoral, and intravenous routes, i.e., any route of administration other than through the alimentary canal.
  • Parenteral administration can be carried to effect systemic or local delivery of a composition of the present disclosure. Where systemic delivery is desired, administration typically involves invasive or systemically absorbed topical or mucosal administration of pharmaceutical preparations.
  • Standard abbreviations may be used, e.g., bp, base pair(s); kb, kilobase(s); pl, picoliter(s); s or sec, second(s); min, minute(s); h or hr, hour(s); aa, amino acid(s); kb, kilobase(s); bp, base pair(s); nt, nucleotide(s); i.m., intramuscular(ly); i.p., intraperitoneal(ly); s.c., subcutaneous(ly); and the like.
  • Example 1 Identifying Bex and Femlb Inhibitors
  • mouse MBP-FEM1B was purified as previously described (Manford, et al.. Cell 2020 183:46-61).
  • TAMRA-labeled BEX3 peptide (5,6- TAMRA-RELQLRNCLRILMGELSNHHDHHDEFCLMP) was purchased from Biomatik. The peptides were prepared in DMSO to a 4mM concentration and diluted into indicated binding buffers to 200pM stock concentration that were aliquoted and frozen down.
  • the peptide and MBP-FEM1B were thawed and diluted into binding buffer containing 40mM HEPES 7.5, 150mM NaCI, 0.01% NP40 substitute, and 100pM TCEP (Tris(2-carboxyethyl)phosphine hydrochloride) made with MilliQ. filtered water, to a concentration of 20nM and 140nM respectively.
  • 40mM HEPES 7.5 150mM NaCI
  • NP40 substitute 0.01% NP40 substitute
  • 100pM TCEP Tris(2-carboxyethyl)phosphine hydrochloride
  • Each analysis group included a peptide and DMSO only plate, and FEMlB-BEX3ctd peptide DMSO only plate containing a dose response of TPEN (N,N,N',N'-Tetrakis(2- pyridylmethyl)ethylenediamine, Sigma-Aldrich, P4413) as a positive control (2 fold dilutions from 80pM to ⁇ 156nM). Data was normalized to DMSO only controls on each plate.
  • TPEN N,N,N',N'-Tetrakis(2- pyridylmethyl)ethylenediamine

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Abstract

The present disclosure provides pharmaceutical compositions and drug delivery devices comprising a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X) or a compound depicted in Fig. 1. Methods are provided for inhibiting the binding of Bex to an E3 ligase in a cell, involving contacting the cell with a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X) or a compound depicted in Fig. 1. The present disclosure provides various treatment methods involving administration of such compounds.

Description

E3 LIGASE AND BEX INHIBITORS AND METHODS OF USE THEREOF
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional Application No. 63/562,619, filed March 7,2024, the disclosure of which is incorporated herein by reference in its entirety.
INTRODUCTION
[0002] E3 ubiquitin ligases are a family of enzymes that play an essential role in ubiquitination of various substrates. E3 ligases confer substrate specificity for ubiquitination, and thus are attractive therapeutic targets due to their specificity for certain protein substrates.
[0003] Femlb is an E3 ligase implicated in the regulation of mitochondrial function and is involved in the system that senses redox balance within the cell. Femlb is sequestered and inhibited by a pseudosubstrate inhibitor Bex (brain expressed and X-linked protein). In the absence of the pseudosubstrate inhibitor Bex, Femlb can bind to and degrade the substrate Fnipl. Degradation of Fnipl leads to increased import of factors for oxidative phosphorylation into the mitochondria, thus leading to further downstream effects such as altering mitochondrial function.
SUMMARY
[0004] Compounds that are E3 ligase Femlb and Bex inhibitors inhibit the binding of Bex to Femlb, thus activating Femlb so Femlb is available to bind, ubiquitylate and degrade Fnipl.
[0005] The present disclosure provides pharmaceutical compositions and drug delivery devices comprising a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a compound depicted in Fig. 1. Methods are provided for inhibiting the binding of Bex to an E3 ligase in a cell, involving contacting the cell with a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a compound depicted in Fig. 1 to inhibit the binding of Bex to an E3 ligase. The present disclosure provides various treatment methods involving administration of such compounds. [0006] Aspects of the present disclosure include compositions comprising: al) a compound of formula (I): wherein:
R1, R2, R3, R4, Rs, R6, R7 and R8 are each independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and bl) a pharmaceutically acceptable excipient; or a2) a compound depicted in FIG. 1; and b2) a pharmaceutically acceptable excipient.
[0007] In some embodiments, R1, R2, R3, R4 and R5 of the compound of formula (I) are independently selected from H, alkyl, alkoxy and halo. In some embodiments, R8 of the compound of formula (I) is H. In some embodiments, R6 and R7 of the compound of formula (I) are independently selected from H, alkyl, substituted alkyl, amino, substituted amino, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl. In some embodiments, R6 and R7 of the compound of formula (I) are independently selected from H and -NR9R10, wherein R9 and R10 are independently selected from H, alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl, or R9 and R10 together with the N to which they are attached form a cycloalkyl or substituted cycloalkyl.
[0008] In some embodiments, the compound is selected from:
[0009] Aspects of the present disclosure include compositions comprising: a compound of formula (II): wherein:
Ra is selected from H, alkyl, and substituted alkyl;
R1, R2, R3, R4 and R5 are each independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
[0010] In some embodiments, R1, R2, R3, R4 and R5 of the compound of formula (II) are each independently selected from H, halo and alkyl.
[0011] In some embodiments, the compound is selected from:
[0012] Aspects of the present disclosure include compositions comprising: a compound of formula (III): wherein:
Ra is selected from H, halo, alkyl, and substituted alkyl;
R6, R7 and R8 are each independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
[0013] In some embodiments, the compound is:
[0014] Aspects of the present disclosure include compositions comprising: a compound of formula (IV): wherein:
R1 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
R2 and R3 are each independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl and substituted alkenyl; and a pharmaceutically acceptable excipient.
[0015] In some embodiments, R2 of the compound of formula (IV) is nitro or halo. In some embodiments, R3 of the compound of formula (IV) is halo.
[0016] In some embodiments, the compound is selected from: [0017] Aspects of the present disclosure include compositions comprising: a compound of formula (V): wherein:
R1 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
R2 and R3 are each independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R2 and R3 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl; and a pharmaceutically acceptable excipient.
[0018] In some embodiments, R1 of the compound of formula (V) is selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl and substituted heterocycloalkyl. In some embodiments, R2 and R3 of the compound of formula (V) are independently selected from H, alkyl and substituted alkyl. In some embodiments, R2 and R3 of the compound of formula (V) together with the N to which they are attached form a heterocycloalkyl or substituted heterocycloalkyl.
[0019] In some embodiments, the compound is selected from:
[0020] Aspects of the present disclosure include compositions comprising: a compound of formula (VI): wherein:
R1 and R2 are independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
[0021] In some embodiments, the compound is selected from:
[0022] Aspects of the present disclosure include compositions comprising: a compound of formula (VII): wherein:
R1 and R2 are each independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R1 and R2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl; and a pharmaceutically acceptable excipient.
[0023] In some embodiments, the compound is selected from:
[0024] Aspects of the present disclosure include compositions comprising: a compound of formula (VIII): wherein:
R1 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
[0025] In some embodiments, the compound is:
[0026] Aspects of the present disclosure include compositions comprising: a compound of formula (IX): wherein:
R1 and R2 are each independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R1 and R2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl; and a pharmaceutically acceptable excipient.
[0027] In some embodiments, the compound is:
[0028] Aspects of the present disclosure include compositions comprising: a compound of formula (X):
wherein:
R1 and R2 are each independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R1 and R2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl;
R3 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
[0029] In some embodiments, the compound is:
[0030] Aspects of the present disclosure include compositions wherein the composition is sterile.
[0031] Aspects of the present disclosure include a drug delivery device comprising the composition. In some embodiments, the drug delivery device comprises a syringe comprising the composition. In some embodiments, the drug delivery device comprises a pump.
[0032] Aspects of the present disclosure include a method of inhibiting the binding of
Bex to an E3 ligase a cell, the method comprising contacting the cell with the compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a compound depicted in Fig. 1 to inhibit the binding of Bex to an E3 ligase. In some embodiments, the contacting causes activation of the E3 ligase. In some embodiments, the E3 ligase is Femlb.
[0033] Aspects of the present disclosure include a method for treating mitochondrial dysfunction in a subject, the method comprising: administering an effective amount of a composition of the present disclosure to treat the subject for mitochondrial dysfunction. In some embodiments, the administering causes mitochondrial activation. In some embodiments, the compound is administered orally, intraperitoneally, intramuscularly, or intravenously. In some embodiments, the subject has a neurodegenerative disease. In some embodiments, the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, amytrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, and neuronopathic Gaucher's disease. In some embodiments, the subject has a cardiovascular disease. In some embodiments, the cardiovascular disease is selected from the group consisting of atherosclerosis, cardiac ischemia reperfusion, stroke, and hypertrophic cardiomyopathy. In some embodiments, the subject has a metabolic disease. In some embodiments, the metabolic disease is diabetes. In some embodiments, the metabolic disease is type 2 diabetes. In some embodiments, the subject has a body mass index greater than 30 kg/m2.
BRIEF DESCRIPTION OF THE DRAWINGS
[0034] FIG. 1 provides the structures of exemplary compounds, according to embodiments of the present disclosure.
[0035] FIG. 2 provides the structures of exemplary compounds and EC50 values for the compounds, according to embodiments of the present disclosure.
DEFINITIONS
[0036] The following terms have the following meanings unless otherwise indicated. Any undefined terms have their art recognized meanings.
[0037] Certain chemical groups named herein may be preceded by a shorthand notation indicating the total number of carbon atoms that are to be found in the indicated chemical group. For example; C7-C12 alkyl describes an alkyl group, as defined below, having a total of 7 to 12 carbon atoms, and C4-C12 cycloalkylalkyl describes a cycloalkylalkyl group, as defined below, having a total of 4 to 12 carbon atoms. The total number of carbons in the shorthand notation does not include carbons that may exist in substituents of the group described.
[0038] In addition to the foregoing, unless specified to the contrary, the following terms have the meaning indicated: "Amino" refers to the — NH2 radical. "Cyano" refers to the — CN radical. "Hydroxy" refers to the —OH radical. "Imino" refers to the =NH substituent. "Nitro" refers to the — NO2 radical. "Oxo" refers to the =0 substituent. "Thioxo" refers to the =S substituent. "Trifluoromethyl" refers to the — CF3 radical.
[0039] "Alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and such as 1 to 6 carbon atoms, or 1 to 5, or 1 to 4, or 1 to 3 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CHshCH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n- pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH3)3CCH2-).
[0040] The term "substituted alkyl" refers to an alkyl group as defined herein wherein one or more carbon atoms in the alkyl chain (except the Ci carbon atom) have been optionally replaced with a heteroatom such as -O-, -N-, -S(O)n- (where n is 0 to 2), -NR- (where R is hydrogen or alkyl) and having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO- aryl, -SO-heteroaryl, -SCh-alkyl, -SCh-aryl, -SCh-heteroaryl, and -NRaRb, wherein R' and R" may be the same or different and are chosen from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic.
[0041] "Alkylene" refers to divalent aliphatic hydrocarbyl groups preferably having from 1 to 6 and more preferably 1 to 3 carbon atoms that are either straight-chained or branched, and which are optionally interrupted with one or more groups selected from -O-, - NR10-, -NR10C(O)-, -C(O)NR10- and the like. This term includes, by way of example, methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), iso-propylene (-CH2CH(CH3)-), (-C(CH3)2CH2CH2-), (-C(CH3)2CH2C(O)-), (-C(CH3)2CH2C(O)NH-), (-CH(CH3)CH2-), and the like. [0042] "Substituted alkylene" refers to an alkylene group having from 1 to 3 hydrogens replaced with substituents as described for carbons in the definition of "substituted" below. [0043] The term "alkane" refers to alkyl group and alkylene group, as defined herein.
[0044] The term "alkylaminoalkyl", "alkylaminoalkenyl" and "alkylaminoalkynyl" refers to the groups R'NHR"- where R' is alkyl group as defined herein and R" is alkylene, alkenylene or alkynylene group as defined herein.
[0045] The term "alkaryl" or "aralkyl" refers to the groups -alkylene-aryl and -substituted alkylene-aryl where alkylene, substituted alkylene and aryl are defined herein. [0046] "Alkoxy" refers to the group -O-alkyl, wherein alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, secbutoxy, n-pentoxy, and the like. The term "alkoxy" also refers to the groups alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and alkynyl-O-, where alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein.
[0047] The term "substituted alkoxy" refers to the groups substituted alkyl-O-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O- where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl are as defined herein.
[0048] The term "alkoxyamino" refers to the group -NH-alkoxy, wherein alkoxy is defined herein.
[0049] The term "haloalkoxy" refers to the groups alkyl-O- wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group and include, by way of examples, groups such as trifluoromethoxy, and the like.
[0050] The term "haloalkyl" refers to a substituted alkyl group as described above, wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group. Examples of such groups include, without limitation, fluoroalkyl groups, such as trifluoromethyl, difluoromethyl, trifluoroethyl and the like. [0051] The term "alkylalkoxy" refers to the groups -alkylene-O-alkyl, alkylene-O- substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene-O-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein. [0052] The term "alkylthioalkoxy" refers to the group -a Iky lene-S-a I kyl, alkylene-S- substituted alkyl, substituted a Ikylene-S-a Ikyl and substituted alkylene-S-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.
[0053] "Alkenyl" refers to straight chain or branched hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and having at least 1 and preferably from 1 to 2 sites of double bond unsaturation. This term includes, by way of example, bi-vinyl, allyl, and but-3-en-l-yl. Included within this term are the cis and trans isomers or mixtures of these isomers.
[0054] The term "substituted alkenyl" refers to an alkenyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO- substituted alkyl, -SO-aryl, -SO-heteroaryl, -SCh-alkyl, -SCh-substituted alkyl, -SCh-aryl and -SO2- heteroaryl.
[0055] "Alkynyl" refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of triple bond unsaturation. Examples of such alkynyl groups include acetylenyl (-C CH), and propargyl (-CH2C CH).
[0056] The term "substituted alkynyl" refers to an alkynyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO- substituted alkyl, -SO-aryl, -SO-heteroaryl, -SCh-alkyl, -SCh-substituted alkyl, -SCh-aryl, and - SOz-heteroaryl.
[0057] "Alkynyloxy" refers to the group -O-alkynyl, wherein alkynyl is as defined herein. Alkynyloxy includes, by way of example, ethynyloxy, propynyloxy, and the like.
[0058] "Acyl" refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl- C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclyl-C(O)-, and substituted heterocyclyl-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. For example, acyl includes the "acetyl" group CH3C(O)-
[0059] "Acylamino" refers to the groups -NR20C(O)alkyl, -NR20C(O)substituted alkyl, N R20C(O)cycloalkyl, -NR20C(O)substituted cycloalkyl, -NR20C(O)cycloalkenyl, -NR20C(O)substituted cycloalkenyl, -NR20C(O)alkenyl, -NR20C(O)substituted alkenyl, -NR20C(O)alkynyl, - NR20C(O)substituted alkynyl, -NR20C(O)aryl, -NR20C(O)substituted aryl, -NR20C(O)heteroaryl, -NR20C(O)substituted heteroaryl, -NR20C(O)heterocyclic, and -NR20C(O)substituted heterocyclic, wherein R20 is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0060] "Aminocarbonyl" or the term "aminoacyl" refers to the group -C(O)NR21R22, wherein R21 and R22 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R21 and R22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0061] "Aminocarbonylamino" refers to the group -NR21C(O)NR22R23 where R21, R22, and R23 are independently selected from hydrogen, alkyl, aryl or cycloalkyl, or where two R groups are joined to form a heterocyclyl group.
[0062] The term "alkoxycarbonylamino" refers to the group -NRC(O)OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclyl wherein alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.
[0063] The term "acyloxy" refers to the groups alkyl-C(O)O-, substituted a I ky l-C(O)O-„ cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, aryl-C(O)O-, heteroaryl-C(O)O-, and heterocyclyl-C(O)O- wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.
[0064] "Aminosulfonyl" refers to the group -SC>2NR21R22, wherein R21 and R22 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where R21 and R22 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.
[0065] "Sulfonylamino" refers to the group -NR21SO2R22, wherein R21 and R22 independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R21 and R22 are optionally joined together with the atoms bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0066] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of from 6 to 18 carbon atoms having a single ring (such as is present in a phenyl group) or a ring system having multiple condensed rings (examples of such aromatic ring systems include naphthyl, anthryl and indanyl) which condensed rings may or may not be aromatic, provided that the point of attachment is through an atom of an aromatic ring. This term includes, by way of example, phenyl and naphthyl. Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryl oxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SOz-alkyl, -SOz-substituted alkyl, -SCh-aryl, -SOz-heteroaryl and trihalomethyl.
[0067] "Aryloxy" refers to the group -O-aryl, wherein aryl is as defined herein, including, by way of example, phenoxy, naphthoxy, and the like, including optionally substituted aryl groups as also defined herein.
[0068] "Amino" refers to the group -NH2.
[0069] The term "substituted amino" refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclyl provided that at least one R is not hydrogen.
[0070] The term "azido" refers to the group -N3.
[0071] "Carboxyl," "carboxy" or "carboxylate" refers to -CO2H or salts thereof. [0072] "Carboxyl ester" or "carboxy ester" or the terms "carboxyalkyl" or "carboxylalkyl" refers to the groups -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substituted alkenyl, -C(O)O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O-substituted aryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-cycloalkenyl, -C(O)O-substituted cycloalkenyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclic, and -C(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0073] "(Carboxyl ester)oxy" or "carbonate" refers to the groups -O-C(O)O-alkyl, -O-C(O)O-substituted alkyl, -O-C(O)O-alkenyl, -O-C(O)O-substituted alkenyl, -O-C(O)O-alkynyl, -O-C(O)O-substituted alkynyl, -O-C(O)O-aryl, -O-C(O)O-substituted aryl, -O-C(O)O-cycloalkyl, -O-C(O)O-substituted cycloalkyl, -O-C(O)O-cycloalkenyl, -O-C(O)O-substituted cycloalkenyl, -O-C(O)O-heteroaryl, -O-C(O)O-substituted heteroaryl, -O-C(O)O-heterocyclic, and -O-C(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0074] "Cyano" or "nitrile" refers to the group -CN.
[0075] "Cycloalkyl" refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems. Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
[0076] The term "substituted cycloalkyl" refers to cycloalkyl groups having from 1 to 5 substituents, or from I to 3 substituents, selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryl oxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SCh-alkyl, -SCh-substituted alkyl, -SCh-aryl and -SCh-heteroaryl.
[0077] "Cycloalkenyl" refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple rings and having at least one double bond and preferably from 1 to 2 double bonds.
[0078] The term "substituted cycloalkenyl" refers to cycloalkenyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO- substituted alkyl, -SO-aryl, -SO-heteroaryl, -SCh-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2- heteroaryl.
[0079] "Cycloalkynyl" refers to non-aromatic cycloalkyl groups of from 5 to 10 carbon atoms having single or multiple rings and having at least one triple bond.
[0080] "Cycloalkoxy" refers to -O-cycloalkyl.
[0081] "Cycloalkenyloxy" refers to -O-cycloalkenyl.
[0082] "Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.
[0083] "Hydroxy" or "hydroxyl" refers to the group -OH.
[0084] "Heteroaryl" refers to an aromatic group of from 1 to 15 carbon atoms, such as from 1 to 10 carbon atoms and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. Such heteroaryl groups can have a single ring (such as, pyridinyl, imidazolyl or furyl) or multiple condensed rings in a ring system (for example as in groups such as, indolizinyl, quinolinyl, benzofuran, benzimidazolyl or benzothienyl), wherein at least one ring within the ring system is aromatic. To satisfy valence requirements, any heteroatoms in such heteroaryl rings may or may not be bonded to H or a substituent group, e.g., an alkyl group or other substituent as described herein. In certain embodiments, the nitrogen and/or sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N->0), sulfinyl, or sulfonyl moieties. This term includes, by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SOz-alkyl, -SO2- substituted alkyl, -SCh-aryl and -SCh-heteroaryl, and trihalomethyl.
[0085] The term "heteroaralkyl" refers to the groups -alkylene-heteroaryl where alkylene and heteroaryl are defined herein. This term includes, by way of example, pyridylmethyl, pyridylethyl, indolylmethyl, and the like.
[0086] "Heteroaryl oxy" refers to -O-heteroaryl.
[0087] "Heterocycle," "heterocyclic," "heterocycloalkyl," and "heterocyclyl" refer to a saturated or unsaturated group having a single ring or multiple condensed rings, including fused bridged and spiro ring systems, and having from 3 to 20 ring atoms, including 1 to 10 hetero atoms. These ring atoms are selected from nitrogen, sulfur, or oxygen, where, in fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through the non-aromatic ring. In certain embodiments, the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N- oxide, -S(O)-, or -SCh- moieties. To satisfy valence requirements, any heteroatoms in such heterocyclic rings may or may not be bonded to one or more H or one or more substituent group(s), e.g., an alkyl group or other substituent as described herein.
[0088] Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like.
[0089] Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SCh-a Ikyl, -SCh-substituted alkyl, -SCh-aryl, -SOz-heteroaryl, and fused heterocycle.
[0090] "Heterocyclyloxy" refers to the group -O-heterocyclyl.
[0091] The term "heterocyclylthio" refers to the group heterocyclic-S-.
[0092] The term "heterocyclene" refers to the diradical group formed from a heterocycle, as defined herein.
[0093] The term "hydroxyamino" refers to the group -NHOH.
[0094] "Nitro" refers to the group -NO2.
[0095] "Oxo" refers to the atom (=0).
[0096] "Sulfonyl" refers to the group -S02-alkyl, -SO2-substituted alkyl, -SO2-alkenyl, - S02-substituted alkenyl, -SO2-cycloalkyl, -S02-substituted cylcoalkyl, -SO2-cycloalkenyl, -SO2- substituted cylcoalkenyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic, and -S02-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Sulfonyl includes, by way of example, methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-. [0097] "Sulfonyloxy" refers to the group -OSOz-alkyl, -OSOz-substituted alkyl, -OSOz- alkenyl, -OSOz-substituted alkenyl, -OSOz-cycloalkyl, -OSOz-substituted cylcoalkyl, -OSO2- cycloalkenyl, -OSOz-substituted cylcoalkenyl, -OSOz-aryl, -OSOz-substituted aryl, -OSOz- heteroaryl, -OSOz-substituted heteroaryl, -OSOz-heterocyclic, and -OSOz-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0098] "Sulfate" or "sulfate ester" refers the group -O-SO2-OH, -O-SOz-O-alkyl, -O-SO2- O-substituted alkyl, -O-SOz-O-alkenyl, -O-SOz-O-substituted alkenyl, -O-SOz-O-cycloalkyl, -O- SOz-O-substituted cylcoalkyl, -O-SOz-O-cycloalkenyl, -O-SOz-O-substituted cylcoalkenyl, -O-SO2- O-aryl, -O-SOz-O-substituted aryl, -O-SOz-O-heteroaryl, -O-SOz-O-substituted heteroaryl, -O- SOz-O-heterocyclic, and -O-SOz-O-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
[0099] The term "aminocarbonyloxy" refers to the group -OC(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
[00100] "Thiol" refers to the group -SH.
[00101] "Thioxo" or the term "thioketo" refers to the atom (=S).
[00102] "Alkylthio" or the term "thioalkoxy" refers to the group -S-alkyl, wherein alkyl is as defined herein. In certain embodiments, sulfur may be oxidized to -S(O)-. The sulfoxide may exist as one or more stereoisomers.
[00103] The term "substituted thioalkoxy" refers to the group -S-substituted alkyl.
[00104] The term "thioaryloxy" refers to the group aryl-S- wherein the aryl group is as defined herein including optionally substituted aryl groups also defined herein.
[00105] The term "thioheteroaryloxy" refers to the group heteroaryl-S- wherein the heteroaryl group is as defined herein including optionally substituted aryl groups as also defined herein. [00106] The term "thioheterocyclooxy" refers to the group heterocyclyl-S- wherein the heterocyclyl group is as defined herein including optionally substituted heterocyclyl groups as also defined herein.
[00107] In addition to the disclosure herein, the term "substituted," when used to modify a specified group or radical, can also mean that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent groups as defined below.
[00108] In addition to the groups disclosed with respect to the individual terms herein, substituent groups for substituting for one or more hydrogens (any two hydrogens on a single carbon can be replaced with =0, =NR70, =N-OR70, =N2 or =S) on saturated carbon atoms in the specified group or radical are, unless otherwise specified, -R60, halo, -O, -OR70, -SR70, -NR80R80, trihalomethyl, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -SO2R70, -SO2Q-M+, -SO2OR70, -OSO2R70, -OSO2O-M+, -OSO2OR70, -P(O)(O-)2(M+)2, -P(O)(OR70)O-M+, -P(O)(OR70) 2, -C(O)R70, -C(S)R70, -C(NR70)R70, -C(0)0“M+, -C(O)OR70, -C(S)OR70, -C(O)NR80R80, -C(NR70)NR80R80, -OC(O)R70, -OC(S)R70, -0C(0)0 M+, -OC(O)OR70, -OC(S)OR70, -NR70C(O)R70, -NR70C(S)R70, -NR70CO2-M+, -NR70CO2R70, -NR70C(S)OR70, -NR70C(O)NR80R80, -NR70C(NR70)R70 and -NR70C(NR70)NR80R80, where R60 is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each R70 is independently hydrogen or R60; each R80 is independently R70 or alternatively, two R80's, taken together with the nitrogen atom to which they are bonded, form a 5-, 6- or 7- membered heterocycloalkyl which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S, of which N may have -H or C1-C3 alkyl substitution; and each M+ is a counter ion with a net single positive charge. Each M+ may independently be, for example, an alkali ion, such as K+, Na+, Li+; an ammonium ion, such as +N(R60)4; or an alkaline earth ion, such as [Ca2+]o.s, [Mg2+]o.s, or [Ba2+]o.s ("subscript 0.5 means that one of the counter ions for such divalent alkali earth ions can be an ionized form of a compound of the invention and the other a typical counter ion such as chloride, or two ionized compounds disclosed herein can serve as counter ions for such divalent alkali earth ions, or a doubly ionized compound of the invention can serve as the counter ion for such divalent alkali earth ions). As specific examples, -NR80R80 is meant to include -NH2, -N H-alkyl, /V-pyrrolidinyl, /V-piperazinyl, 4/V-methyl-piperazin-l-yl and A/-morpholinyl.
[00109] In addition to the disclosure herein, substituent groups for hydrogens on unsaturated carbon atoms in "substituted" alkene, alkyne, aryl and heteroaryl groups are, unless otherwise specified, -R60, halo, -O M+, -OR70, -SR70, -S_M+, -NR80R80, trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R70, -SO3 M+, -SO3R70, -OSO2R70, -OSO3 M+, -OSO3R70, -PO3’2(M+)2, -P(O)(OR70)O-M+, -P(O)(OR70)2, -C(O)R70, -C(S)R70, -C(NR70)R70, -C02’M+, -CO2R70, -C(S)OR70, -C(O)NR80R80, -C(NR70)NR80R80, -OC(O)R70, -OC(S)R70, -OCO2 M ', -OCO2R70, -OC(S)OR70, -NR70C(O)R70, -NR70C(S)R70, -NR70CO2’M+, -NR70CO2R70, -NR70C(S)OR70, -NR70C(O)NR80R80, -NR70C(NR70)R70 and -NR70C(NR70)NR80R80, where R60, R70, R80 and M+ are as previously defined, provided that in case of substituted alkene or alkyne, the substituents are not -O M+, -OR70, -SR70, or -S"M+.
[00110] In addition to the groups disclosed with respect to the individual terms herein, substituent groups for hydrogens on nitrogen atoms in "substituted" heteroalkyl and cycloheteroalkyl groups are, unless otherwise specified, -R60, -O M+, -OR70, -SR70, -S M+, -NR8°R8°, trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R70, -S(O)2O’M+, -S(O)2OR70, -OS(O)2R70, -OS(O)2O M+, -OS(O)2OR70, -P(O)(Oj2(M+)2, -P(O)(OR70)O M+, -P(O)(OR70)(OR70), -C(O)R70, -C(S)R70, -C(NR70)R70, -C(O)OR70, -C(S)OR70, -C(O)NR80R80, -C(NR70)NR80R80, -OC(O)R70, -OC(S)R70, -OC(O)OR70, -OC(S)OR70, -NR70C(O)R70, -NR70C(S)R70, -NR70C(O)OR70, -NR70C(S)OR70, -NR70C(O)NR80R80, -NR70C(NR70)R70 and -NR70C(NR70)NR80R80, where R60, R70, R80 and M+ are as previously defined.
[00111] In addition to the disclosure herein, in a certain embodiment, a group that is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.
[00112] It is understood that in all substituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves (e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, which is further substituted by a substituted aryl group, etc.) are not intended for inclusion herein. In such cases, the maximum number of such substitutions is three. For example, serial substitutions of substituted aryl groups specifically contemplated herein are limited to substituted aryl-(substituted aryl)-substituted aryl.
[00113] Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to the group (a ryl)-(a Ikyl)-O-C(O)-.
[00114] As to any of the groups disclosed herein which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible. In addition, the subject compounds include all stereochemical isomers arising from the substitution of these compounds.
[00115] "Optional" or "optionally" means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, "optionally substituted aryl" means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution. When a functional group is described as "optionally substituted," and in turn, substituents on the functional group are also "optionally substituted" and so on, for the purposes of this disclosure, such iterations are limited to five, and in some cases, such iterations are limited to two.
[00116] "Pharmaceutically acceptable carrier, diluent or excipient" includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier which has been approved by the United States Food and Drug Administration as being acceptable for use in humans or domestic animals. [00117] The term "pharmaceutically acceptable salt" means a salt which is acceptable for administration to a patient, such as a mammal (salts with counterions having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids. "Pharmaceutically acceptable salt" refers to pharmaceutically
T1 acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, and the like. "Pharmaceutically acceptable salt" includes both acid and base addition salts.
[00118] "Pharmaceutically acceptable acid addition salt" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as, but not limited to, acetic acid, 2,2-dichloroacetic acid, adipic acid, alginic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, 4- acetamidobenzoic acid, camphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-l,2-disulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid, isobutyric acid, lactic acid, lactobionic acid, lauric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, mucic acid, naphthalene-l,5-disulfonic acid, naphthalene-2-sulfonic acid, l-hydroxy-2-naphthoic acid, nicotinic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, propionic acid, pyroglutamic acid, pyruvic acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, and the like.
[00119] "Pharmaceutically acceptable base addition salt" refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Examples of suitable inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, diethanolamine, ethanolamine, deanol, 2- dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, benethamine, benzathine, ethylenediamine, glucosamine, methylglucamine, theobromine, triethanolamine, tromethamine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Examples of suitable organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
[00120] A "pharmaceutical composition" refers to a formulation of a compound and a medium generally accepted in the art for the delivery of the biologically active compound to a mammal, e.g., humans. Such a medium can include a pharmaceutically acceptable carrier, diluent, or excipient.
[00121] "Therapeutically effective amount" refers to that amount of a compound which, when administered to a mammal, e.g., a human, is sufficient to effect treatment of the disease or condition of interest in a mammal, e.g., a human, having the disease or condition. The amount of a compound which constitutes a "therapeutically effective amount" will vary depending on the compound, the disease or condition and its severity, the manner of administration, and the age of the mammal to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.
[00122] A compound as disclosed herein, or a pharmaceutically acceptable salt thereof, may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. A compound as disclosed herein is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.
[00123] "Solvate" refers to a complex formed by combination of solvent molecules with molecules or ions of the solute. The solvent can be an organic compound, an inorganic compound, or a mixture of both. Some examples of solvents include, but are not limited to, methanol, N, A/-di methylformamide, tetra hydrofuran, dimethylsulfoxide, and water. When the solvent is water, the solvate formed is a hydrate.
[00124] A "stereoisomer" refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers", which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.
[00125] "Tautomer" refers to alternate forms of a molecule that differ only in electronic bonding of atoms and/or in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a -N=C(H)-NH- ring atom arrangement, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. A person of ordinary skill in the art would recognize that other tautomeric ring atom arrangements are possible.
[00126] It will be appreciated that the term "or a salt or solvate or stereoisomer thereof" is intended to include all permutations of salts, solvates and stereoisomers, such as a solvate of a pharmaceutically acceptable salt of a stereoisomer of subject compound.
[00127] While it may be possible for the compounds of the subject invention to be administered as the raw chemical, it is also possible to present them as a pharmaceutical composition. Accordingly, provided herein are pharmaceutical compositions which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. Pharmaceutically acceptable carriers and other therapeutic ingredients may include one or more excipients and/or one or more vehicles. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, drageemaking, levigating, emulsifying, encapsulating, entrapping or compression processes.
[00128] The use of parentheses in substituent groups is used herein to conserve space. Accordingly, the use of parenthesis in a substituent group indicates that the group enclosed within the parentheses is attached directly to the atom preceding the parenthesis.
[00129] The term "drug delivery device" shall be understood to encompass any type of device, system or apparatus designed to immediately dispense a drug to a human or nonhuman body. By "immediately dispense" is meant an absence of any necessary intermediate manipulation of the drug by a user between discharge of the drug from the drug delivery device and administration to the human or non-human body. Without limitation, typical examples of drug delivery devices may be found in injection devices, inhalers, and stomach tube feeding systems. Again without limitation, exemplary injection devices may include, e.g., syringes, autoinjectors, injection pen devices and spinal injection systems.
[00130] A "ubiquitin ligase binding moiety" refers to a portion of a bifunctional compound that binds to a ubiquitin ligase (e.g., an E3 ligase).
[00131] A "protein targeting moiety" refers to a portion of a bifunctional compound that binds to a protein of interest. The protein targeting moiety, when in the presence of a ubiquitin ligase binding moiety, brings a protein of interest in close proximity of a ubiquitin ligase thereby leading to the ubiquitination and degradation of said protein of interest.
[00132] The terms "peptide," "polypeptide," and "protein" are used interchangeably herein, and refer to a polymeric form of amino acids of any length, which can include coded and non-coded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides having modified peptide backbones. [00133] A "secondary treatment modality" refers to a secondary treatment (i.e. a second treatment following administration of a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a compound depicted in Fig. 1) that is directed to the disease or disorder that is being treated by a composition of the present disclosure. Secondary treatment modalities are often used to supplement a treatment that is currently in use in order to improve the outcomes of individuals in need thereof relative to any single treatment.
[00134] As used herein, the terms "treatment," "treating," and the like, refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse effect attributable to the disease. "Treatment," as used herein, covers any treatment of a disease in a mammal, e.g., in a human, and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) relieving the disease, i.e., causing regression of the disease.
[00135] The terms "individual," "subject," "host," and "patient," used interchangeably herein, refer to an individual organism, e.g., a mammal, including, but not limited to, murines, simians, humans, non-human primates, mammalian farm animals, mammalian sport animals, and mammalian pets.
[00136] The term "binding" refers to a direct association between two molecules, due to, for example, covalent, electrostatic, hydrophobic, and ionic, and/or hydrogen-bond interactions, including interactions such as salt bridges and water bridges.
[00137] The term "inhibitor" refers to a compound having the ability to inhibit a biological function of a target protein or a target biological process. When inhibiting a target protein, an inhibitor can inhibit the activity of the target protein.
[00138] The terms "simultaneous" or "simultaneously" as applied to administering compounds to a subject refer to administering one or more compounds at the same time, or at two different time points that are separated by no more than 1 hour. [00139] The term "sequentially" refers to administering more than one compound at two different time points that are separated by more than 1 hour, e.g., about 2 hours, about 5 hours, 8 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, or even longer.
[00140] Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.
[00141] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.
[00142] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
[00143] It must be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an E3 ligase in a cell" includes a plurality of such E3 ligases in a plurality of cells and reference to "the metabolic disorder" includes reference to one or more metabolic disorders and equivalents thereof known to those skilled in the art, and so forth. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended to serve as antecedent basis for use of such exclusive terminology as "solely," "only" and the like in connection with the recitation of claim elements, or use of a "negative" limitation.
[00144] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments pertaining to the invention are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed. In addition, all sub-combinations of the various embodiments and elements thereof are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub-combination was individually and explicitly disclosed herein.
[00145] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.
DETAILED DESCRIPTION
[00146] The present disclosure provides pharmaceutical compositions and drug delivery devices comprising a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a compound depicted in Fig. 1. Methods are provided for inhibiting the binding of Bex to an E3 ligase in a cell, involving contacting the cell with a compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a compound depicted in Fig. 1 to inhibit the binding of Bex to an E3 ligase. The present disclosure provides methods of treatment of mitochondrial dysfunction, including methods of treatment of neurodegenerative disease, cardiovascular disease and metabolic disease.
COMPOSITIONS
[00147] The present disclosure provides compositions comprising: i) a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, or X; and ii) a pharmaceutical acceptable excipient. The present disclosure provides compositions comprising: i) a compound depicted in FIG. 1; and ii) a pharmaceutical acceptable excipient. A compound of formula I, II, III, IV, V, VI, VII, VIII, IX, or X binds to an E3 ligase non-covalently. In other words, the binding of a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, or X binds to an E3 ligase is non-covalent and is reversible. A compound depicted in FIG. 1 binds to an E3 ligase non-covalently. In other words, the binding of a compound depicted in FIG. 1 to an E3 ligase is non-covalent and is reversible.
[00148] A composition of the present disclosure can comprise, in addition to a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, or X of the present disclosure, or a compound depicted in FIG. 1, one or more of: a salt, e.g., NaCI, MgCh, KCI, MgSC , etc.; a buffering agent, e.g., a Tris buffer, N-(2-Hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), 2-(N- Morpholino)ethanesulfonic acid (MES), 2-(N-Morpholino)ethanesulfonic acid sodium salt (MES), 3-(N-Morpholino)propanesulfonic acid (MOPS), N- tris[Hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS), etc.; a solubilizing agent; a detergent, e.g., a non-ionic detergent such as Tween-20, etc.; a protease inhibitor; glycerol; and the like. In some cases, the composition does not include dimethyl sulfoxide (DMSO). [00149] The composition may comprise a pharmaceutically acceptable excipient, a variety of which are known in the art and need not be discussed in detail herein.
Pharmaceutically acceptable excipients have been amply described in a variety of publications, including, for example, "Remington: The Science and Practice of Pharmacy", 19th Ed. (1995), or latest edition, Mack Publishing Co; A. Gennaro (2000) "Remington: The Science and Practice of Pharmacy", 20th edition, Lippincott, Williams, & Wilkins; Pharmaceutical Dosage Forms and Drug Delivery Systems (1999) H.C. Ansel et al., eds 7th ed., Lippincott, Williams, & Wilkins; and Handbook of Pharmaceutical Excipients (2000) A.H. Kibbe et aL, eds., 3rd ed. Amer.
Pharmaceutical Assoc. In some cases, the pharmaceutical acceptable excipient is not dimethyl sulfoxide (DMSO).
[00150] A pharmaceutical composition can comprise: i) a compound comprising formula I, II, III, IV, V, VI, VII, VIII, IX, or X, or a compound depicted in FIG. 1; and ii) a pharmaceutically acceptable excipient. In some cases, a subject pharmaceutical composition will be suitable for administration to a subject, e.g., will be sterile. For example, in some embodiments, a subject pharmaceutical composition will be suitable for administration to a human subject, e.g., where the composition is sterile and is free of detectable pyrogens and/or other toxins.
[00151] The protein compositions may comprise other components, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium, carbonate, and the like. The compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents and the like, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, hydrochloride, sulfate salts, solvates (e.g., mixed ionic salts, water, organics), hydrates (e.g., water), and the like.
[00152] For example, compositions may include aqueous solution, powder form, granules, tablets, pills, suppositories, capsules, suspensions, sprays, and the like. The composition may be formulated according to the various routes of administration described below.
[00153] Suitable excipients (e.g., for oral formulations) include, e.g., croscarmellose sodium (disintegrant), microcrystalline cellulose (filler), magnesium stearate, (antiadherent, lubricant), povidone (disintegrant), sodium starch glycolate (disintegrant), silica, and colloidal anhydrous (glidant, lubricant).
[00154] Suitable excipients include, e.g., pyrazole-based heterocycle core excipient oral tablet formulation for cluster 47 compounds, croscarmellose sodium, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate (sodium dodecyl sulfate; SDS).
[00155] Suitable excipients include, e.g., oxazole core with sulfone moiety excipient oral tablet formulation for cluster 75 compounds, microcrystalline cellulose, docusate sodium, magnesium stearate, povidone, and sodium starch glycolate.
[00156] Suitable excipients include, e.g., sulfone-based excipient oral tablet formulation for cluster 75 compounds, including: croscarmellose sodium, docusate sodium, microcrystalline cellulose, povidone, sodium benzoate, sodium starch glycolate, and stearic acid.
[00157] Suitable excipients include, e.g., sodium chloride, poly(ethylene glycol) (PEG), benzyl alcohol, sorbitol, saccharin sodium, sodium citrate, citric acid anhydrous, methyl parahydroxybenzoate, propyl parahydroxybenzoate, propylene glycol, maltodextrin, lactic acid, and glyceryl triacetate.
[00158] Aspects of the present disclosure include compositions comprising: a compound of formula (I): wherein:
R1, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
[00159] The substituents related to compounds of formula (I) are described in more detail below.
[00160] In certain embodiments, R1 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R1 is H. In certain embodiments, R1 is halo (e.g., F, Cl, Br, I). In certain embodiments, R1 is hydroxyl. In certain embodiments, R1 is alkoxy. In certain embodiments, R1 is nitro. In certain embodiments, R1 is amino or substituted amino. In certain embodiments, R1 is carboxyl. In certain embodiments, R1 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R1 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R1 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R1 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C35 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R1 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R1 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a C& aryl or Ce substituted aryl. In certain embodiments, R1 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R1 is selected from H, alkyl, alkoxy and halo. In certain embodiments, R1 is methyl. In certain embodiments, R1 is CL [00161] In certain embodiments, R2 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R2 is H. In certain embodiments, R2 is halo (e.g., F, Cl, Br, I). In certain embodiments, R2 is hydroxyl. In certain embodiments, R2 is alkoxy. In certain embodiments, R2 is nitro. In certain embodiments, R2 is amino or substituted amino. In certain embodiments, R2 is carboxyl. In certain embodiments, R2 is carboxylalkyl, such as C1-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R2 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R2 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R2 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R2 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R2 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a C& aryl or Ce substituted aryl. In certain embodiments, R2 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R2 is selected from H, alkyl, alkoxy and halo. In certain embodiments, R2 is methyl. In certain embodiments, R2 is Cl. In certain embodiments, R2 is F.
[00162] In certain embodiments, R3 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R3 is H. In certain embodiments, R3 is halo (e.g., F, Cl, Br, I). In certain embodiments, R3 is hydroxyl. In certain embodiments, R3 is alkoxy. In certain embodiments, R3 is nitro. In certain embodiments, R3 is amino or substituted amino. In certain embodiments, R3 is carboxyl. In certain embodiments, R3 is carboxylalkyl, such as C1-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R3 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R3 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R3 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R3 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R3 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl. In certain embodiments, R3 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a Cs heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R3 is selected from H, alkyl, alkoxy and halo. In certain embodiments, R3 is methoxy or ethoxy. In certain embodiments, R3 is methyl. In certain embodiments, R3 is tert-butyl. In certain embodiments, R3 is F. In certain embodiments, R3 is Br. In certain embodiments, R3 is Cl.
[00163] In certain embodiments, R4 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R4 is H. In certain embodiments, R4 is halo (e.g., F, Cl, Br, I). In certain embodiments, R4 is hydroxyl. In certain embodiments, R4 is alkoxy. In certain embodiments, R4 is nitro. In certain embodiments, R4 is amino or substituted amino. In certain embodiments, R4 is carboxyl. In certain embodiments, R4 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R4 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R4 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R4 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R4 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R4 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a C& aryl or C& substituted aryl. In certain embodiments, R4 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a C& heteroaryl or CK substituted heteroaryl. In certain embodiments, R4 is selected from H, alkyl, alkoxy and halo. In certain embodiments, R4 is methyl. In certain embodiments, R4 is Cl. In certain embodiments, R4 is F.
[00164] In certain embodiments, R5 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R5 is H. In certain embodiments, R5 is halo (e.g., F, Cl, Br, I). In certain embodiments, R5 is hydroxyl. In certain embodiments, R5 is alkoxy. In certain embodiments, R5 is nitro. In certain embodiments, R5 is amino or substituted amino. In certain embodiments, R5 is carboxyl. In certain embodiments, R5 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R5 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R5 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R5 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R5 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R5 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl. In certain embodiments, R5 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R5 is selected from H, alkyl, alkoxy and halo. In certain embodiments, R5 is methyl. In certain embodiments, R5 is CL
[00165] In certain embodiments, R5 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R6 is H. In certain embodiments, R6 is halo (e.g., F, Cl, Br, I). In certain embodiments, R6 is hydroxyl. In certain embodiments, R6 is alkoxy. In certain embodiments, R6 is nitro. In certain embodiments, R6 is amino or substituted amino. In certain embodiments, R6 is carboxyl. In certain embodiments, R6 is carboxylalkyl, such as C1-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R6 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R6 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C23 substituted alkenyl. In certain embodiments, R6 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R6 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R6 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl. In certain embodiments, R6 is selected from H, alkyl, alkoxy and halo. In certain embodiments, R6 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R6 is selected from H, alkyl, substituted alkyl, amino, substituted amino, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl. In certain embodiments, R6 is selected from H and -NR9R10, wherein R9 and R10 are independently selected from H, alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl, or R9 and R10 together with the N to which they are attached form a cycloalkyl or substituted cycloalkyl. In certain embodiments, R6 is -NR9R10, wherein R9 and R10 together with the N to which they are attached form a substituted cyclohexyl ring, a cyclopentyl ring or a cycloheptyl ring. In certain embodiments, R6 is -NR9R10, wherein R9 is propyl and R10 is propyl. In certain embodiments, R6 is -NR9R10, wherein R9 is and R10 is ethyl. In certain embodiments, R6 is -NR9R10, wherein R9 is methyl
[00166] In certain embodiments, R7 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R7 is H. In certain embodiments, R7 is halo (e.g., F, Cl, Br, I). In certain embodiments, R7 is hydroxyl. In certain embodiments, R7 is alkoxy. In certain embodiments, R7 is nitro. In certain embodiments, R7 is amino or substituted amino. In certain embodiments, R7 is carboxyl. In certain embodiments, R7 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R7 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R7 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R7 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R7 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R7 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl. In certain embodiments, R7 is selected from H, alkyl, alkoxy and halo. In certain embodiments, R7 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R7 is selected from H, alkyl, substituted alkyl, amino, substituted amino, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl. In certain embodiments, R7 is selected from H and -NR9R10, wherein R9 and R10 are independently selected from H, alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl, or R9 and R10 together with the N to which they are attached form a cycloalkyl or substituted cycloalkyl. In certain embodiments, R7 is -NR9R10, wherein R9 and R10 together with the N to which they are attached form a substituted cyclohexyl ring or a cycloheptyl ring. In certain embodiments, R7 is -NR9R10, wherein R9 is butyl and R10 is phenyl.
[00167] In certain embodiments, R8 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R8 is H. In certain embodiments, R8 is halo (e.g., F, Cl, Br, I). In certain embodiments, R8 is hydroxyl. In certain embodiments, R8 is alkoxy. In certain embodiments, R8 is nitro. In certain embodiments, R8 is amino or substituted amino. In certain embodiments, R8 is carboxyl. In certain embodiments, R8 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R8 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R8 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R8 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R8 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R8 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl. In certain embodiments, R8 is selected from H, alkyl, alkoxy and halo. In certain embodiments, R8 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
[00168] In some embodiments, the compound is selected from:
[00169] Aspects of the present disclosure include compositions comprising: a compound of formula (II): wherein:
Ra is selected from H, alkyl, and substituted alkyl;
R1, R2, R3, R4 and R5 are each independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
[00170] The substituents related to compounds of formula (II) are described in more detail below. [00171] In certain embodiments, Ra is selected from H, alkyl, and substituted alkyl. In certain embodiments, Ra is H. In certain embodiments, Ra is alkyl. In certain embodiments, Ra is substituted alkyl. In certain embodiments, Ra is methyl. In certain embodiments, Ra is ethyl. [00172] In certain embodiments, R1 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R1 is H. In certain embodiments, R1 is halo (e.g., F, Cl, Br, I). In certain embodiments, R1 is hydroxyl. In certain embodiments, R1 is alkoxy. In certain embodiments, R1 is nitro. In certain embodiments, R1 is amino or substituted amino. In certain embodiments, R1 is carboxyl. In certain embodiments, R1 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R1 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R1 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R1 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R1 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R1 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl. In certain embodiments, R1 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R1 is selected from H, alkyl and halo. In certain embodiments, R1 is Cl. In certain embodiments, R1 is Br.
[00173] In certain embodiments, R2 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R2 is H. In certain embodiments, R2 is halo (e.g., F, Cl, Br, I). In certain embodiments, R2 is hydroxyl. In certain embodiments, R2 is alkoxy. In certain embodiments, R2 is nitro. In certain embodiments, R2 is amino or substituted amino. In certain embodiments, R2 is carboxyl. In certain embodiments, R2 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R2 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R2 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R2 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R2 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R2 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl. In certain embodiments, R2 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R2 is selected from H, alkyl, alkoxy and halo. In certain embodiments, R2 is F.
[00174] In certain embodiments, R3 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R3 is H. In certain embodiments, R3 is halo (e.g., F, Cl, Br, I). In certain embodiments, R3 is hydroxyl. In certain embodiments, R3 is alkoxy. In certain embodiments, R3 is nitro. In certain embodiments, R3 is amino or substituted amino. In certain embodiments, R3 is carboxyl. In certain embodiments, R3 is carboxylalkyl, such as C1-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R3 is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R3 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R3 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R3 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R3 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a C& aryl or Ce substituted aryl. In certain embodiments, R3 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R3 is selected from H, alkyl, alkoxy and halo. In certain embodiments, R3 is methoxy or ethoxy. In certain embodiments, R3 is methyl. In certain embodiments, R3 is Br.
[00175] In certain embodiments, R4 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R4 is H. In certain embodiments, R4 is halo (e.g., F, Cl, Br, I). In certain embodiments, R4 is hydroxyl. In certain embodiments, R4 is alkoxy. In certain embodiments, R4 is nitro. In certain embodiments, R4 is amino or substituted amino. In certain embodiments, R4 is carboxyl. In certain embodiments, R4 is carboxylalkyl, such as C1-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R4 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R4 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R4 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C35 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R4 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C36 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R4 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a C& aryl or Ce substituted aryl. In certain embodiments, R4 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R4 is selected from H, alkyl, alkoxy and halo. In certain embodiments, R4 is F.
[00176] In certain embodiments, R5 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R5 is H. In certain embodiments, R5 is halo (e.g., F, Cl, Br, I). In certain embodiments, R5 is hydroxyl. In certain embodiments, R5 is alkoxy. In certain embodiments, R5 is nitro. In certain embodiments, R5 is amino or substituted amino. In certain embodiments, R5 is carboxyl. In certain embodiments, R5 is carboxylalkyl, such as C1-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R5 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R5 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R5 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R5 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R5 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl. In certain embodiments, R5 is heteroaryl or substituted heteroaryl, such as Cs s heteroaryl or Cs s substituted heteroaryl, such as a Cs heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R5 is selected from H, alkyl, alkoxy and halo. In certain embodiments, R5 is Br. In certain embodiments, Rs is Cl.
[00177] In certain embodiments, the compound is selected from:
[00178] Aspects of the present disclosure include compositions comprising: a compound of formula (III): wherein:
Ra is selected from H, halo, alkyl, and substituted alkyl;
R6, R7 and R8 are each independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
[00179] The substituents related to compounds of formula (III) are described in more detail below.
[00180] In certain embodiments, Ra is selected from H, alkyl, and substituted alkyl. In certain embodiments, Ra is H. In certain embodiments, Ra is alkyl. In certain embodiments, Ra is substituted alkyl. In certain embodiments, Ra is methyl. In certain embodiments, Ra is ethyl. [00181] In certain embodiments, Re is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R6 is H. In certain embodiments, R6 is halo (e.g., F, Cl, Br, I). In certain embodiments, R6 is hydroxyl. In certain embodiments, R6 is alkoxy. In certain embodiments, R6 is nitro. In certain embodiments, R6 is amino or substituted amino. In certain embodiments, R6 is carboxyl. In certain embodiments, R6 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R6 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R6 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R6 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R6 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R6 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl. In certain embodiments, R6 is selected from H, alkyl, alkoxy and halo. In certain embodiments, R6 is heteroaryl or substituted heteroaryl, such as Cs s heteroaryl or Cs s substituted heteroaryl, such as a Cs heteroaryl or Cs substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
[00182] In certain embodiments, R7 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R7 is H. In certain embodiments, R7 is halo (e.g., F, Cl, Br, I). In certain embodiments, R7 is hydroxyl. In certain embodiments, R7 is alkoxy. In certain embodiments, R7 is nitro. In certain embodiments, R7 is amino or substituted amino. In certain embodiments, R7 is carboxyl. In certain embodiments, R7 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R7 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R7 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R7 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R7 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R7 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl. In certain embodiments, R7 is selected from H, alkyl, alkoxy and halo. In certain embodiments, R7 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R7 is selected from H, alkyl, substituted alkyl, amino, substituted amino, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl. In certain embodiments, R7 is selected from H and -NR9R10, wherein R9 and R10 are independently selected from H, alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl, or R9 and R10 together with the N to which they are attached form a cycloalkyl or substituted cycloalkyl. In certain embodiments, R7 is -NR9R10, wherein R9 and R10 together with the N to which they are attached form a substituted cyclohexyl ring. In certain embodiments, R7 is -NR9R10, wherein R9 is methyl and R10
[00183] In certain embodiments, R8 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R8 is H. In certain embodiments, R8 is halo (e.g., F, Cl, Br, I). In certain embodiments, R8 is hydroxyl. In certain embodiments, R8 is alkoxy. In certain embodiments, R8 is nitro. In certain embodiments, R8 is amino or substituted amino. In certain embodiments, R8 is carboxyl. In certain embodiments, R8 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R8 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R8 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R8 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R8 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R8 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a C& aryl or Ce substituted aryl. In certain embodiments, R8 is selected from H, alkyl, alkoxy and halo. In certain embodiments, R8 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
[00184] In some embodiments, the compound is:
[00185] Aspects of the present disclosure include compositions comprising: a compound of formula (IV): wherein:
R1 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
R2 and R3 are each independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl and substituted alkenyl; and a pharmaceutically acceptable excipient.
[00186] The substituents related to compounds of formula (IV) are described in more detail below.
[00187] In certain embodiments, R1 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R1 is H. In certain embodiments, R1 is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R1 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R1 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or Cs s substituted cycloalkyl. In certain embodiments, R1 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R1 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl. In certain embodiments, R1 is heteroaryl or substituted heteroaryl, such as C5- 8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R1 is benzyl. In certain embodiments, R1 is isobutyl. In certain embodiments, R1 is CH2CH2CI.
[00188] In certain embodiments, R2 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R2 is H. In certain embodiments, R2 is halo (e.g., F, Cl, Br, I). In certain embodiments, R2 is hydroxyl. In certain embodiments, R2 is alkoxy. In certain embodiments, R2 is nitro. In certain embodiments, R2 is amino or substituted amino. In certain embodiments, R2 is carboxyl. In certain embodiments, R2 is carboxylalkyl, such as C1-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R2 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R2 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R2 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R2 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R2 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Cg aryl or Cg substituted aryl. In certain embodiments, R2 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Cg heteroaryl or Cg substituted heteroaryl. In certain embodiments, R2 is nitro or halo. In certain embodiments, R2 is nitro. In certain embodiments, R2 is Br.
[00189] In certain embodiments, R3 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R3 is H. In certain embodiments, R3 is halo (e.g., F, Cl, Br, I). In certain embodiments, R3 is hydroxyl. In certain embodiments, R3 is alkoxy. In certain embodiments, R3 is nitro. In certain embodiments, R3 is amino or substituted amino. In certain embodiments, R3 is carboxyl. In certain embodiments, R3 is carboxylalkyl, such as C1-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R3 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R3 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R3 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R3 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R3 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Cg aryl or C substituted aryl. In certain embodiments, R3 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Cg heteroaryl or C& substituted heteroaryl. In certain embodiments, R3 is Cl. In certain embodiments, R3 is Br.
[00190] In some embodiments, the compound is selected from:
[00191] Aspects of the present disclosure include compositions comprising: a compound of formula (V): wherein:
R1 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
R2 and R3 are each independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R2 and R3 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl; and a pharmaceutically acceptable excipient.
[00192] The substituents related to compounds of formula (V) are described in more detail below.
[00193] In certain embodiments, R1 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R1 is selected from H, halo, hydroxyl, amino, substituted aminoalkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl. In certain embodiments, R1 is H. In certain embodiments, R1 is halo (e.g., F, Cl, Br, I). In certain embodiments, R1 is hydroxyl. In certain embodiments, R1 is alkoxy. In certain embodiments, R1 is nitro. In certain embodiments, R1 is amino or substituted amino. In certain embodiments, R1 is carboxyl. In certain embodiments, R1 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R1 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R1 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R1 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R1 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R1 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a C& aryl or Ce substituted aryl. In certain embodiments, R1 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a C& heteroaryl or Ce substituted heteroaryl. In certain embodiments, R1 is Br. In certain embodiments, R1 is selected from -NR9R10, wherein R9 and R10 are independently selected from H, alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl, or R9 and R10 together with the N to which they are attached form a heterocycloalkyl or substituted heterocycloalkyl. In certain embodiments, R1 is -NR9R10, wherein R9 and R10 together with the N to which they are attached form a substituted cyclohexyl ring. In certain embodiments, R6 is -NR9R10, wherein R9 is ethyl and R10 is ethoxy. [00194] In certain embodiments, R2 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R2 and R3 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl. In certain embodiments, R2 is H. In certain embodiments, R2 is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-6 substituted alkyl, or Ci-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R3 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R2 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R2 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3- 6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R2 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or C& substituted aryl. In certain embodiments, R2 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R2 is selected from H, alkyl and substituted alkyl. In certain embodiments, R2 is CH2CH2OCH3. In certain embodiments, R2 is CH2CH2CH2COOH. In certain embodiments, R2 is CH2CH2OH. In certain embodiments, R2 is CH2CH2O(CO)CH3.
[00195] In certain embodiments, R3 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R2 and R3 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl. In certain embodiments, R3 is H. In certain embodiments, R3 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R3 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R3 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C35 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R3 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3- 6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R3 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or C& substituted aryl. In certain embodiments, R3 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R3 is selected from H, alkyl and substituted alkyl. In certain embodiments, R3 is CH2CH2OCH3. In certain embodiments, R3 is CH2CH2CH2COOH. In certain embodiments, R3 is CH2CH2OH. In certain embodiments, R3 is CH2CH2O(CO)CH3.
[00196] In certain embodiments, R2 and R3 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl. In certain embodiments, R2 and R3 together with the N to which they are attached form a heterocycloalkyl or substituted heterocycloalkyl. In certain embodiments, R2 and R3 together with the N to which they are attached form a substituted cyclohexyl ring.
[00197] In some embodiments, the compound is selected from:
[00198] Aspects of the present disclosure include compositions comprising: a compound of formula (VI): wherein:
R1 and R2 are independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
[00199] The substituents related to compounds of formula (VI) are described in more detail below.
[00200] In certain embodiments, R1 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R1 is H. In certain embodiments, R1 is halo (e.g., F, Cl, Br, I). In certain embodiments, R1 is hydroxyl. In certain embodiments, R1 is alkoxy. In certain embodiments, R1 is nitro. In certain embodiments, R1 is amino or substituted amino. In certain embodiments, R1 is carboxyl. In certain embodiments, R1 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R1 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R1 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R1 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R1 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R1 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a C& aryl or C& substituted aryl. In certain embodiments, R1 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a Cs heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R1 is . In certain embodiments, R1 is
[00201] In certain embodiments, R2 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R2 is H. In certain embodiments, R2 is halo (e.g., F, Cl, Br, I). In certain embodiments, R2 is hydroxyl. In certain embodiments, R2 is alkoxy. In certain embodiments, R2 is nitro. In certain embodiments, R2 is amino or substituted amino. In certain embodiments, R2 is carboxyl. In certain embodiments, R2 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R2 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R2 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R2 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R2 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R2 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl. In certain embodiments, R2 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl.
In certain embodiments,
[00202] In some embodiments, the compound is selected from:
[00203] Aspects of the present disclosure include compositions comprising: a compound of formula (VII): wherein:
R1 and R2 are each independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R1 and R2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl; and a pharmaceutically acceptable excipient.
[00204] The substituents related to compounds of formula (VII) are described in more detail below.
[00205] In certain embodiments, R1 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R1 and R2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl. In certain embodiments, R1 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R1 is H. In certain embodiments, R1 is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R1 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R1 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R1 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R1 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a C& aryl or Ce substituted aryl. In certain embodiments, R1 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R1 is propyl. In certain embodiments, R1
[00206] In certain embodiments, R2 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R1 and R2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl. In certain embodiments, R2 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R2 is H. In certain embodiments, R2 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R2 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R2 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C35 cycloalkyl or C35 substituted cycloalkyl. In certain embodiments, R2 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R2 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a C& aryl or Ce substituted aryl. In certain embodiments, R2 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R2 is propyl. In certain embodiments, R2
[00207] In certain embodiments, R1 and R2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl. In certain embodiments, R1 and R2 together with the N to which they are attached form a heterocyclohexyl ring or substituted heterocyclohexyl ring.
[00208] In some embodiments, the compound is selected from: [00209] Aspects of the present disclosure include compositions comprising: a compound of formula (VIII): wherein:
R1 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
[00210] The substituents related to compounds of formula (VIII) are described in more detail below.
[00211] In certain embodiments, R1 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R1 is H. In certain embodiments, R1 is halo (e.g., F, Cl, Br, I). In certain embodiments, R1 is hydroxyl. In certain embodiments, R1 is alkoxy. In certain embodiments, R1 is nitro. In certain embodiments, R1 is amino or substituted amino. In certain embodiments, R1 is carboxyl. In certain embodiments, R1 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or C1-3 carboxylalkyl. In certain embodiments, R1 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R1 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R1 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R1 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R1 is aryl or substituted aryl, such as C5-8 aryl or Cs s substituted aryl, such as a C5 aryl or C5 substituted aryl, or a C& aryl or Ce substituted aryl. In certain embodiments, R1 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or C& substituted heteroaryl.
[00212] In some embodiments, the compound is:
[00213] Aspects of the present disclosure include compositions comprising: a compound of formula (IX): wherein:
R1 and R2 are each independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R1 and R2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl; and a pharmaceutically acceptable excipient.
[00214] The substituents related to compounds of formula (IX) are described in more detail below.
[00215] In certain embodiments, R1 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R1 and R2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl. In certain embodiments, R1 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R1 is H. In certain embodiments, R1 is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R1 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R1 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R1 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R1 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl. In certain embodiments, R1 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R1 is methyl.
[00216] In certain embodiments, R2 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R1 and R2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl. In certain embodiments, R2 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R2 is H. In certain embodiments, R2 is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R2 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R2 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R2 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R2 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or C& substituted aryl. In certain embodiments, R2 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R2 is methyl.
[00217] In certain embodiments, R1 and R2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl. In certain embodiments, R1 and R2 together with the N to which they are attached form a heterocyclopentyl ring.
[00218] In some embodiments, the compound is:
[00219] Aspects of the present disclosure include compositions comprising: a compound of formula (X): wherein:
R1 and R2 are each independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R1 and R2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl;
R3 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
[00220] The substituents related to compounds of formula (X) are described in more detail below.
[00221] In certain embodiments, R1 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R1 and R2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl. In certain embodiments, R1 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R1 is H. In certain embodiments, R1 is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R1 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R1 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R1 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R1 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Cg aryl or C& substituted aryl. In certain embodiments, R1 is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5 heteroaryl or C5 substituted heteroaryl, or a Cg heteroaryl or Cg substituted heteroaryl. In certain embodiments, R1 is
[00222] In certain embodiments, R2 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R1 and R2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl. In certain embodiments, R2 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R2 is H. In certain embodiments, R2 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R2 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R2 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R2 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R2 is aryl or substituted aryl, such as Cs s aryl or Cs s substituted aryl, such as a Cs aryl or Cs substituted aryl, or a C& aryl or C& substituted aryl. In certain embodiments, R2 is heteroaryl or substituted heteroaryl, such as Cs s heteroaryl or Cs s substituted heteroaryl, such as a Cs heteroaryl or Cs substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R2 is
[00223] In certain embodiments, R1 and R2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl. In certain embodiments, R1 and R2 together with the N to which they are attached form a substituted heterocyclohexyl ring.
[00224] In certain embodiments, R3 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R3 is H. In certain embodiments, R3 is halo (e.g., F, Cl, Br, I). In certain embodiments, R3 is hydroxyl. In certain embodiments, R3 is alkoxy. In certain embodiments, R3 is nitro. In certain embodiments, R3 is amino or substituted amino. In certain embodiments, R3 is carboxyl. In certain embodiments, R3 is carboxylalkyl, such as Ci-6 carboxylalkyl, or C1-4 carboxylalkyl, or Ci 3 carboxylalkyl. In certain embodiments, R3 is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R3 is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R3 is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R3 is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R3 is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5 aryl or C5 substituted aryl, or a Ce aryl or Ce substituted aryl. In certain embodiments, R3 is heteroaryl or substituted heteroaryl, such as Cs s heteroaryl or Cs s substituted heteroaryl, such as a Cs heteroaryl or C5 substituted heteroaryl, or a Ce heteroaryl or Ce substituted heteroaryl. In certain embodiments, R3 is Cl.
[00225] In some embodiments, the compound is:
DELIVERY DEVICES
[00226] The present disclosure provides a drug delivery device comprising a composition of the present disclosure. Suitable drug delivery devices include, without limitation, an injection device (e.g., syringe, pen injector, auto injector, large-volume device, pump, perfusion system, or other device configured for subcutaneous, intramuscular, or intravenous delivery; a skin patch (e.g., osmotic, chemical, micro-needle); an inhaler (e.g., nasal or pulmonary); an implantable device; and a feeding system for the gastro-intestinal tract.
METHODS OF INHIBITING THE BINDING OF BEX TO AN E3 LIGASE
[00227] The present disclosure provides methods of inhibiting the binding of Bex to an E3 ligase in a cell. The methods comprise contacting the cell with a compound of the present disclosure to inhibit the binding of Bex to an E3 ligase. In some cases, the contacting of the cell with a compound of the present disclosure causes activation of the E3 ligase. In some cases, the activation of the E3 ligase is characterized by the ability of the E3 ligase to bind to a substrate peptide, such as Fnipl. In some cases, the E3 ligase is present in a cell in vitro. In some cases, the E3 ligase is present in a cell that is in a tissue, an organ, or an extracellular fluid in an individual.
[00228] An E3 ligase is a complex of polypeptides. In some cases, the E3 ligase is a Cullin- RING ligase. In some cases, the E3 ligase is a CULE2 ligase. [00229] In some cases, a compound of the present disclosure inhibits a FEM1B polypeptide. In some cases, the E3 ligase comprises a FEM1B polypeptide; for example, in some cases, the E3 ligase is composed of CUL2, EloB/C, RBX1, and FEM1B. FEM1B is a component of an E3 ligase, and may act as a substrate recognition subunit.
[00230] In some cases, the E3 ligase comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 1-627 of the following amino acid sequence of the following human Femlb amino acid sequence:
MEGLAGYVYKAASEGKVLTLAALLLNRSESDIRYLLGYVSQQGGQRSTPLIIAARNGHAKVVRLLLEHYRVQT QQTGTVRFDGYVIDGATALWCAAGAGHFEVVKLLVSHGANVNHTTVTNSTPLRAACFDGRLDIVKYLVEN NANISIANKYDNTCLMIAAYKGHTDVVRYLLEQRADPNAKAHCGATALHFAAEAGHIDIVKELIKWRAAIVV NGHGMTPLKVAAESCKADVVELLLSHADCDRRSRIEALELLGASFANDRENYDIIKTYHYLYLAMLERFQDG DNILEKEVLPPIHAYGNRTECRNPQELESIRQDRDALHMEGLIVRERILGADNIDVSHPIIYRGAVYADNMEF EQCIKLWLHALHLRQKGNRNTHKDLLRFAQVFSQMIHLNETVKAPDIECVLRCSVLEIEQSMNRVKNISDAD VHNAMDNYECNLYTFLYLVCISTKTQCSEEDQCKINKQIYNLIHLDPRTREGFTLLHLAVNSNTPVDDFHTND VCSFPNALVTKLLLDCGAEVNAVDNEGNSALHIIVQYNRPISDFLTLHSIIISLVEAGAHTDMTNKQNKTPLDK STTGVSEILLKTQMKMSLKCLAARAVRANDINYQDQIPRTLEEFVGFH (SEQ. ID NO:1).
[00231] In some cases, the E3 ligase comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to amino acids 1-627 of the following amino acid sequence of the following mouse Femlb amino acid sequence:
MEGLAGYVYKAASEGKVLTLAALLLNRSESDIRYLLGYVSQQGGQRSTPLIIAARNGHAKVVRLLLEHYRVQT QQTGTVRFDGYVIDGATALWCAAGAGHFEVVKLLVSHGANVNHTTVTNSTPLRAACFDGRLDIVKYLVEN NANISIANKYDNTCLMIAAYKGHTDVVRYLLEQRADPNAKAHCGATALHFAAEAGHIDIVKELIKWRAAIVV NGHGMTPLKVAAESCKADVVELLLSHADCDRRSRIEALELLGASFANDRENYDIMKTYHYLYLAMLERFQD GDNILEKEVLPPIHAYGNRTECRNPQELEAIRQDRDALHMEGLIVRERILGADNIDVSHPIIYRGAVYADNME FEQCIKLWLHALHLRQKGNRNTHKDLLRFAQVFSQMIHLNEAVKAPDIECVLRCSVLEIEQSMNRVKNISDA DVHSAMDNYECNLYTFLYLVCISTKTQCSEEDQCRINKQIYNLIHLDPRTREGFSLLHLAVNSNTPVDDFHTN DVCSFPNALVTKLLLDCGAEVNAVDNEGNSALHIIVQYNRPISDFLTLHSIIISLVEAGAHTDMTNKQNKTPLD KSTTGVSEILLKTQMKMSLKCLAARAVRANDINYQDQIPRTLEEFVGFH (SEQ ID NO:2) [00232] A Bex (Brain Expressed and X-linked) protein is a protein of the Bex family of proteins. In humans, Bex family proteins are comprised of five proteins including BEX1, BEX2, BEX3, BEX4, and BEX5. In some cases, the Bex protein is BEX3. In some cases, the BEX protein comprises an amino acid sequence having at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 98%, at least 99%, or 100%, amino acid sequence identity to the following amino acid sequence: RELQLRNCLRILMGELSNHHDHHDEFCLMP (SEQ ID NO:3).
[00233] A subject compound (e.g., a compound of any one of Formulas I, II, III, IV, V, VI, VII, VIII, IX, X; a compound depicted in FIG. 1) can inhibit the binding of Bex to an E3 ligase in a cell by at least about 10 %, compared to the inhibition of the binding of Bex to an E3 ligase in a cell not contacted with the compound. In some cases, a subject compound can inhibit the binding of Bex to an E3 ligase by greater than 10 % compared to the inhibition of the binding of E3 ligase and Bex not contacted with the compound. For example, a subject compound may inhibit the activity of an E3 ligase by 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40- 45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, 85-90%, 90-95%, or 95-100%, compared to the inhibition of the binding of Bex to an E3 ligase not contacted with the compound.
[00234] The compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, or the compound depicted in FIG. 1 is administered in an amount effective to selectively inhibit the binding of Bex to an E3 ligase in a subject. In some cases, subject compound inhibits the binding of Bex to an E3 ligase by 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, 85-90%, 90-95%, or 95-100%, compared to the inhibition of binding of Bex to an E3 ligase not contacted with the compound. In some cases, the E3 ligase is Femlb.
[00235] In some cases, the E3 ligase and Bex are present in a cell in vitro. In some cases, the E3 ligase and Bex are present in a cell in vivo.
[00236] Whether a compound inhibits the binding of Bex to an E3 ligase in a cell can be determined using an assay such as those described in Example 1. For example, a Bex peptide comprising a fluorescent label can be used as the substrate and contacted with the E3 ligase in the presence or absence of a compound being tested for inhibitory activity toward the E3 ligase. As another example, a degron reporter assay as described in Example 1 can be used to determine whether a compound inhibits an E3 ligase (e.g., a FEM1B polypeptide). A reduction in the activity of the E3 ligase in the presence of the compound, compared to the activity of the E3 ligase in the absence of the compound, indicates that the compound inhibits E3 ligase activity.
TREATMENT METHODS
[00237] A compound of the present disclosure is useful for treating various diseases, disorders and dysfunctions. The present disclosure provides a method of treating mitochondrial dysfunction in a subject, the method comprising administering an effective amount of a composition comprising: i) a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, or a compound depicted in FIG. 1; and ii) a pharmaceutically acceptable excipient to treat the subject for mitochondrial dysfunction.
[00238] Mitochondrial dysfunction is characterized by misregulation of ATP generation and oxidative/reductive stress. Mitochondrial dysfunction includes, but is not limited to, loss of efficiency in the electron transport chain, reduction in the synthesis of ATP, loss of maintenance of electrical and chemical transmembrane potentials of the inner mitochondrial membrane, reduction in the transport of metabolites into the mitochondria, and reduced efficiency of oxidative phosphorylation.
[00239] Mitochondrial dysfunction and mitochondrial disorders can also be caused by mutations (acquired or inherited), in mitochondrial DNA (mtDNA), or in nuclear genes that code for mitochondrial components. They may also be the result of acquired mitochondrial dysfunction due to adverse effects of drugs, infections, or other environmental causes. Oxalate may enter cells where it is known to cause mitochondrial dysfunction.
[00240] In some cases, mitochondrial activation can serve to reverse and/or treat mitochondrial dysfunction. In some cases, mitochondrial activation is characterized by increased import of factors for oxidative phosphorylation into the mitochondria.
[00241] In some cases, the administration of the composition comprising: i) a compound of formula I, II, III, IV, V, VI, VII, VIII, IX, X, or a compound depicted in FIG. 1; and ii) a pharmaceutical acceptable excipient, causes mitochondrial activation. In some cases, subject compound increases mitochondrial activation by 10-15%, 15-20%, 20-25%, 25-30%, 30-35%, 35-40%, 40-45%, 45-50%, 50-55%, 55-60%, 60-65%, 65-70%, 70-75%, 75-80%, 80-85%, 85-90%, 90-95%, or 95-100%, compared to mitochondrial activation when the compound is not administered.
[00242] In some cases, a treatment method of the present disclosure comprises administering to an individual in need thereof a composition of the present disclosure. In some cases, a treatment method of the present disclosure comprises administering to an individual in need thereof a composition of the present disclosure in addition to a secondary treatment modality directed towards treating said condition.
Methods of treating mitochondrial dysfunction
[00243] The present disclosure provides methods for treating mitochondrial dysfunction. The methods generally involve administering to an individual having mitochondrial dysfunction an effective amount of a compound of the present disclosure. [00244] Using methods of the present disclosure, mitochondrial dysfunction can be treated in subjects with neurodegenerative diseases. Neurodegenerative diseases can include, but are not limited to, Alzheimer's disease, Parkinson's disease, Huntington's disease, amytrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, and neuronopathic Gaucher's disease.
[00245] Using methods of the present disclosure, mitochondrial dysfunction can be treated in subjects with cardiovascular diseases. Cardiovascular diseases can include, but are not limited to, atherosclerosis, cardiac ischemia reperfusion, stroke, and hypertrophic cardiomyopathy.
[00246] Using methods of the present disclosure, mitochondrial dysfunction can be treated in subjects with metabolic diseases. Metabolic diseases can include, but are not limited to, diabetes. In some cases, diabetes can be type 2 diabetes.
[00247] Using methods of the present disclosure, mitochondrial dysfunction can be treated in subjects with a body mass index greater than 30 kg/m2.
[00248] In some cases, an "effective amount" of a composition is an amount that, when administered in one or more doses to an individual in need thereof, reduces adverse symptoms in the individual. For example, in some cases, an "effective amount" of a composition of the present disclosure is an amount that, when administered in one or more doses to an individual in need thereof, reduces at least one adverse symptom of the dysfunction or disease in the individual by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 95%, compared to the symptoms in the individual before administration of the composition, or in the absence of administration with the composition. In some cases, an "effective amount" of a composition of the present disclosure is an amount that, when administered in one or more doses to an individual in need thereof, reduces adverse symptoms in the individual to undetectable levels. For example, in some cases, an "effective amount" of a composition of the present disclosure is an amount that, when administered in one or more doses to an individual in need thereof, increases survival time of the individual by at least 1 month, at least 2 months, at least 3 months, from 3 months to 6 months, from 6 months to 1 year, from 1 year to 2 years, from 2 years to 5 years, from 5 years to 10 years, or more than 10 years, compared to the expected survival time of the individual in the absence of administration with the composition of the present disclosure.
[00249] In some cases, a secondary treatment modality is used in addition to a composition of the present disclosure to treat a metabolic disorder in an individual in need thereof. Secondary treatment modalities may be directed to the disease or disorder being treated. Secondary treatment modalities that find use in the present disclosure, include, without limitation, insulin, glucagon, a statin, a thiazolidinedione, sulfonylureas, glinides, metformin, starch blockers, incretin therapies, pramlintide, SGLT2 inhibitors, etc. When insulin is used as a secondary treatment modality, any suitable insulin may be used, including, without limitation, rapid-acting insulin, short-acting insulin, intermediate-acting insulin, long-acting insulin, etc. In some cases, the insulin administered is a combination of the insulins listed above. When a statin is used as a secondary treatment modality, any suitable statin may be used, including, without limitation, Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin, Simvastatin, etc. When a thialzolidinedione is used as a secondary treatment modality, any suitable thialzolidinedione may be used, including, without limitation, rosiglitazone, pioglitazone, etc. When a sulfonylureas are used as a secondary treatment modality, any suitable sulfonylurea may be used, including, without limitation, chlorpropamide, tolbutamide, glipizide, glyburide, glimepiride, etc. When a glinides are used as a secondary treatment modality, any suitable glinides may be used, including, without limitation, repaglinide, nateglinide, mitiglinide, etc. When starch blockers are used as a secondary treatment modality, any suitable starch blocker may be used, including, without limitation, acarbose, miglitol, etc. When incretin therapies are used as a secondary treatment modality, any suitable incretin therapy may be used, including, without limitation, sitagliptin, saxagliptin, linagliptin, exenatide, liraglutide, etc. When SGLT2 inhibitors are used as a secondary treatment modality, any suitable SGLT2 inhibitor may be used, including, without limitation, canagliflozin, dapagliflozin, and empagliflozin, etc.
Subjects suitable for treatment
Subjects suitable for treatment with a method of the present disclosure include individuals who are in need of treatment for mitochondrial dysfunction. Subjects suitable for treatment for mitochondrial dysfunction with a method of the present disclosure include individuals who have a neurodegenerative disease, including individuals who have been diagnosed as having a neurodegenerative disease, and individuals who have been treated for a neurodegenerative disease but who failed to respond to the treatment. Subjects suitable for treatment for mitochondrial dysfunction with a method of the present disclosure include individuals who have a cardiovascular disease, including individuals who have been diagnosed as having a cardiovascular disease, and individuals who have been treated for a cardiovascular disease but who failed to respond to the treatment. Subjects suitable for treatment for mitochondrial dysfunction with a method of the present disclosure include individuals who have a metabolic disease, including individuals who have been diagnosed as having a metabolic disease, and individuals who have been treated for a metabolic disease but who failed to respond to the treatment. Subjects suitable for treatment for mitochondrial dysfunction with a method of the present disclosure include individuals who have a body mass index greater than 30 kg/m2 or an obesity-related disorder, including individuals who have been diagnosed as having a body mass index greater than 30 kg/m2 or an obesity-related disorder, and individuals who have been treated for an obesity-related disorder but who failed to respond to the treatment.
Formulations
[00250] Suitable formulations are described above, where suitable formulations include a pharmaceutically acceptable excipient. In some cases, a suitable formulation comprises: a) a compound comprising Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a compound depicted in Fig. 1; and b) a pharmaceutically acceptable excipient. Suitable pharmaceutically acceptable excipients are described above.
Dosages
[00251] A suitable dosage can be determined by an attending physician or other qualified medical personnel, based on various clinical factors. As is well known in the medical arts, dosages for any one patient depend upon many factors, including the patient's size, body surface area, age, the particular compound to be administered, sex of the patient, time, and route of administration, general health, and other drugs being administered concurrently. A composition of the present disclosure may be administered in amounts between 1 ng/kg body weight and 20 mg/kg body weight per dose, e.g. between 0.1 mg/kg body weight to 10 mg/kg body weight, e.g. between 0.5 mg/kg body weight to 5 mg/kg body weight; however, doses below or above this exemplary range are envisioned, especially considering the aforementioned factors. If the regimen is a continuous infusion, it can also be in the range of 1 pg to 10 mg per kilogram of body weight per minute. A composition of the present disclosure can be administered in an amount of from about 1 mg/kg body weight to 50 mg/kg body weight, e.g., from about 1 mg/kg body weight to about 5 mg/kg body weight, from about 5 mg/kg body weight to about 10 mg/kg body weight, from about 10 mg/kg body weight to about 15 mg/kg body weight, from about 15 mg/kg body weight to about 20 mg/kg body weight, from about 20 mg/kg body weight to about 25 mg/kg body weight, from about 25 mg/kg body weight to about 30 mg/kg body weight, from about 30 mg/kg body weight to about 35 mg/kg body weight, from about 35 mg/kg body weight to about 40 mg/kg body weight, or from about 40 mg/kg body weight to about 50 mg/kg body weight.
[00252] In some cases, a suitable dose of a composition of the present disclosure is from 0.01 pg to 100 g per kg of body weight, from 0.1 pg to 10 g per kg of body weight, from 1 pg to 1 g per kg of body weight, from 10 pg to 100 mg per kg of body weight, from 100 pg to 10 mg per kg of body weight, or from 100 pg to 1 mg per kg of body weight. Persons of ordinary skill in the art can easily estimate repetition rates for dosing based on measured residence times and concentrations of the administered agent in bodily fluids or tissues. Following successful treatment, it may be desirable to have the patient undergo maintenance therapy to prevent the recurrence of the disease state, wherein a multimeric polypeptide of the present disclosure is administered in maintenance doses, ranging from 0.01 pg to 100 g per kg of body weight, from 0.1 pg to 10 g per kg of body weight, from 1 pg to 1 g per kg of body weight, from 10 pg to 100 mg per kg of body weight, from 100 pg to 10 mg per kg of body weight, or from 100 pg to 1 mg per kg of body weight. [00253] Those of skill will readily appreciate that dose levels can vary as a function of the specific composition of the present disclosure, the severity of the symptoms and the susceptibility of the subject to side effects. Preferred dosages for a given compound are readily determinable by those of skill in the art by a variety of means.
[00254] In some cases, multiple doses of a composition of the present disclosure are administered. The frequency of administration of a composition of the present disclosure can vary depending on any of a variety of factors, e.g., severity of the symptoms, etc. For example, in some cases, a composition of the present disclosure is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (qid), or three times a day (tid).
[00255] The duration of administration of a composition of the present disclosure, e.g., the period of time over which a composition of the present disclosure can vary, depending on any of a variety of factors, e.g., patient response, etc. For example, a composition of the present disclosure can be administered over a period of time ranging from about one day to about one week, from about two weeks to about four weeks, from about one month to about two months, from about two months to about four months, from about four months to about six months, from about six months to about eight months, from about eight months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years, or more.
Routes of administration
[00256] An active agent (a composition or a compound of the present disclosure) is administered to an individual using any available method and route suitable for drug delivery, including in vivo and ex vivo methods, as well as systemic and localized routes of administration.
[00257] Conventional and pharmaceutically acceptable routes of administration include intratumoral, peritumoral, intramuscular, intratracheal, intracranial, subcutaneous, intradermal, topical application, intravenous, intraarterial, rectal, nasal, oral, and other enteral and parenteral routes of administration. Routes of administration may be combined, if desired, or adjusted depending upon the composition of the present disclosure and/or the desired effect. A composition of the present disclosure can be administered in a single dose or in multiple doses.
[00258] In some cases, a composition of the present disclosure is administered orally. In some cases, a composition of the present disclosure is administered intraperitoneally. In some cases, a composition of the present disclosure is administered intramuscularly. In some cases, a composition of the present disclosure is administered intravenously. In some cases, a composition of the present disclosure is administered locally. In some cases, a composition of the present disclosure is administered intratumorally. In some cases, a composition of the present disclosure is administered peritumorally. In some cases, a composition of the present disclosure is administered intracranially. In some cases, a composition of the present disclosure is administered subcutaneously.
[00259] A composition of the present disclosure can be administered to a host using any available conventional methods and routes suitable for delivery of conventional drugs, including systemic or localized routes. In general, routes of administration contemplated for use in a method of the present disclosure include, but are not necessarily limited to, enteral, parenteral, and inhalational routes.
[00260] Parenteral routes of administration other than inhalation administration include, but are not necessarily limited to, topical, transdermal, subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intratumoral, peritumoral, and intravenous routes, i.e., any route of administration other than through the alimentary canal. Parenteral administration can be carried to effect systemic or local delivery of a composition of the present disclosure. Where systemic delivery is desired, administration typically involves invasive or systemically absorbed topical or mucosal administration of pharmaceutical preparations.
EXAMPLES
[00261] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. Standard abbreviations may be used, e.g., bp, base pair(s); kb, kilobase(s); pl, picoliter(s); s or sec, second(s); min, minute(s); h or hr, hour(s); aa, amino acid(s); kb, kilobase(s); bp, base pair(s); nt, nucleotide(s); i.m., intramuscular(ly); i.p., intraperitoneal(ly); s.c., subcutaneous(ly); and the like.
Example 1: Identifying Bex and Femlb Inhibitors
Chemical Library Composition
[00262] Food and Drug Administration (FDA)-approved and Bioactive chemical libraries containing 1,200 and 4,170 small molecule compounds, respectively, were stored at lOmM in dimethyl sulfoxide (DMSO) in 384-well master plates (Targetmol, Wellesley Hills, MA) as well as 2mM screening master plates. Diversity and Antibacterial chemical libraries containing 100,000 and 15,000 small molecule compounds, respectively, were purchased from (Chemdiv, San Diego, CA) with the same storage conditions. Primary screening plates were generated by spotting 0.5 pl of 2mM concentration screening master plates into 384 well non-binding plates (Greiner, 781900) using a Cybio Well Vario liquid handler (Analytik Jena, Jena, Germany) for a final concentration of 40pM with a DMSO concentration of 2% (v/v). Hits were cherry picked from lOmM master plates and serial diluted with Tecan Freedom Evo 150 (Tecan Systems Inc, San Jose, CA)
Fluorescence Polarization Screen
[00263] For all fluorescence polarization screens, mouse MBP-FEM1B was purified as previously described (Manford, et al.. Cell 2020 183:46-61). TAMRA-labeled BEX3 peptide (5,6- TAMRA-RELQLRNCLRILMGELSNHHDHHDEFCLMP) was purchased from Biomatik. The peptides were prepared in DMSO to a 4mM concentration and diluted into indicated binding buffers to 200pM stock concentration that were aliquoted and frozen down. [00264] For the FEM1B-Bex3ctd degron screen, the peptide and MBP-FEM1B were thawed and diluted into binding buffer containing 40mM HEPES 7.5, 150mM NaCI, 0.01% NP40 substitute, and 100pM TCEP (Tris(2-carboxyethyl)phosphine hydrochloride) made with MilliQ. filtered water, to a concentration of 20nM and 140nM respectively. All working FEM1B and peptide solutions were prepared in polystyrene bottles.12.5pl pf MBP-FEM1B was added to each well of opaque black non-binding 384 well plates (Greiner Bio-one, Cat# 781900) containing 0.5 pl of 2mM compound or DMSO using a Cybio Well Vario liquid handler (Analytik Jena, Jena, Germany). Plates were incubated for 1 hour at room temperature. After the incubation, 12.5pl of the BEX3ctd peptide was added to each well bringing the final concentration to lOnM for the peptide, 70 nM for MBP-FEM1B, and 40pM each compound. Plates were mixed for 45 seconds at 2400 rpm using a Qlnstruments BioShake ELM3000 orbital shaker (Qlnstruments, Jena, Germany) and after 60 minutes of incubation plates were measured on a 2104 Envision plate reader with TAMRA FP filter set (Perkin Elmer, Waltham, MA). Data was calculated from mP values (1000*(S-G*P)/(S+G*P), S = 595s channel 2 and P = 595p channel 1, G-l.l) with background subtraction calculated from a peptide only control plate. Each analysis group included a peptide and DMSO only plate, and FEMlB-BEX3ctd peptide DMSO only plate containing a dose response of TPEN (N,N,N',N'-Tetrakis(2- pyridylmethyl)ethylenediamine, Sigma-Aldrich, P4413) as a positive control (2 fold dilutions from 80pM to ~156nM). Data was normalized to DMSO only controls on each plate.
Generation of EC50 Values and Dose-Response Curves
[00265] The curve fit for graphs is performed using the variable Hill slope model or the four-parameter logistic curve:
(Maximum response ™ Baseline response)
Response Base ine response
[00266] Using this equation, nonlinear regression was performed with the Levenberg-
Marquardt algorithm. Response is the measured response on the Y axis. Baseline response (Min Measured %) is the minimum response at the bottom of the plateau. Maximum response (Max Measured %) is the maximum response at the top of the plateau. EC50 is the concentration at 50% response.
[00267] While the present invention has been described with reference to the specific embodiments thereof, it should be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the true spirit and scope of the invention. In addition, many modifications may be made to adapt a particular situation, material, composition of matter, process, process step or steps, to the objective, spirit and scope of the present invention. All such modifications are intended to be within the scope of the claims appended hereto.

Claims

CLAIMS What is claimed is:
1. A composition comprising: al) a compound of formula (I): wherein:
R1, R2, R3, R4, R5, R6, R7 and R8 are each independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and bl) a pharmaceutically acceptable excipient; or a2) a compound depicted in FIG. 1; and b2) a pharmaceutically acceptable excipient.
2. The composition of claim 1, wherein R1, R2, R3, R4 and R5 are independently selected from H, alkyl, alkoxy and halo.
3. The composition of claims 1 or 2, wherein R8 is H.
4. The composition of any one of claims 1-3, wherein R6 and R7 are independently selected from H, alkyl, substituted alkyl, amino, substituted amino, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, and substituted heterocycloalkyl.
5. The composition of claim 4, wherein R6 and R7 are independently selected from H and - NR9R10, wherein R9 and R10 are independently selected from H, alkyl, substituted alkyl, cycloalkyl and substituted cycloalkyl, or R9 and R10 together with the N to which they are attached form a cycloalkyl or substituted cycloalkyl.
6. The composition of any one of claims 1-5, wherein the compound is selected from:
7. A composition comprising: a compound of formula (II): wherein:
Ra is selected from H, alkyl, and substituted alkyl;
R1, R2, R3, R4 and R5 are each independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
8. The composition of claim 7, wherein R1, R2, R3, R4 and R5 are each independently selected from H, halo and alkyl.
9. The composition of claims 7 or 8, wherein the compound is selected from:
10. A composition comprising: a compound of formula (III): wherein:
Ra is selected from H, halo, alkyl, and substituted alkyl;
R6, R7 and R8 are each independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
11. The composition of claim 10, wherein the compound is:
12. A composition comprising: a compound of formula (IV): wherein:
R1 is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R2 and R3 are each independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl and substituted alkenyl; and a pharmaceutically acceptable excipient.
13. The composition of claim 12, wherein R2 is nitro or halo.
14. The composition of claims 12 or 13, wherein R3 is halo.
15. The composition of any one of claims 12-15, wherein the compound is selected from:
16. A composition comprising: a compound of formula (V): wherein:
R1 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; R2 and R3 are each independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R2 and R3 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl; and a pharmaceutically acceptable excipient.
17. The composition of claim 16, wherein R1 is selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl and substituted heterocycloalkyl.
18. The composition of claims 16 or 17, wherein R2 and R3 are independently selected from H, alkyl and substituted alkyl.
19. The composition of claim 18, wherein R2 and R3 together with the N to which they are attached form a heterocycloalkyl or substituted heterocycloalkyl.
20. The composition of any one of claims 16-19, wherein the compound is selected from:
21. A composition comprising: a compound of formula (VI): wherein:
R1 and R2 are independently selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
22. The composition of claim 21, wherein the compound is selected from:
23. A composition comprising: a compound of formula (VII): wherein:
R1 and R2 are each independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R1 and R2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl; and a pharmaceutically acceptable excipient.
24. The composition of claim 23, wherein the compound is selected from:
25. A composition comprising: a compound of formula (VIII): wherein:
R1 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
26. The composition of claim 25, wherein the compound is:
27. A composition comprising: a compound of formula (IX): wherein:
R1 and R2 are each independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R1 and R2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl; and a pharmaceutically acceptable excipient.
28. The composition of claim 27, wherein the compound is:
29. A composition comprising: a compound of formula (X):
wherein:
R1 and R2 are each independently selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R1 and R2 together with the N to which they are attached form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl;
R3 is selected from H, halo, hydroxyl, alkoxy, acyloxy, nitro, amino, substituted amino, carboxyl, carboxylalkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; and a pharmaceutically acceptable excipient.
30. The composition of claim 29, wherein the compound is:
31. The composition of any one of claims 1-30, wherein the composition is sterile.
32. A drug delivery device comprising the composition of any one of claims 1-31.
33. The drug delivery device of claim 32, wherein the device comprises a syringe comprising the composition.
34. The drug delivery device of claim 33, wherein the device comprises a pump.
35. A method of inhibiting the binding of Bex to an E3 ligase in a cell, the method comprising contacting the cell with the compound of Formula I, II, III, IV, V, VI, VII, VIII, IX, X or a compound depicted in Fig. 1 to inhibit the binding of Bex to an E3 ligase.
36. The method of claim 35, wherein the contacting causes activation of the E3 ligase.
37. The method of claims 35 or 36, wherein the E3 ligase is Femlb.
38. A method of treating mitochondrial dysfunction in a subject, the method comprising: administering an effective amount of a composition of any one of claims 1-30 to treat the subject for mitochondrial dysfunction.
39. The method of claim 38, wherein the administering causes mitochondrial activation.
40. The method of any one of claims 38-39, wherein compound is administered orally, intraperitoneally, intramuscularly, or intravenously.
41. The method of any one of claims 38-40, wherein the subject has a neurodegenerative disease.
42. The method of claim 41, wherein the neurodegenerative disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Huntington's disease, amytrophic lateral sclerosis, spinal muscular atrophy, Friedreich's ataxia, and neuronopathic Gaucher's disease.
43. The method of any one of claims 38-40, wherein the subject has a cardiovascular disease.
44. The method of claim 43, wherein the cardiovascular disease is selected from the group consisting of atherosclerosis, cardiac ischemia reperfusion, stroke, and hypertrophic cardiomyopathy.
45. The method of any one of claims 38-40, wherein the subject has a metabolic disease.
46. The method of claim 45, wherein the metabolic disease is diabetes.
47. The method of claim 46, wherein the metabolic disease is type 2 diabetes.
48. The method of any one of claims 38-40, wherein the subject has a body mass index greater than 30 kg/m2.
PCT/US2025/017209 2024-03-07 2025-02-25 E3 ligase and bex inhibitors and methods of use thereof Pending WO2025188508A1 (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150011551A1 (en) * 2012-02-22 2015-01-08 Sanford- Burnham Medical Reseach Institute Sulfonamide compounds and uses as tnap inhibitors

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
US20150011551A1 (en) * 2012-02-22 2015-01-08 Sanford- Burnham Medical Reseach Institute Sulfonamide compounds and uses as tnap inhibitors

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Title
DATABASE Compound 14 July 2005 (2005-07-14), PUBCHEM: "5-(Benzenesulfonamido)pyridine-3-carboxylic acid", XP093356147, Database accession no. 2052690 *
OMARI DERAR M, AKKAM YAZAN, SALLAM ASSAYED: "Drug-Excipient Interactions: An Overview on Mechanisms and Effects on Drug Stability and Bioavailability", ANNALS OF THE ROMANIAN SOCIETY FOR CELL BIOLOGY, "VASILE GOLDIS" WESTERN UNIVERSITY ARAD, ROMANIA, ARAD, 1 January 2021 (2021-01-01), Arad, pages 8402 - 8429, XP093102914 *

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