WO2019109099A1 - Asymmetric triazole benzamide derivatives and the compositions and methods of treatment regarding the same - Google Patents

Asymmetric triazole benzamide derivatives and the compositions and methods of treatment regarding the same Download PDF

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WO2019109099A1
WO2019109099A1 PCT/US2018/063678 US2018063678W WO2019109099A1 WO 2019109099 A1 WO2019109099 A1 WO 2019109099A1 US 2018063678 W US2018063678 W US 2018063678W WO 2019109099 A1 WO2019109099 A1 WO 2019109099A1
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cancer
compound
alkyl
optionally substituted
phenyl
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French (fr)
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Jennifer Johnston
Paul Ross Fatheree
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An2H Discovery Limited
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    • C07—ORGANIC CHEMISTRY
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    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/14—Nitrogen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to asymmetric tri azole benzamide compounds and their derivatives as well as methods of modulating Parkin ligase or methods of treating various diseases and conditions with the triazole benzamide compounds and their derivatives.
  • Ubiquitin-Proteasome Pathway System is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPS is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases. Posttranslational modification of proteins by ubiquitin is a fundamental cellular mechanism that regulates protein stability and activity and underlies a multitude of functions, from almost ever) ' aspect of biology. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. These !igases comprise over 500 different proteins and are categorized into multiple classes defined by the structural element of their E3 functional activity.
  • both HECT and RING ligases transfer an activated ubiquitin from a thioester to the e-amino acid group of a lysine residue on a substrate; however, HECT ligases have an active site cysteine that forms an intermediate thioester bond with ubiquitin, while RI G ligases function as a scaffold to allow direct ubiquitin transfer from the E2 to substrate.
  • a subfamily of RING ligases the RING- between-RING (RBR) family, may contain a catalytic cysteine residue 1,2 in addition to a canonical RING domain. (Riley et al. 2013. Nat Commun. 4: 1982,“Riley et al.”), which is herein incorporated by reference in its entirely.
  • DIJBs and USPs Deubiquitinating proteins and ubiquitin-specific proteases (DIJBs and USPs) and E3 Ligases play a vital role in the UPS. These proteins are supported by flexible Zinc Finger (ZnF) domains which stabilize the binding of ubiquitin (Ub) for specialized functions.
  • ZnF Zinc Finger
  • Parkin is a RING-between-RING E3 ligase that functions in the covalent attachment of ubiquitin to specific substrates, and mutations in Parkin are linked to Parkinson’s disease, cancer and mycobacterial infection.
  • the individual RING domains for Parkin have been the subject of much debate, in regards to the specific residues that coordinate Zn ions, as well as their relationship to canonical RING crossbrace structures defining classical E2-bindmg domains.
  • RO is a novel domain structure, but is more similar to Zn-finger domains than to E3 RING domains (Riley et al. 2013. Nat Comrnun. 4: 1982)
  • the compounds of the present disclosure can modulate or active Parkin ligase and may be useful in treating various diseases and conditions as disclosed herein.
  • the present disclosure provides compounds comprising the structure of formula (I):
  • L 1 , L 2 and L 3 are each independently selected from a bond, alkylene, or alkenylene;
  • M 1 and M 2 are each independently selected from -NR 4 -, -NR 4 C(0)-, -
  • R 1 and R 2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryd, cydoalkylalkyl, arylalkyl, ar lalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroary alkenyl, or lieteroarylalkynyL wherein each eycloalkyl, aryl, heteroaryd, and heterocyclyl portion is optionally substituted with one or more R 5 ;
  • R 3 is selected from an alkyl alkenyl, cycloalkyl, aryl, biphenyl, heterocyciyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroary
  • R 4 is each independently H, alkyl, wherein each alkyl is optionally substituted with one or more R 5 ;
  • R 5 is each independently I, Br, Cl, F, -CFI;F, -Cl si ;. -CFs, -OCF3, -CN, - alkyl -CN, -CON H r -CONHR 6 , -CONR 6 R 6 , -COOH, -M i ⁇ . -M IR". -NO;, -NR 6 R 6 , -Ns, - OH, OR 6 , -COOR 6 , -OSOsR 6 , oxo, R 6 , -SH, -SQ2R 6 , -SOiH, -SOsR 6 , or -SR 6 ;
  • R 6 is each independently alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl; or alternatively two R 6 on the same N atom can together form a 3-6 membered N-heterocycly!;
  • R 7 is each independently I, Br, Cl, F, -CH2F, -CHF 2 , -CFs, -OCFs, -CN, - alkyl-CN, -CONH2, -CONHR 6 , -CONR 6 R 6 , -COOH, -XI I w -NHR 6 , -NO2, -NR 6 R 6 , -Ns, - OH, OR 6 , -COOR 6 , -OSOsR 6 , oxo, R 6 , -SH, -SO2R 6 , -SOsH, -SOsR 6 , -SR 6 , cycloalkyl, heterocyciyl, and, or heteroaryl, wherein each cycloalkyl, heterocyciyl, aryl, and heteroaryl is optionally substituted with one or more R 5 ;
  • m is 0, 1 , or 2;
  • I, 1 , L 2 and IF are each independently a bond.
  • M 1 and M 2 are each
  • M ] and M 2 are each independently selected from -NR 4 -, -NR 4 C(0)- or - C(0)NR 4 ⁇ .
  • R 4 at each occurrence is independently H or Ci-Cs alkyl.
  • U is a bond and R 3 is an aryl or a heteroaryl, optionally substituted with one or more R 7 .
  • R 3 is a phenyl or phenyl fused bicy cle, optionally substituted with one or more R 7 .
  • R 3 is heteroaryl selected from imidazolyl or pyrazolyl, optionally substituted with one or more R 7 .
  • R 7 is each independently I, Br,
  • R 3 is a phenyl substituted with a
  • R ’! and R 2 are each independently selected from phenyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, phenyl-(Ci-Cs alkyl)-, phenyl -(C -C3 alkenyl)-, 5-6 membered heteroaryl -(Ci- Cs alkyl)-, or heteroaryl-(C?-C3 alkenyl)-, wherein each cycloalkyl, aryl, heteroaryl portion is optionally substituted with one or more R 3 .
  • 5-10 membered heteroaryl is a bicyclic ring.
  • R 3 is selected from I, Br, Cl, F, Ci-Ce alkyl, alkynyl, -CN, -(Ci-Cs alkyleneVCN, -NH?, -NO?, -Ns, -OH, -OCF 3 , -OMe, - NMe?, or -NEt?.
  • At least one of R 1 , R 2 , and R 3 is phenyl and substituted with at least one of methyl, ethyl, -CoCH, I, Br, Cl, F, -CF3, -CN, - CH?CN, -CH2CH2CN, -N ⁇ ?, -NO?, -Ns, -OH, -OCFs, -OMe or -NMe?
  • R 1 , R 2 , and R 3 is phenyl and substituted with at least one of methyl, ethyl, -CoCH, I, Br, Cl, F, -CF3, -CN, - CH?CN, -CH2CH2CN, -N ⁇ ?, -NO?, -Ns, -OH, -OCFs, -OMe or -NMe?
  • At least two of R 1 , R 2 , and R 3 is phenyl and substituted with at least one of methyl, ethyl, -C CI L I, Br, Cl, F, -CF :. -CN, -CH?CN, -CH?CH?CN, -M l ⁇ . -NO?, -N 3 , -OH, -OCF3, -OMe or -NMe?.
  • At least one of R 1 , R 2 , and 3 is pyridyl, optionally substituted with one or more of methyl, ethyl, -CoCH, I, Br, Cl, F, -CF3, -CN, - ( ⁇ 1 ⁇ ( ' ⁇ .-( ! K ! l C ⁇ . -M l?. -NO?, -Ns, -OH, -OCFs, -OMe or -NMe?..
  • the compound of formula (I) has the structure of formula (F):
  • M 1 and M 2 are each independently selected from -NR 4 -, -NR 4 C(0)-, -C(0)NR 4 -, -N(C(Q)R f j-, or -NR 4 S(0)m-.
  • R 1 and R 2 are each
  • each cycloalkyl, and, heteroaryi portion is optionally substituted with one or more R 5 ; and R 3 is an aryl or a heteroaryl, optionally substituted with one or more R 7 .
  • the compound of formula (I) has the structure of formula (IA):
  • M 1 and M 2 are each independently selected from -NR 4 C(0)- or -C(0)NR 4 -;
  • [3 / R 3 is selected from
  • R 4 is each independently H or C -Cr alkyl
  • R 7a , R 7b , R 7e , and R 7e is each independently H, I, Br, Cl, F, -CH 2 F, -CHFz, - CF3 ⁇ 4, -OCF3, -N3, -CN, -OH, methyl, ethyl, propyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C C3 haloa!koxy; [40] R 7c is H, I, Br, Cl, F, -( I FF. -d l l ⁇ .
  • R 5 is I, Br, Cl, F, -CH2F, -CHF ⁇ . -CF3, -Ci-Ce alkyl, alkynyl, -CN, -(C1-C3 alkylene)-CN, -NH 2 , -NO2, -Ns, -OH, -OCF3, -OMe, -NMe 2 , -NEt 2 , or -C(0)0(Ci-Ce alkyl);
  • R 7a , R 7b , R 7c , R 7e , and R 7e is not FI.
  • R 7a , R 71 *, R 7c , R 7e , and R 7e is H.
  • three of R /a , R 7b , R 7c , R 7e , and R 7e is H.
  • R 7a , R 7b , R 7c , R 7e , and R 7e is each independently H, I, Br, Cl, F, -Cl i d . -CHF2, C F ⁇ .. -OCF3, -N3, -CN, -OH, methyl, ethyl, propyl, -CoCH; -CN, -M l ⁇ . -NO2, -N3, -OI L - OCF 3 , -OMe, -NMe2, or -NEt 2 .
  • R 7c is I, Br, -CFI2F, -CHF2, -CF3, methyl, ethyl, propyl, -CoCH; -CN, -NH2, - NO2, -Ns, -OH, -OCF3, -OMe, -NMe 2 , or -NEt2.
  • R 7c is I, Br, -CH2F, - CHF 2 , -CFS, -OCF3, or -OMe.
  • R 7c is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or pyrazolyl, each optionally substituted with one or more R 5 .
  • the compound of formula (I) has the structure of formula (IB):
  • M 3 and M 2 are each independently selected from -NR 4 -, -NR 4 C(0)- or -
  • R 1 and R 2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyi, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or
  • heteroarylalkynyl wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 5 ;
  • one of -V R 1 and -Vi’R ' is ⁇ NR 4 ⁇ (cycloalkylalkyl), -NR 4 - (heterocyclylalkyl), -NR 4 -(arylalkyl), or -NR 4 -(heteroarylalkyl), wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 5 ;
  • R 3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaxyl, and heterocyclyl portion is optionally substituted with one or more R 7 ;
  • R 4 is each independently H or C1-C3 alkyl
  • R 5 is I, Br, Cl, F, -CH2F, -CHF2, -CFs, -Ci-Ce alkyl, alkynyl, -CN, -(C1-C3 alkyl ene)-CN, -NH2, -NO2, -Ns, -OH, -OCF3, -OMe, -NMe 2 , -NEt 2 , or -C(0)0(Ci-Ce alkyl); and
  • R 7 is each independently I, Br, Cl, F, -CH2F, -CHF? remedy -CF3, -OCF3, -CN, - alkyl-CN, -CONH2, -CON HR ".
  • one of -MF R 1 and -M 2 R 2 is - NR 4 -(C I-C3 a!ky!ene)-cycloa!kyl, -NR 4 -(CI-C3 alkylene)-heterocyclyl, -NR 4 -(CI-C3 alkylene)-aryl, or -NR 4 -(CI -C3 alkylene)-heteroaryl; wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl is each optionally substituted with one or more R 5 In some embodiments, one of -M !
  • R f and ⁇ M 2 R Z is -NR 4 -(Ci-C3 aikyiene)-phenyl, or -NR 4 -(CI-C3 alkylenej-pyridyl, wherein phenyl and pyridyl is each optionally substituted with one or more Rk
  • one of -M 1_ R ! and -M 2 R 2 is -NR 4 -CH2-phenyl, -NR 4 -CH2CH2-phenyl, -NR 4 -
  • phenyl and pyridyl is each optionally substituted with one or more R 5 .
  • R 1 and R 2 are each
  • one of -Mf R 1 and -M R 2 is - NR 4 -(Ci-C3 a!ky!ene)-pheny!, or -NR 4 -(CI-CJ alkyl ene)-pyridyl
  • the other one of -M ⁇ R 1 and -M 2 R 2 is -NR 4 C(0)-phenyl, -NR 4 C(0)-pyridyl, -C(0)NR 4 -phenyl, or -C(0)NR 4 -pyridyJ; wherein each phenyl and pyridyl is optionally substituted with one or more R’.
  • R f and -M 2 R is -NR 4 -(CI-CJ alkylene)-phenyl, or -NR 4 -(CI-C3 alkylene)-pyridyl, wherein each phenyl and pyridyl is optionally substituted with one or more
  • one of -M ⁇ R 1 and ⁇ M 2 R 2 is -
  • R 3 is phenyl, optionally substituted with one or more R 7 ; and R 7 is each independently I, Br, Cl, F, -CHzF, -CHFz, - CFs, -OCFs, -CN, -Ns, -OH, methyl, ethyl, propyl, -CoCH; -CN, -NH 2 , -NO2, -Ns, -OH, - OCFs, -OMe, -NMez, or -NEtz.
  • R 5 is selected from I, Br, Cl, F, -CHzF, -CHFz, -CFs, -OCFs, -Ns, -CN, -OH, methyl, ethyl, propyl, -CoCH; -CN, -NHz, - NOz, -Ns, -OH, -OCFs, -OMe, -NMez, or -NEtz.
  • the compound of formula (I) has the structure of formula (IB 1 ):
  • R 1 is cycloalkyl alkyl, heteroeyclylalky!, ary!alkyl, or heteroarylalkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 5 ;
  • R is selected from cycloalkyl, aryl, biphenyl, heterocyclyl, or heteroaryl, wherein each optionally substituted with one or more R 5 ;
  • R 3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocycly!a!kyl, heteroarylalkyl, heteroarylalkenyl, or heteroaryl alkyny!, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 7 ;
  • R 4 is each independently H or Ci-Cs alkyl
  • R 5 is I, Br, Cl, F, -CH2F, -CHF2, -CF3, -Ci-Ce alkyl, alkynyl, -CN, -(C1-C3 alkylene)-CN, -NH2, -NO2, -Ns, -OH, -OCFs, -OMe, -NMez, -NEtz, or -C(0)0(Ci-Ce alkyl); and [68] R 7 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CFs, -OCF3, -CN, - alkyl -CN, -CONH2, -CONHR 6 , -CONR 6 R 6 , -COOH, -M l ⁇ .
  • -M IR -NO2, ⁇ NR 6 R 6 , -Ns, - OH, OR 6 , -COOR 6 , -OSOsR 6 , oxo, R 6 , -SH, -SO2R 6 , -SOsH, -SO3R 6 , -SR 6 , cycloalkyl, heterocyciyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R 5 .
  • R 1 is -C1-C3 alkyl ene- cycloalkyl, -C1-C3 alkylene-heterocyclyl, -C1-C3 alkylene-aryl, or -C1-C3 alkylene-heteroaryl; wherem cycloalkyl, aryl, heteroaryl, and heterocyclyl is each optionally substituted with one or more R 5 .
  • R 3 is -C1-C3 alkylene-phenyl or -C1-C3 alkylene-pyridyl, wherein phenyl and pyridyl is each optionally substituted with one or more R 5 .
  • R 1 is -CF -phenyl, -CHaCHz-phenyl, -CHz-pyridyl, -CHzCHa-pyridyl,
  • phenyl and pyridyl is each optionally substituted with one or more
  • R 2 is aryl or 5-6 membered heteroaryl, each optionally substituted with one or more R 5 . In another embodiment, R 2 is
  • R 2 is
  • R 3 is phenyl, optionally substituted with one or more R 7 ; and R 7 is each independently I, Br, Cl, F, -CH2F, -CHF2, -
  • [72] in one embodiment of the compound of formula (IB 1 ), 4 is selected from I, Br, Cl, F, - CH2F, -CFIF2, -CFs, -OCFs, -Ns, -CN, -OH, methyl, ethyl, propyl, -CoCH; -CN, -NH2, -NO2, -Ns, -OH, -OCFs, -OMe, -NMe 2 , or -NEts.
  • the compound of formula (I) has the structure of formula (IC):
  • M 1 and M 2 are each independently selected from -NR 4 -, -NR 4 C(0)- or -
  • R 1 and R 2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocydyl heterocycloalkyl, 5-6 membered heteroaryl, cycloalkylalkyl, arylalkyl, axylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, and, heteroaryl, and heterocydyl portion is optionally substituted with one or more R 5 ;
  • -Mk R 1 and -M 2 R 2 is -NR 4 -(4-6 membered heterocydyl), -NR 4 -(5-6 membered heteroaryl), or -NR 4 -naphthalenyl, wherein 4-6 membered heterocydyl, 5-6 membered heteroaryl, and naphtha!enyl is each optionally substituted with one or more R 5 ;
  • R 3 is selected phenyl, optionally substituted with one or more R 7 ;
  • R 4 is each independently H or C1-C3 alkyl
  • R 5 and R 7 are each independently selected from I, Br, Cl, F, -CH2F, -CHF2, -
  • CFs -Ci-C6 alkyl, alkynyl, -CN, -(C1-C3 a!kylene)-CN, -NH2, -NO2, -Ns, -OH, -OCFs, - OMe, -NMer, ⁇ NEt 2 , or -C(0)0(Ci-C6 alkyl).
  • At least one of -Md R 1 and -M 2 ⁇ R 2 is -NR 4 -azetidinyl, -NR 4 -pyrrohdinyl, -NR 4 -piperidinyl, -NR 4 -imidazoIyl, -NR 4 - isoxazolyl, -NR 4 ⁇ oxazolyl, -NR 4 -thiazolyl, -NR 4 -thiophenyl, -NR 4 -pyridyl, -NR 4 -pyridazinyl, ⁇ NR 4 ⁇ pyrazinyl, -NR 4 -pyrimidinyl, or -NR 4 -pyridinone, wherein each of azetidinyl, pyrrolidinyl, piperidinyl, imidazolyl, isoxazolyl, oxazolyl, tlnazolyl, pyrid
  • At least one of -M’tR 1 and ⁇ M 2 R 2 is -NR 4 -pyridyl, wherein pyridyl is optionally substituted with one or more Rk
  • -M ⁇ R 1 and ⁇ M 2 R 2 are each -NR 4 -pyridyl, wherein pyridyl is optionally substituted with one or more R 3 .
  • R 2 is -NR 4 -azetidinyi, -NR 4 -pyrrolidinyl, -NR 4 - piperidinyl, -NR 4 -imidazolyl, -NR 4 -isoxazolyl, ⁇ NR 4 ⁇ oxazolyl, -NR 4 -thiazolyl, -NR 4 - thiophenyl, -NR 4 -pyridyl, -NR 4 -pyridazinyl, -NR 4 -pyrazinyl, -NR 4 -pyrimidinyl, or -NR 4 - pyridinone, wherein each of azetidinyi, pyrrolidinyl, pipendinyl, imidazolyl, isoxazolyi, oxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, or
  • one of -MF R 1 and -M 2 R 2 is-
  • R 5 and R 7 is each selected from I, Br, Cl, F, -CH2F, -CHF2, ⁇ CF 3 , -OCFJ, -Ns, -CN, -OH, methyl, ethyl, propyl, -CoCFI; -CN, -NH 2 , -NO '. -N 3 , -OH, -0CF3, -OMe, -NMei, or -NEti.
  • M 1 and M 2 are each independently selected from -NR 4 -, -NR 4 C(0)- or - C(0)NR 4 -;
  • R 1 and R 2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, aryla!kyl, arylalkenyl, arylalkynyl, heterocyclyl alkyl, heteroarylalkyl, heteroaryl alkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R s :
  • R 3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalky 1, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 7 ;
  • R 4 is each independently H or C1-C3 alkyl
  • R 5 and R 7 are each independently selected from I, Br, Cl, F, -CH2F, -CHF2, - CFs, -Ci-Ce alkyl, alkynyl, -CN, -(C1-C3 alkylene)-CN, -NFL ⁇ , -NO2, -Ns, -OH, -OCF3, - OMe, -NMe2, -NEt2, or -C(0)0(Ci-C6 alkyl);
  • R 1 and R 2 is a phenyl substituted with at least one of - ( C! i or -N3.
  • M 1 and M 2 are each -NR 4 C(0)-.
  • At least one of R 1 and R 2 is a phenyl substituted with at least one of -CoCH or -N3 and the other one of R 1 and R 2 is a phenyl or pyridyl, optionally substituted with one or more R 5 .
  • R 3 is phenyl optionally substituted with one or more R 7 .
  • R 3 and R 7 is each selected from I, Br, Cl, F, -CH 2 F, -CHF 2 , -CF 3 , -OCF3, -Ns, -CN, -OH, methyl, ethyl, propyl, -CoCH, -CN, -NH 2 , -NO '. -N 3 , -OH, -0CF3, -OMe, ⁇ NMe 2 , or -NEt 2 .
  • the compound of formula (I) has the structure of formula (IE):
  • M 1 and M 2 are each independently selected from -NR 4 -, -NR 4 C(0)-, -C(0)NR 4 - , or -S(0)mNR 4 -;
  • R 1 and R 2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocydyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocydyl portion is optionally substituted with one or more R 5 ;
  • R 2 is selected from an aryl or heteroaryl, wherein aryl and heteroaryl is optionally substituted with one or more R 7 ;
  • R 4 is each independently H or Ci-C 3 alkyl
  • R 5 and R 7 are each independently selected from I, Br, Cl, F, -CH2F, -CHF2, - CF 3 , -Ci-Ce alkyl, alkynyl, -CN, -(Ci-C 3 aIkylene)-CN, -NH 2 , -N0 2 , -N 3 , -OH, -OCF 3 , - OMe, -NMe 2 , -NEC, or -C(0)0(Ci-C6 alkyl);
  • M 1 and M 2 are both - S(0)mNR 4 -. In another embodiment, M 3 and M 2 are both -C(0)NR 4 -.
  • R 1 and R 2 are a phenyl or pyndyi, optionally substituted with one or more R 5 .
  • R 3 and R 2 is phenyl, optionally substituted with one or more R 5 .
  • at least one of R 1 and R 2 is a phenyl or pyndyi, optionally substituted with one or more R 5 .
  • R 3 and R 2 is phenyl, optionally substituted with one or more R 5 .
  • at least one of R 1 and R 2 is a phenyl or pyndyi, optionally substituted with one or more R 5 .
  • At least one of R* is a phenyl or pyridyl, optionally substituted with one or more R 7 .
  • R 5 and R 7 is each selected from I, Br, Cl, F, -CH2F, -CHF 2 , -CFS, -OCFJ, -NS, -CN, -OH, methyl, ethyl, propyl, -CoCH, -CN, -NH2, -NO2, -Ns, -OH, -OCF3, -OMe, -NMe2, or -NEt2.
  • the compound is not
  • the compound of formula (I) has the structure of formula (IF):
  • M 3 is selected from -NR 4 -, -NR 4 C(0)- or -C(0)NR 4 -;
  • R 1 and R 2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyi heterocycloalkyl, 5-6 membered heteroaryl, cycioa!kylalkyl, arylalkyl, aryl alkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroaryl alkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyi portion is optionally substituted with one or more R 5 ;
  • R 3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyi heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R :
  • R 4 is each independently H or CJ -CT alkyl
  • R 5 and R 7 are each independently selected from I, Br, Cl, F, -CT-fcF, -CHF2, - CF 3 , -C1-C6 alkyl, alkyny!, -CN, -(C1-C3 alkylene)-CN, -NH2, -NO2, -Ns, -OH, -OCF3, - OMe, -NMe?., -NEt 2 , or -C(0)0(C]-C6 alkyl).
  • R 1 and R 2 are each
  • R 2 is phenyl optionally
  • R 2 is
  • R 3 is cycloalkyl, aryl, heterocy clyl, or heteroaryl, each optionally substituted with one or more R 7 .
  • R 3 is phenyl optionally substituted with one or more R'.
  • the compound of formula (I), (G), (IA), (IB), (1B ! ), (IC), (ID), (IE), or (IF) is selected from Table 1.
  • the compound of formula (I), (G), (IA), (IB), (1B ! ), (IC), (ID), (IE), or (IF) is selected from Table 1.
  • the compound of formula (I), (G), (IA), (IB), (1B ! ), (IC), (ID), (IE), or (IF) is selected from Table 1.
  • the compound of the present disclosure is selected from Table 2.
  • the compound of formula (I), excludes compounds of Table A.
  • the compound of formula (I), (G), (IA), (IB), ( ⁇ B'), (IC), (ID), (IE), or (IF) excludes compounds of " fable A.
  • the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound of any one of formula (I), (I'), (I A), (IB), ( ⁇ B
  • the pharmaceutical composition comprises eutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound of Table 1.
  • the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable earner or a pharmaceutically acceptable excipient and a compound of Table 2.
  • the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and
  • the present disclosure provides a pharmaceutical composition as disclosed herein comprises one additional therapeutically active agent.
  • the present disclosure provides compounds comprising the structure of formula (II): ] or a pharmaceutically acceptable salt or solvate thereof, wherein:
  • M 3 and M 2 are each independently selected from a bond, -NR 4 -, or -NR 4 C(0)- , -C(0)NR 4 -;
  • R ! and R 2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, axylalkyl, aryl alkenyl, ary!a!kynyl, heterocydylalkyl, heteroaryialkyl, heteroaryl alkenyl, or
  • heteroarylalkynyl wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 5 ;
  • R 1 is cycloalkylalkyl, heterocydylalkyl, arylalkyl, or heteroaryialkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 5 ;
  • R 2 is cycloalkylalkyl, heterocydylalkyl, arylalkyl, or heteroaryialkyl, wherein cycloalkyl, a ryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 5 ;
  • R 3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaiyl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkyny!, heterocydylalkyl, heteroaryialkyl, heteroarylalkenyi, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 7 ;
  • R 4 is each independently H, alkyl, wherein each alkyl is optionally substituted with one or more R 5 ;
  • R 5 is each independently I, Br, Cl, F, -CH 2 F, -CHF 2 , -CF3, -OCF3, -CN, - a!kyl-CN, -CONH?, -CONHR 6 , -CONR 6 R 6 , -COGH, -M l ⁇ . -M I ' . -NO-.. -NR 6 R 6 , -N3, - OH, OR 6 , -CQOR 6 , -QSQ3R 6 , oxo, R 6 , -SH, -SQ2R 6 , -SO3H, -SO3R 6 , or -SR 6 ;
  • R 6 is each independently alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl; or alternatively two R 6 on the same N atom can together form a 3-6
  • R 7 is each independently I, Br, Cl, F, -CFHF, -C l li e. -CFs, -OCF3, -CN, - alkyl -CN, -CONH2, -CONHR 6 , -CONR 6 R 6 , -COOH, - l ⁇ .
  • At least one of -M 1_ R ] and -M 2 R 2 is -NR 4 -(CI-C3 alkylene) ⁇ eycloalkyl, -NR 4 -(CI-C3 alkylene)-heterocyclyl, -NR 4 -(CI-C3 alkylene)-aryl, or -MR 4 -(CI-C3 alkylene)-heteroaryl; wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl is each optionally substituted with one or more R 5 .
  • At least one of and -M 2 R 2 is -NR 4 -(CI-C alkyiene) ⁇ phenyl, or -NR 4 -(Ci-C3 alkylene)-pyridyl, wherein phenyl and pyridyl is each optionally substituted with one or more R 5 .
  • at least one of -M ⁇ R 1 and -M 2 R 2 is -NR 4 -CH 2 -phenyl, -NR 4 -CH 2 CH2-phenyl, -NR 4 -CH 2 -pyridyl, -NR 4 -
  • pyridyl is each optionally substituted with one or more R 5 .
  • -M ⁇ R 1 and -M 2 R 2 are each selected from -NR 4 -CH?-phenyl, -NR 4 -CH 2 CH 2 -phenyl, -NR 4 -CH 2 -
  • phenyl and pyridyl is each optionally substituted with one or more R 5 .
  • R 1 and R 2 are each
  • one of M 1 and M 2 is a bond.
  • R 1 and R 2 are each
  • R 3 and R 2 are each independently selected from phenyl, azetidinyl, pyrrolidinyl, pipendinyl, imidazolyl, isoxazolyl, oxazolyi, thiazolyl, pyridyl, pyridazinyl, pyrazinyi, pyrimidmyl, pyridinoneor, or pyridine N-oxide, each optionally substituted with one or more R 5 .
  • M 1 is a bond and R 3 is pyridyl, optionally substituted with one or more R 3 .
  • M 2 is a bond and R 2 is pyridyl, optionally substituted with one or more R ⁇
  • M 1 is a bond and M 2 is -NR 4 - or -NR 4 C(0)-.
  • M 2 is a bond and M 1 is -NR 4 - or ⁇ NR 4 C(G) ⁇ .
  • R 3 is phenyl, optionally substituted with one or more R 7 ; and R 7 is each independently I, Br, Cl, F, -CFFF, -CHF? remedy - CF , -OCF3, -CN, -N , -OH, methyl, ethyl, propyl, -CoCH; -CN, -NH2, -NO2, -N3, -OH, - OCFs, -OMe, -NMe 2 , or -NEta.
  • R 5 and R 7 are each independently I, Br, Cl, F, -CFFF, -CHF? remedy - CF , -OCF3, -CN, -N , -OH, methyl, ethyl, propyl, -CoCH; -CN, -NH2, -NO2, -N3, -OH, - OCFs, -OMe, -NMe 2 , or -NEta.
  • R 4 is each independently H or C1-C3 alkyl
  • the compound of formul a (P) has the structure of formula (II A) :
  • R 1 and R 2 are each independently selected from an cycioalky!, aryl, biphenyl, heterocyclyl, or heteroaryl, each optionally substituted with one or more R 5 ;
  • R 3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryi, cycloalkylalkyl, arylalkyi, arylalkenyl, aiylalkynyl, heterocydylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 7 ;
  • R 4 is each independently H, alkyl, wherein each alkyl is optionally substituted with one or more R 3 ;
  • R 5 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CFs, -OCF3, -CN, - alkyl -CN. -CONH2, -CONHR 6 , -CONR 6 R 6 , -COOH, -M l '. M IR' . -NO2, -NR 6 R 6 , -Ns, - OH, OR 6 , -COOR 6 , -OSOsR 6 , oxo, R 6 , -SH, -SO2R 6 , -SOsH, -SOsR 6 , or -SR 6 ;
  • R 6 is each independently alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl; or alternatively two R 6 on the same N atom can together form a 3-6 membered N -heterocyclyl;
  • R 7 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CFs, -OCF3, -CN, - alkyl-CN, -CONH2, -CONHR 6 , -CONR 6 R 6 , -COOH, -M l ⁇ . -M I ' . -NO.-..
  • R 1 is aryl, optionally substituted with one or more R 5 .
  • R 1 is phenyl, optionally substituted with one or more R 5 .
  • 5 is 5-6 membered heteroaryl, optionally substituted with one or more R 5 .
  • R 1 is pyridyl, optionally substituted with one or more R 5 .
  • R 2 is phenyl optionally
  • R 2 is
  • R 3 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more R 7 .
  • R 3 is phenyl optionally substituted with one or more R 7 .
  • R 5 is I, Br, Cl, F, -CH2F, -
  • R 5 and R 7 are each
  • the compound of formula (II) or (PA) excludes the compounds of Table C.
  • the compound is selected from Table 3A.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound of formula (II) or (IIA).
  • the pharmaceutical composition further comprising one additional therapeutically active agent.
  • the compounds of Table C are excluded.
  • R ! and R 2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aiyl, biphenyl, heterocyc!yi heterocycloalkyl, heteroaiyl, cycloalkylalkyl, arylalkyl, aiylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 5 ;
  • R 3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, aryla!kenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, and, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 7 ;
  • R 4 is each independently H, alkyl, wherein each alkyl is optionally substituted with one or more R 5 ;
  • R 5 is each independently I, Br, Cl, F, -CH 2 F, -CHF 2 , -CFs, -OCFs, -CN, - alkyl-CN, -CONH2, -CONHR 6 , -CONR 6 R 6 , -COR 6 , -COOH, -M l;.
  • R 6 is each independently alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl; or alternatively two R 6 on the same N atom can together form a 3-6 rnembered N-heterocy cly 1 ;
  • R 7 is each independently I, Br, Cl, F, -CH2F, -CHF 2 , -CFs, -OCF 3 , -CN, - alkyl-CN, -CONH2, -CONHR 6 , -CONR 6 R 6 , -COOH, -NH2, -NHR 6 , -NO2, -NR 6 R 6 , -N3, - OH, OR 6 , -COOR 6 , -OSO3R 6 , oxo, R 6 , -SH, -SO2R 6 , -SO3H, -SO3R 6 , -SR 6 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and
  • heteroaryl is optionally substituted with one or more R 5 ;
  • m 0, 1, or 2:
  • the compound of formul a (III) has the spliture of formula (III A):
  • M 1 and M 2 are each independently selected from -NR 4 -, -NR 4 C(0)- or - C(0)NR 4 -, provided that M 1 and M 2 are not both -NR 4 -;
  • R 1 and R 2 are each independently phenyl, optionally substituted with one or more R " :
  • alkylene NHCO(Ci-Cio alkyl) or -(Ci-Ce alkylene)N(Ci-C3 alkyl)CO(Ci-Cio alkyl);
  • R 4 is each independently H or C1-C3 alkyl
  • R 5 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CF3, -Ci-Ce alkyl, alkynyl, -CN, -(C1-C3 alkylene)-CN, -NH2, -NO2, -Ns, -OH, -OCR.
  • R 7a , R 7 **, R 7e , and R 7e is each independently H, I, Br, Cl, F, -CH2F, -CHF2, - CF3, -OCF3, -N3, -CN, -OH, methyl, ethyl, propyl, C1-C3 haloalkyl, C1-C3 alkoxy, or Ci- C3 haloalkoxy; and
  • R 7c is H, 1, Br, Cl, F, -CH2F, -CHF2, -CFs, -OCFs, -N3, -CN, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, 4-6 membered heterocydyl, or 5-6 membered heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one or more R 5
  • R 1 is phenyl substituted with -(C1-C3 alkylene)NHCO(Ci-C8 alkyl) or -(C1-C3 alkylene)N(Ci-C: ⁇
  • R 1 is phenyl substituted with -CH 2 NHCO(CI- Cs alkyl) or -CH 2 N(CI-C3 alkyl)CO(Ci-Cg alkyl).
  • R 7a , R 71 ’, R 7c , R 7e , and R 7e is each independently H, I, Br, Cl, F, -CH2F, -CHF2, -CFs, -OCFs, -Ns, -CN, -OH, methyl, ethyl, propyl, -CoCH; -CN, -NH2, -NO2, -N 3 , -OH, -OCFs, -OMe, -NMe 2 , or -NEt 2,
  • R 7a , R 75 , R 7e , and R 7e is each independently H.
  • the compound of formula (III) has the structure of formula (IIIB):
  • M 1 and M 2 are each independently selected from -NR 4 -, -NR 4 C(G)- or - C(0)NR 4 ⁇ , provided that M 1 and M 2 are not both -NR 4 -;
  • R 1 and R 2 are each independently phenyl, optionally substituted with one or more R 5 :
  • R 3 is phenyl, substituted with one or more R 7 ;
  • R 4 is each independently H or Ci-Cs alkyl
  • R 5 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CF3, -Ci-Cs alkyl, alkynyl, -CN, -(C1-C3 alkylene)-CN, -NH2, -NO2, -Ns, -OH, -OCFs, -OMe, -NMe 2 , -NEfc, -C(0)0(Ci-C6 alkyl), -CO(Ci-Cio alkyl), -NHCO(Ci-Cio alkyl), -N(Ci-Cs alkyl)CO(Ci- Cio alkyl), -(Ci-Ce alkylene)NHCO(Ci-Cio alkyl), or -(Ci-Ce alkylene)N(Ci-C 3 alkyl)CO(Ci-Cio alkyl); and
  • R 7 is heterocyclyl substituted with -CO(Ci-Cio alkyl), which is optionally further substituted with one or more R 5 .
  • R 3 is phenyl, substituted with 6-membered heterocyclyl and wherein the 6-membered heterocyclyl is substituted with -CO(Ci-Cio alkyl).
  • R 3 is phenyl substituted with a piperidine or a piperazine, wherein the piperidine or the piperazine is substituted with -CO(Ci-Cio alkyl).
  • R 1 and R 2 are each independently phenyl, optionally substituted with one or more substitutent selected from I, Br, Cl, F, -CtfcF, -CHF 2 , -CFs, -OCFs, -Ns, -CN, -OH, methyl, ethyl, propyl, -CoCH; -CN, -NHz, -NO’.
  • the compound of formula (III), excludes compounds of Table A. In one embodiment, the compound of formula (III), excludes compounds of Table B.
  • a method of modulating a Parkin ligase comprising administering to a subject in need thereof an effective amount of a compound of (I), (F), (IA), (IB), (IB 1 ), (IC), (ID), (IE), (IF), (III), (III A), (IIIB), (II) and/or (IIA), or a pharmaceutically acceptable salt thereof.
  • a method of treating a disease or a condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of (I), (G), (IA), (IB), (IB’), (IC), (ID), (IE), (IF), (III), (IIIA), (IIIB), (II) and/or (IIA), or a pharmaceutically acceptable salt thereof is provided.
  • the disease or the condition is cancer.
  • the cancer is colon cancer, lung cancer, or ovarian cancer.
  • a method of treating Parkinson’s Disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound
  • a method of slowing the progression of Parkinson’s Disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of (I), (G), (IA), (IB), (IB'), (IC), (ID), (IE), (IF), (III), (III A), (IIIB), (II) and/or (IIA), or a pharmaceutically acceptable salt thereof.
  • a method of restoring dopamine neuronal balance in a subject in need thereof comprising administering to a subject in need thereof a therapeutically effective amount of a compound of (I), (I'), (I A), (IB), (IB'), (IC), (ID), (IE), (IF), (III), (IPA), (IIIB), (II) and/or (IIA), or a pharmaceutically acceptable salt thereof
  • a method of delaying or preventing dopamine neuron loss in a subject in need thereof comprising administering to a subject in need thereof a therapeutically effective amount of a compound of (I), (G), (IA), (IB), (IB'), (IC), (ID), (IE), (IF), (III), (III A), (IIIB), (II) and/or (IIA), or a pharmaceutically acceptable salt thereof.
  • a method of increasing mitophagy of damaged mitochondria m a subject in need thereof comprising administering to a subject in need thereof a therapeutically effective amount of a compound of (I), (G), (IA), (IB), (IB 1 ), (IC), (ID), (IE), (IF), (III), (1IIA), (IIIB), (II) and/or (IIA), or a pharmaceutically acceptable salt thereof.
  • the compound is Compound 42 or a pharmaceutically acceptable salt thereof. In one embodiment of any one of the methods disclosed herein,
  • a compound selected from Table 1 , 2, 3A and/or 3B is administered to a subject in need thereof in another embodiment of any one of the methods disclosed herein.
  • a pharmaceutically acceptable salt thereof is administered to a subject in need thereof.
  • a compound selected from Tables A and C are excluded.
  • Figure 1 shows a Xenograft study testing Compound 42 efficacy to delay subcutaneous HCT-116 tumor growth.
  • Compound 42, Compound F or control were administered daily (IP).
  • Group 1 Vehicle Control
  • Group 2 Compound F (25 mg/kg).
  • Group 3 Compound 42 (1 mg/kg),
  • Group 4 Compound 42 (5 mg/kg)
  • Figure 2 shows the % inhibition of cancer cell line proliferation with Compound 42
  • Figure 3 shows mean plasma concentration of Compound 42 in mice after IV, IP, and PC) administration.
  • Figure 4 show's mitophagy by Compound 42 treated with CCCP (carbonyl cyanide m- chloroph eny 1 hy drazine) .
  • CCCP carbonyl cyanide m- chloroph eny 1 hy drazine
  • the terms‘about” and/or“approximately” may be used in conjunction with numerical values and/or ranges.
  • the term“about” is understood to mean those values near to a recited value.
  • “about 40 [units]” may mean within ⁇ 25% of 40 (e.g., from 30 to 50), within ⁇ 20%, ⁇ 15%, ⁇ 10%, ⁇ 9%, ⁇ 8%, ⁇ 7%, ⁇ 6%, ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2%, ⁇ 1%, less than ⁇ 1 %, or any other value or range of values therein or therebelowi
  • the phrases“less than about [a value]” or“greater than about [a value]” should be understood in view of the definition of the term“about” provided herein.
  • the term“a” or“an” refers to one or more of that entity 7 ; for example,“a kinase inhibitor” refers to one or more kinase inhibitors or at least one kinase inhibitor. As such, the terms“a” (or“an”). “one or more” and“at least one” are used interchangeably herein.
  • reference to“an inhibitor” by the indefinite article“a” or“an” does not exclude the possibility that more than one of the inhibitors is present, unless the context clearly requires that there is one and only one of the inhibitors.
  • the verb“comprise” as is used in this description and in the claims and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded.
  • the present invention may suitably“comprise”,“consist of’, or“consist essentially of’, the steps, elements, and/or reagents described in the claims.
  • salts include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesuifonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc.
  • acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • the term “treating” means one or more of relieving, alleviating, delaying, reducing, reversing, improving, or managing at least one symptom of a condition in a subject.
  • the term “treating” may also mean one or more of arresting, delaying the onset (i.e., the period prior to clinical manifestation of the condition) or reducing the risk of developing or worsening a condition.
  • An “effective amount” means the amount of a formulation according to the invention that, when administered to a patient for treating a state, disorder or condition is sufficient to effect such treatment.
  • the "effective amount” will vary' depending on the active ingredient, the state, disorder, or condition to be treated and its severity', and the age, weight, physical condition and responsiveness of the mammal to be treated.
  • terapéuticaally effective applied to dose or amount refers to that quantity of a compound or pharmaceutical formulation that is sufficient to result in a desired clinical benefit after administration to a patient in need thereof.
  • substantially refers to the complete or nearly complete extent or degree of an action, characteristic, properly, state, structure, item, or result.
  • an object that is “substantially” enclosed would mean that the object is either completely enclosed or nearly completely enclosed.
  • the exact allowable degree of deviation from absolute completeness may in some cases depend on the specific context. However, generally speaking, the nearness of completion will be so as to have the same overall result as if absolute and total completion were obtained.
  • the use of “substantially” is equally applicable when used in a negative connotation to refer to the complete or near complete lack of action, characteristic, property, state, structure, item, or result.
  • compositions that is "substantially free of' other active agents would either completely lack other active agents, or so nearly completely lack other active agents that the effect would be the same as if it completely lacked other active agents.
  • a composition that is "substantially free of an ingredient or element or another active agent may still contain such an item as long as there is no measurable effect thereof
  • the“alignment” of two or more protem/amino acid sequences may be performed using the alignment program ClustalW2, available at wwwvebi. ac.uk/Toois/insa ' elustalw2/.
  • Ubiquitin Proteasorne Pathway System relates to the ubiquitin proteasome pathway, conserved from yeast to mammals, and is required for the targeted degradation of most short-lived proteins in the eukaryotic cell. Targets include cell cycle regulator ' proteins, whose timely destruction is vital for controlled cell division, as well as proteins unable to fold properly within the endoplasmic reticulum. Ubiquitin modification is an ATP-dependent process carried out by three classes of enzymes. An“ubiquitin activating enzyme” (El) forms athio-ester bond with ubiquitin, a highly conserved 76-amino acid protein.
  • El ubiquitin activating enzyme
  • E3 ligases can be single- or multi-subunit enzymes. In some cases, the ubiquitin-binding and substrate binding domains reside on separate polypeptides brought together by adaptor proteins or culling. Numerous E3 ligases provide specificity in that each can modify only a subset of substrate proteins. Further specificity is achieved by post-translational modification of substrate proteins, including, but not limited to, phosphorylation.
  • Effects of mono ubiquitination include changes in subcellular localization. However, multiple ubiquitination cycles resulting in a polyubiquitin chain are required for targeting a protein to the proteasome for degradation.
  • the multisubunit 26S proteasome recognizes, unfolds, and degrades polyubiquitinated substrates into small peptides. The reaction occurs within the cylindrical core of the proteasome complex, and peptide bond hydrolysis employs a core threonine residue as the catalytic nucleophile. It has been shown that an additional layer of complexity, in the form of multiubiquitin chain receptors, may lie between the poly ubiquitination and degradation steps.
  • Protein degradation through the ubiquitin-proteasome system is the major pathway of non-lysosomal proteolysis of intracellular proteins. It plays important roles m a variety 7 of fundamental cellular processes such as regulation of cell cycle progression, division, development and differentiation, apoptosis, cell traffi cking, and modulation of the immune and inflammatory responses.
  • the central element of this system is the covalent linkage of ubiquitin to targeted proteins, which are then recognized by the 26S proteasome, an adenosine triphosphate-dependent, multi-catalytic protease. Damaged, oxidized, or misfolded proteins as well as regulatory proteins that control many critical cellular functions are among the targets of this degradation process.
  • Parkin ligase or“Parkin” as used herein relates to a protein which in humans is encoded by the PARK2 gene.
  • "Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism”. Nature 392 (6676): 605-608. doi: 10.1038/33416.
  • PMID 9560156 Matsumine H, Yamamura Y, Hattori N, Kobayashi T, Kitada T, Yoritaka A, Mizuno Y (April 1998). "A microdeletion of D6S305 in a family of autosomal recessive juvenile parkinsonism (PARK2)". Genomics 49 (1): 143-146. doi: l0.1006/geno.1997.5196. PMID 9570960.
  • the protein is a component of a multiprotein E3 ubiquitin ligase complex which in turn is part of the ubiquitin-proteasome system that mediates the targeting of proteins for degradation. Mutations in the PARK2 gene are known to cause a familial form of Parkinson's disease known as autosomal recessive j uvenile Parkinson's disease (AR-JP).
  • “Ligase” as used herein, is an enzyme that can catalyze the joining of two or more compounds or biomolecules by bonding them together with a new chemical bond.
  • the “ligation” of the two usually with accompanying hydrolysis of a small chemical group dependent to one of the larger compounds or biomolecules, or the enzyme catalyzing the linking together of two compounds, e.g., enzymes that catalyze joining of groups C-O, OS, C- N, etc.
  • Ubiquitin-protein (E3) ligases are a large family of highly di verse enzymes selecting proteins for ubiquitination.
  • E3 ligases are involved in disease pathogenesis for oncology, inflammation & infectious disease.
  • RBR RING-between-RTNG
  • Parkin is recognized as a neuroprotective protein with a role in mitochondrial integrity.
  • Human genetic data implicate loss of Parkin activity as a mechanism for pathogenesis of Parkinson’s disease (PD).
  • Zinc Finger (ZnF) Domain as used herein relates to a protein structure characterized by coordinating zinc ions to stabilize the functional activity. ZnF stabilize the binding of Ub, Deubiquitinating Enzymes (DUBs), and Ligases (E3) in the UPS.
  • Ligands as used herein bind to metal via one or more atoms in the ligand, and are often termed as chelating ligands.
  • a ligand that binds through two sites is classified as bidentate, and three sites as tridentate.
  • the "bite angle” refers to the angle between the two bonds of a bidentate chelate.
  • Chelating ligands are commonly formed by linking donor groups via organic linkers.
  • a classic bidentate ligand is ethylenedi amine, which is derived by the
  • J2 linking of two ammonia groups with an ethylene (-CH2CH2-) linker is the hexadentate chelating agent EDTA, which is able to bond through six sites, completely surrounding some metals.
  • the binding affinity of a chelating system depends on the chelating angle or bite angle.
  • Many ligands are capable of binding metal ions through multiple sites, usually because the ligands have lone pairs on more than one atom. Some ligands can bond to a metal center through the same atom but with a different number of lone pairs.
  • the bond order of the metal ligand bond can be in part distinguished through the metal ligand bond angle (M-X-R).
  • This bond angle is often referred to as being linear or bent with further discussion concerning the degree to which the angle is bent.
  • an imido ligand in the ionic form has three lone pairs. One lone pair is used as a sigma X donor, the other two lone pairs are available as L type pi donors. If both lone pairs are used in pi bonds then the M- N-R geometry is linear. However, if one or both of these lone pairs are non-bonding then the M-N-R bond is bent and the extent of the bend speaks to how much pi bonding there may be. It was found that few heteroatoms, such as nitrogen, oxygen, and sulfur atoms, interacted with zinc, ideal distances between the zinc and these heteroatoms were identified.
  • Simple organic species are also very common, be they anionic (RO and RCCh-) or neutral (R2O, R2S, R3 X NH X , and R3P).
  • Complexes of polydentate ligands are called chelate complexes. They tend to be more stable than complexes derived fro monodentate ligands. This enhanced stability , the chelate effect, is usually attributed to effects of entropy, which favors the displacement of many ligands by one polydentate ligand.
  • the chelating ligand forms a large ring that at least partially surrounds the central atom and bonds to it, leaving the central atom at the center of a large ring. The more rigid and the higher its denticity, the more inert will be the macrocyciic complex.
  • “Chelator” as used herein relates to a binding agent that suppresses chemical activity by forming a chelate (a coordination compound in which a metal ato or ion is bound to a ligand at two or more points on the ligand, so as to form, for example, a heterocyclic ring containing a metal atom).
  • a chelate a coordination compound in which a metal ato or ion is bound to a ligand at two or more points on the ligand, so as to form, for example, a heterocyclic ring containing a metal atom.
  • Chelation as used herein relates to a parti cul ar way that ions and molecul es bind metal ions. According to the International Union of Pure and Applied Chemistry (IUPAC), chelation involves the formation or presence of two or more separate coordinate bonds between a poly dentate (multiple bonded) ligand and a single central atom. Usually these ligands are organic compounds, and are called chelants, chelators, chelating agents, or sequestering agents.
  • Electrophile as used herein relates to species that is attracted to an electron rich center.
  • an electrophile is a reagent attracted to electrons. It participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carries a partial positive charge, or have an atom that does not have an octet of electrons.
  • Amino refers to the -NH2 radical.
  • Halo or“halogen” refers to hromo, chloro, fluoro or iodo radical.
  • Niro refers to the -NO2 radical .
  • Alkyl or“alkyl group” refers to a fully saturated, straight or branched hydrocarbon chain radical having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 are included. An alkyl comprising up to 12 carbon atoms is a C1-C12 alkyl, an alkyl comprising up to 10 carbon atoms is a C1-C10 alkyl, an alkyl comprising up to 6 carbon atoms is a Ci-Ce alkyl and an alkyl comprising up to 5 carbon atoms is a C1-C5 alkyl.
  • a Ci-Cs alkyl includes C5 alkyls, C4 alkyls, C3 alkyls, C2 alkyls and Ci alkyl (i.e., methyl).
  • a CVCe alkyl includes all moieties described above for C1-C5 alkyls but also includes Ce alkyls.
  • a C1-C10 alkyl includes all moieties described above for C1-C5 alkyls and Ci-Ce alkyls, but also includes C7, Ce, C9 and Cio alkyls.
  • a C1-C12 alkyl includes all the foregoing moieties, but also includes C11 and C12 alkyls.
  • Ci-Ci 2 alkyl include methyl, ethyl, «-propyl, /-propyl, sec-propyl, «-butyl, /-butyl, sec-butyl, ⁇ -butyl, «-pentyl, /-amyl, «-hexyl, n-heptyl, «-octyl, «- nonyl, w-decyl, n-undecyl, and ra-dodecyl. Unless staled otherwise specifically in the specification, an alkyl group can be optionally substituted.
  • Alkylene or“alkylene chain” refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, and having from one to twelve carbon atoms.
  • C1-C12 alkylene include methylene, ethylene, propylene, «-butylene, ethenylene, propenylene, «-butenylene, propynylene, «-butynylene, and the like.
  • the alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted.
  • Alken l or“alkenyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from 2 to 12 are included.
  • An alkenyl group comprising up to 12 carbon atoms is a C2-C12 alkenyl
  • an alkenyl comprising up to 10 carbon atoms is a C2-C10 alkenyl
  • an alkenyl group comprising up to 6 carbon atoms is a C2-C6 alkenyl
  • an alkenyl comprising up to 5 carbon atoms is a C2-C5 alkenyl.
  • a C2-C5 alkenyl includes Cs alkenyls, Cs alkenyls, Cs alkenyls, and C2 alkenyls.
  • a C2-C0 alkenyl includes all moieties described above for C2-C5 alkenyls but also includes C0 alkenyls.
  • a C2-C10 alkenyl includes all moieties described above for C2-C5 alkenyls and C2-C6 alkenyls, but also includes C?, Cs, C9 and Cio alkenyls.
  • a C2-C12 alkenyl includes all the foregoing moieties, but also includes Cn and C12 alkenyls.
  • Non-limiting examples of C2-C12 alkenyl include ethenyl (vinyl), 1 -propenyl, 2-propenyl (ally!), iso-propenyl, 2-methyl-l-propenyl, l-butenyl, 2-butenyl, 3- hutenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pen tenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4- hexenyl, 5-hexenyl, l-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1- octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-non
  • alkyl group can be optionally substituted.
  • alkenylene or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds.
  • C2-C12 alkenylene include ethene, propene, butene, and the like.
  • the alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond.
  • the points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain.
  • an alkenylene chain can be optionally substituted.
  • Alkynyl or“alkynyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl group comprising any number of carbon atoms from 2 to 12 are included.
  • An alkynyl group comprising up to 12 carbon atoms is a C2-C12 alkynyl
  • an alkynyl comprising up to 10 carbon atoms is a C2-C10 alkynyl
  • an alkynyl group comprising up to 6 carbon atoms is a CVCe alkynyl
  • an alkynyl comprising up to 5 carbon atoms is a C2-C5 alkynyl.
  • a C2-C5 alkynyl includes Cs alkynyls, Cfi alkynyls, C3 alkynyls, and C2 alkynyls.
  • a C2-C6 alkynyl includes all moieties described above for C2-C5 alkynyls but also includes Ce alkynyls.
  • a C2-Cio alkynyl includes all moieties described above for C2-C5 alkynyls and C2-C6 alkynyls, but also includes CT, Cs, C9 and C 10 alkynyls.
  • a C2-C 12 alkynyl includes all the foregoing moieties, but also includes C11 and C12 alkynyls.
  • Non-limiting examples of C2-C12 alkenyl include ethyny!, propynyl, butynyl, pentynyl and the like. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.
  • Alkynyl ene or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds.
  • C2-C12 alkynylene include ethynylene, propargylene and the like.
  • the alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkynylene chain can be optionally substituted.
  • Alkoxy refers to a radical of the formula -ORa where R a i s an alkyl, alkenyl or alkny! radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted.
  • Alkylamino refers to a radical of the formula -NHRa or -NRaRa where each R a is, independently, an alkyl, alkenyl or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically m the specification, an alkylamino group can be optionally substituted.
  • R a is an alkyl, alkenyl or alkynyl radical as defined above.
  • a non-limiting example of an alkyl carbonyl is the methyl carbonyl (‘acetal’) moiety .
  • Alkylcarbonyl groups can also be referred to as“Cw-Cz acyl” where w and z depicts the range of the number of carbon in R a , as defined above.
  • Cl-Cio acyl refers to alkylcarbonyl group as defined above, where R a is Ci-Cio alkyl, Ci-Cio alkenyl, or Ci-Cio alkynyl radical as defined above. Unless stated otherwise specifically in the specification, an alkyl carbonyl group can be optionally substituted.
  • Ary 1 refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring.
  • the aryl radical can be a monocyclic, bicyclie, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems.
  • Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, x-indacene, indane, indene, naphthalene, phena!ene, phenanthrene, pleiadene, pyrene, and triphenylene.
  • the term“aryl” is meant to include aryl radicals that are optionally substituted.
  • “Aralkyl” or“arylalky!” refers to a radical of the formula -Rb-Rc where 3 ⁇ 4 is an alkyl ene group as defined above and Rc is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group can be optionally substituted.
  • alkenyl or“aryla!keny!” refers to a radical of the formula -R b -R c where Rt > is an alkenylene o group as defined above and Rc is one or more aryl radicals as defined above. Unless stated otherwise specifically in the specification, an aralkenyl group can be optionally substituted.
  • Alkynyl or“aiylalkynyl” refers to a radical of the formula -Rb-Rc where Rb is an alkynylene group as defined above and Rc is one or more aryl radicals as defined above. Unless stated otherwise specifically in the specification, an aralkynyl group can be optionally substituted.
  • Carbocyelyl “carbocyclic ring” or“carbocycle” refers to a rings structure, wherein the atoms which form the ring are each carbon. Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryls and cycloalkyl cycloalkenyl and cydoalkynyl as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group can be optionally substituted.
  • Cycloalkyl refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecul e by a single bond.
  • Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cydoheptyl, and cyclooctyl.
  • Polycyclic cycloalkyl radicals include, for example, adamantyl, norhornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2. l ]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted.
  • Cycloalkenyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, which can include fused or bridged ring systems, having from three to twenty' carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexeny!, cycloheptenyl, cycloctenyl, and the like.
  • Polycyclic cycloalkenyl radicals include, for example, bicycloj 2.2.1 ]hept-2-enyi and the like. Unless otherwise stated specifically in the specification, a cycloalkenyl group can be optionally substituted.
  • Cydoalkynyl refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond.
  • Monocyclic cydoalkynyl radicals include, for example, cycloheptynyl, cyclooetynyl, and the like. Unless otherwise stated specifically in the specification, a cydoalkynyl group can be optionally substituted.
  • Cycloalkyl alkyl refers to a radical of the formula -R h -Ra where R* is an alky!ene, alkenylene, or alkynylene group as defined above and Rd is a cycloalkyl, cycloalkenyl, cydoalkynyl radical as defined above. Unless stated otherwise specifically m the specification, a cycloalky lalkyl group can be optionally substituted.
  • Haloalkyl refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-diiluoroethyl, 3-bromo-2-fluoropropyl, 1 ,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloaikyi group can be optionally substituted.
  • Haloalkenyl refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 1-fluoropropenyl, 1,1-difluorobutenyl, and the like. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted .
  • Haloalkynyl refers to an alkynyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., l-fluoropropynyJ, 1-fluorobutynyl, and the like. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted.
  • Heterocyclyl refers to a stable 3- to 20-membered non-aromatic, partially aromatic, or aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Heterocyclycl or heterocyclic rings include heteroaryls as defined below.
  • the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated.
  • heterocyclyl radicals include, but are not limited to, dioxolany!, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazoiiny!, imidazolidmyi, isothiazolidmyl, isoxazolidmyi, morpholinyl, oetahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyi, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryi, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorph
  • Heterocyclylalkyl refers to a radical of the formula -Rb-Re where Rb is an a!ky!ene group as defined above and Re is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocycloaiky!alkyi group can he optionally substituted.
  • Heterocyclylalkenyl refers to a radical of the formula ⁇ Rb ⁇ R e where Rb is an alkenyiene group as defined above and R e i s a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocycloalkylalkenyl group can be optionally substituted .
  • “Heterocyclylalkynyl” refers to a radical of the formula -Rb-Re where R3 ⁇ 4 is an alkynylene group as defined above and R s is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocycloalky !aikynyl group can be optionally substituted.
  • 'W-heierocyclyr refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise specifically in the specification, a.Y-heterocyclyl group can be optionally substituted.
  • Heteroaryl refers to a 5- to 20-rnemhered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring.
  • the heteroaryl radical can he a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quatemized.
  • Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyi, benzindolyl, benzodioxolyl, benzofuranyl, henzooxazolyl, benzothiazolyi, benzothiadiazolyl, benzofb] [1 ,4]dioxepinyl, 1 ,4-benzodioxanyl, benzonaphthofuranyi, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzoihiophenyl), benzoiriazoly 1, henzo[4,6]imidazo[ 1 ,2 ⁇ a]pyridinyl, carbazo!y!, cinnolinyl, dibenzofuranyl
  • heteroaryU refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical .
  • an L-heteroaryi group can be optionally substituted.
  • Heteroaiylalkyl refers to a radical of the formula -Rb-Rr where Rb is an alkylene chain as defined above and Rf is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroary!alkyl group can be optionally substituted.
  • Heteroaiylalkeny P refers to a radical of the formula -Rb-Rf where Rb is an alkenylene, chain as defined above and Rr is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkeny! group can be optionally substituted.
  • HeteroarylalkynyF refers to a radical of the formula -Rb-Rr where Rb is an alkynylene chain as defined above and Rr is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkynyl group can be optionally substituted.
  • Thioalkyl refers to a radical of the formula -SRa where Ra is an alkyl, alkenyl, or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group can be optionally substituted.
  • the term‘"substituted” used herein means any of the above groups (/. e., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, aikylcarbonyl, thioalkyl, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cydoalkylaikyl, haloalkyl, heterocyclyl, /V-heterocyclyl, heterocyclylalkyl, heteroaryl, /V-heteroaiyl and'or heteroaiydalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and 1; an oxygen atom in groups such as
  • “Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as i ines, oximes, hydrazones, and nitriles.
  • “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as i ines, oximes, hydrazones, and nitriles.
  • “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to
  • R g and Rh are the same or different and independently hydrogen, alkyl, alkenyl, alky
  • a point of attachment bond denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of
  • the compound of the present disclosure can be useful for modulating Parkin hgase. Further, the compound of the present disclosure can be useful for treating various diseases and conditions including, but not limited to, cancer, neurological disease, a disorder characterized by abnormal accumulation of a-synuclein, a disorder of an aging process, cardiovascular disease, bacterial infection, viral infection, mitochondrial related disease, mental retardation, deafness, blindness, diabetes, obesity, autoimmune disease, glaucoma, Leber's Hereditary Optic Neuropathy, and rheumatoid arthritis.
  • L 3 , L 2 and L 3 are each independently selected from a bond, alkyl ene, or alkenylene:
  • M ! and M 2 are each independently selected from -NR 4 -, -NR 4 C(0)-, -
  • R 1 and R 2 are each independently selected from an alkyl, alkenyl, cycloalkyl, and, biphenyl, heterocyclyl heterocycloalkyl, heteroar l, eycloalkylalkyl, ary!a!kyl, andalkenyl, arylalkynyl, heterocyclylalkyl, lieteroaiydaikyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalky!, aryl, heteroaiyi, and heterocyclyl portion is optionally substituted with one or more R 5 ;
  • R 3 is selected from an alkyl, alkenyl, cycloalkyl, and, biphenyl, heterocyclyl heterocycloalkyl, heteroaiyi, eycloalkylalkyl, arylaikyi, ary!alkenyi, arylalkynyl, heterocyclylalkyl, heieroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, a yl, heteroaiyi, and heterocyclyl portion is optionally substituted with one or more R 7 :
  • R 4 is each independently H, alkyl, wherein each alkyl is optionally substituted with one or more R 5 ;
  • R 5 is each independently I, Br, Cl, F, -CFFF, -CHF2, -CFs, -OCF3, -CN, - alkyl -CN, -CONH2, -CONHR 6 , -CONR 6 R 6 , -COOH, -M l ⁇ .
  • -M IR is each independently H, alkyl, wherein each alkyl is optionally substituted with one or more R 5 ;
  • R 6 is each independently alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl; or alternatively two R 6 on the same N atom can together form a 3-6
  • R 7 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CFs, -OCFs, -CN, - alkyl-CN, -CONH2, -CONHR 6 , -CONR 6 R 6 , -COOH, -Ni l ⁇ .
  • rn is 0, 1 , or 2;
  • I, 1 , L 2 and IF are each independently a bond.
  • M 1 and M 2 are each
  • M 1 and M are each independently selected from -NR 4 -, -NR 4 C(0) ⁇ or - C(0)NR 4 -.
  • -M ⁇ R 1 is -NR 4 C(0)R ! .
  • -M R 2 is -NR 4 C(0)R 2 .
  • -JVF R 1 is -NR 4 C(0)R 1 and -M 2 R 2 is ⁇ NR 4 C(0)R 2 .
  • R 4 at each occurrence is independently H or C1-C3 alkyl.
  • L 3 is a bond and R 3 is an aryl or a heieroaiyl, optionally substituted with one or more R 7 .
  • R 3 is a phenyl or phenyl fused bicycle, optionally substituted with one or more R 7 .
  • R 3 is heieroaiyl selected from imidazolyl or pyrazolyl, optionally substituted with one or more R 7 .
  • R 7 is each independently I, Br,
  • R 3 is a phenyl substituted with a
  • R 1 and R 2 are each independently selected from phenyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyi, phenyl-(Ci-C3 alkyl)-, phenyl-(C2-C3 alkenyl)-, 5-6 membered heteroaryl -(Ci- C3 alkyl)-, or heteroaryl-CCc-CN alkenyl)-, wherein each cycloalkyl, aryl, heteroaryl portion is optionally substituted with one or more R 5 .
  • 5-10 membered heteroaryl is a bi cyclic ring.
  • R 5 is selected from I, Br, Cl, F, C1-C6 alkyl, alkynyl, -CN, -(C1-C3 alkylene)-CN, -NHz, -NO2, -Ns, -OH, -OCF3, -OMe, - NMe2, or -NEt2.
  • At least one of R 1 , R 2 , and R 3 is phenyl and substituted with at least one of methyl, ethyl, -GoCH, I, Br, Cl, F, -CF3, -CN, - CH2CN, -CH2CH2CN, -M l ⁇ . -NO'. -Ns, -OH, -OCF3, -OMe or -NMe 2 .
  • R 1 , R 2 , and R 3 is phenyl and substituted with at least one of methyl, ethyl, -GoCH, I, Br, Cl, F, -CF3, -CN, - CH2CN, -CH2CH2CN, -M l ⁇ . -NO'. -Ns, -OH, -OCF3, -OMe or -NMe 2 .
  • At least two of R 1 , R 2 , and R 3 is phenyl and substituted with at least one of methyl, ethyl, -CoCH, I, Br, Cl, F, -CFs, -CN, -CH2CN, -CH2CH2CN, -NHa, -NO2, -Ns, -OH, -OCF3, -OMe or -NMe?.
  • at least one of R ! , R 2 , and R 3 is pyridyl, optionally substituted with one or more of methyl, ethyl, -CoCH, I, Br, Cl, F, -CF3, -CN, -
  • the compound of formula (I) has the structure of formula (G):
  • M 1 and M 2 are each
  • -M l R’ is -NR 4 C(0)R 1 .
  • ⁇ M 2 R 2 is -NR 4 C(0)R 2 .
  • -M ⁇ R 1 is -NR 4 C’(0)R 1 and -M 2 R 2 is -NR 4 C(0)R 2 .
  • R ! and R 2 are each
  • each cycloalkyl, aryl, heteroaryl portion is optionally substituted with one or more R 5 ; and " is an aryl or a heteroaryl, optionally substituted with one or more R 7 .
  • the compound of formula (1) has the structure of formula (IA):
  • M 1 and M 2 are each independently selected from -NR 4 C(0) ⁇ or
  • R 4 is each independently H or C1-C3 alkyl
  • R 73 , R 7b , R 7e , and R 7e is each independently H, I, Br, Cl, F, -CH2F, -CHF2, -
  • R 7c is H, I, Br, Cl, F, -CFI2F, -CHF2, -CFs, -OCF3, -Nr, -CN, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, 4-6 membered heterocyclyl, or 5-6 membered heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one or more R 5 ;
  • R 5 is I, Br, Cl, F, -C1 H-. -CHF 2, -CFs, -Ci-Ce alkyl, alkynyl, -CN, -(C1-C3 alkylene)-CN, -Ni l’. -NO?., -N3, -OH, -OCFs, -OMe, -NMe?, -NEt?, or -C(0)0(Ci-C6 alkyl);
  • R 7a , R 7b , R 7c , R 7e , and R 7e is not H.
  • -JVF R 1 is -NR 4 C(0)R 1 .
  • -M 2 R 2 is -NR 4 C(0)R 2 .
  • -M ⁇ R 1 is -NR ⁇ OjR 1 and -M 2 R 2 is -NR 4 C(0)R 2 .
  • R 3 is selected from R 3 is
  • R 7a , R 71 ', R /c , R 7e , and R 7e is H.
  • three of R 7a , R 7b , R 7c , R 7e , and R 7e is H.
  • R 7a , R 7b , R 7c , R 7e , and R 7e is each independently H, I, Br, Cl, F, -CH?F, -CHF?, -CFs, -OCFS, -NS, -CN, -OH, methyl, ethyl, propyl, -CoCH; -CN, -NH?, -NO?, -Ns, -OH, - OCFs, -OMe, -NMe?, or -NEt?.
  • R 7c is I, Br, -CH?F, -CHF?, -CFs, methyl, ethyl, propyl, -CoCH; -CN, -NH?, - NO?, -N3, -OH, -OCF3, -OMe, -NMe?, or -NEt?.
  • R 7c is I, Br, -CH?F, -
  • R 7c is azetidmyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or pyrazolyl, each optionally substituted with one or more R 5 .
  • the compound of formul a (I) has the structure of formula (IB):
  • M 1 and M 2 are each independently selected from -NR 4 C(0>- or -
  • R 1 and R 2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 5 ;
  • one of -V R 1 and -Vi’R ' is ⁇ NR 4 ⁇ (cycloalkylalkyl), -NR 4 - (heterocyclylalkyl), -NR 4 -(arylalkyl), or -NR 4 -(heteroarylalkyl), wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 5 ;
  • R 3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, ary!alkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 7 ;
  • R 4 is each independently H or C1-C3 alkyl
  • R 5 is I, Br, Cl, F, -CH2F, -CHF2, -CFs, -Ci-C 6 alkyl, alkynyl, -CN, -(C1-C3 alkyl ene)-CN, -NH2, -NO2, -Ns, -OH, -OCF3, -OMe, -NMe 2 , -NEt 2 , or -C(0)0(Ci-Ce alkyl); and
  • R 7 is each independently I, Br, Cl, F, -CH2F, -CHF? remedy -CF3, -OCF3, -CN, - alkyl-CN, -CONH2, -CON HR ".
  • -CONR 6 R 6 -COOH, -NH2, -NHR 6 , -NO2, -NR 6 R 6 , -N3, - OH, OR 6 , -CQQR 6 , -OSO3R 6 , oxo, R 6 , -SH, -SO2R 6 , -SO3H, -SO3R 6 , -SR 6 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more Rk
  • one of -MRR 1 and -M 2 R 2 is - NR 4 -(CI ⁇ C3 alkylene)-cycloalkyl, -NR 4 -(CI-C3 alkylene)-heterocyclyl, -NR 4 -(Ci-C3 alkylene)-aryl, or -NR 4 -(CI-C3 alkylene)-heteroaryl; wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl is each optionally substituted with one or more R 5 .
  • -VP R 1 and -M 2 R 2 is -NR 4 -(CI-C3 alkylene)-phenyl, or -NR 4 -(CI-C3 alkylene)- pyridyl, wherein phenyl and pyridyl is each optionally substituted with one or more R 5 .
  • one of -VP R 1 and -M 2 R 2 is -NR 4 -CH 2 -phenyl, -NR 4 -CH 2 CH 2 -phenyl, -
  • -M ⁇ R 1 is -NR 4 C(0)R 1 .
  • -M 2 R 2 is -NR 4 C(0)R 2 .
  • R 1 and R 2 are each
  • one of -M ! R ] and -M 2 R 2 is - NR 4 -(Ci-Cs alkylene)-phenyl, or -NR 4 -(CI-C3 alkylenej-pyridyl, and the other one of -M 3 R 3 and -M R 2 is -NR 4 C(0)-phenyi, -NR 4 C(0)-pyridyl, -C(0)NR 4 -phenyi, or -C(0)NR 4 -pyridyl; wherein each phenyl and pyridyl is optionally substituted with one or more Rk
  • R 2 is -NR 4 -(Ci-C: ⁇ alkylene)-phenyl, or -NR 4 -(CI-C3 alkylenej-pyridyl, wherein each phenyl and pyridyl is optionally substituted with one or more
  • one of and -M 2 R 2 is -
  • R 3 is phenyl, optionally substituted with one or more R 7 ; and R 7 is each independently I, Br, Cl, F, -CH 2 F, -CHF?, - CFs, -OCFS, -CN, -NS, -OH, methyl, ethyl, propyl, -C ( ⁇ 1: -CN, -XI I w -NO?., -Ns, -OH, - OCFs, -OMe, -NMe?, or -NEt?.
  • R 5 is selected from 1, Br, Cl, F, -CH?F, -CHF?, -CFs, -OCFs, -Ns, -CN, -OH, methyl, ethyl, propyl, -CoCH; -CN, -NH?, - NO?, -Ns, -OH, -OCFs, -OMe, -NMe?, or -NEt?.
  • the compound of formula (I) has the structure of formula (IB'):
  • R 1 is cycioalkylaikyi, heterocydyialkyl, aiylalkyl, or heteroaryl alky I, wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 5 ;
  • R 2 is selected from cycloalkyl, aryl, biphenyl, heterocyclyl, or heteroaryl, wherein each optionally substituted with one or more R’;
  • R 3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyi, aiylalkyl, arylalkenyl, arylalkynyl, heterocydyialkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 7 ;
  • R 4 is each independently H or C1-C3 alkyl;
  • R 5 is I, Br, Cl, F, -CFbF, -CHF2, -CFs, -Ci-C 6 alkyl, alkynyl, -CN, -(C1-C3 alky ] ene)-CN, -NH 2 , -NO2, -Ns, -OH, -OCF3, -OMe, -NMe 2 , -NEt 2 , or -C(0)0(Ci-Ce alkyl); and
  • R 7 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CF3, -OCFs, -CN, - alkyl-CN, -CONH2, -CON HR ". -CONR 6 R 6 , -COOH, -M b. -NHR 6 , -NO ⁇ .
  • R 1 is -C1-C3 alkylene- cycloalkyl, -C1-C3 alkylene-heterocyclyl, -C1-C3 alkylene-aryl, or -C1-C3 alkylene-heteroary ; wherein cycioalkyl, aryl, heteroaryl, and heterocyclyl is each optionally substituted with one or more Rb
  • R 1 is -C1-C3 alkylene-phenyl or -C1-C3 alkylene-pyridyl, wherein phenyl and pyridyl is each optionally substituted with one or more Rb
  • R 1 is -CH 2 -phenyl, -CH 2 CH 2 -phenyl, -CH 2 -pyridyl, -CH 2 CH 2 -pyridyl,
  • phenyl and pyridyl is each optionally substituted with one or more
  • R 2 is aryl or 5-6 membered heteroaryl, each optionally substituted with one or more Rb In another embodiment, R 2 is
  • R 2 is
  • R J is phenyl, optionally substituted with one or more R 7 ; and R 7 is each independently I, Br, Cl, F, -CH2F, -CHF2, - CFs, -OCF3, -CN, -NJ, -OH, methyl, ethyl, propyl, -C ( 1 1; -CN, -NH2, -NO2, -Nj, -OH, - OCF3, -OMe, -NMer, or -NEt2.
  • s is selected from I, Br, Cl, F, - ( i l l . -CHF2, -CFs, -OCF3, -N3, -CN, -OH, methyl, ethyl, propyl, ⁇ ( C! l; -CN, Al l ⁇ . -NO?, -N 3 , -OH, -OCF3, -OMe, -NMe2, or -NEt?.
  • the compound of formula (I) has the structure of formula (IC):
  • M 1 and M 2 are each independently selected from -NR 4 -, -NR 4 C(0)- or - C(0)NR 4 -;
  • R 1 and R 2 are each independently selected from an alkyl, alkenyl, cycloalkyl, and, biphenyl, heterocyclyl heterocycloalkyl, 5-6 membered heteroaiyl, cyc!oalky!alkyl, aiylalkyl, arylalkenyl, arylalkynyl, lieterocyclyialkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 5 ;
  • -M ⁇ R 1 and -M 2 R 2 is -NR 4 -(4-6 membered heterocyclyl), -NR 4 -(5-6 membered heteroaryl), or -NR 4 -naphthalenyl, wherein 4-6 membered heterocyclyl, 5-6 membered heteroaiyl, and naphthalenyl is each optionally substituted with one or more R 5 ;
  • R 3 is selected phenyl, optionally substituted w ith one or more R 7 ;
  • R 4 is each independently H or C1-C3 alkyl
  • R 5 and R 7 are each independently selected from I, Br, Cl, F, -CH2F, -CHF?, - CF3, -C1-C6 alkyl, aikynyl, -CN, -(C1-C3 alkylene)-CN, -NH2, -NO2, -Ns, -OH, -OCF3, - OMe, -NMe?., -NEt 2 , or -C(0)0(Ci-Ce alkyl).
  • At least one of dVF R 1 and -M 2 R 2 is -NR 4 -azetidinyl, -NR 4 ⁇ pyrrolidinyl, ⁇ NR 4 ⁇ piperidinyl, -NR 4 -imidazolyl, -NR 4 - isoxazolyl, -NR 4 -oxazolyl, -NR 4 -thiazolyl, -NR 4 -thiophenyl, -NR 4 -pyridyl, -NR 4 -pyridazinyl, -NR 4 -pyrazinyl, -NR 4 -pyrimidinyl, or -NR 4 -pyridmone, wherein each of azetidmyl, pyrrolidinyl, piperidinyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, pyridyl, wherein each of azetidmyl, pyr
  • At least one of -MHl 1 and -M 2 R 2 is -NR 4 -pyridyl, wherein pyridyl is optionally substituted with one or more R 5 .
  • -MF R 1 and -M 2 R 2 are each -NR 4 -pyridyl, wherein pyridyl is optionally substituted with one or more R 3 .
  • one of -M ⁇ R 1 and -M 2 ⁇ R 2 is -NR 4 ⁇ azetidinyl, ⁇ NR 4 ⁇ pyrrolidinyl, -NR 4 - piperidinyl, -NR 4 -imidazolyl, -NR 4 -isoxazolyl, -NR 4 -oxazolyl, -NR 4 -thiazolyl, -NR 4 - thiophenyl, -NR 4 -pyridyl, -NR 4 -pyridazinyl, -NR 4 -pyrazinyl, -NR 4 -pyrimidinyl, or -NR 4 - pyridinone, wherein each of azetidinyl, pyrrolidinyl, piperidinyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, pyridyl, pyridazinyl,
  • one of -M ⁇ R 1 and -M 2 R 2 is- NR 4 -azetidinyl, -NR 4 -pyrrolidinyL -NR 4 -piperidinyl, -NR 4 -imidazolyl, -NR 4 -isoxazolyl, -
  • R 5 and R 7 is each selected from
  • the compound of formula (I) has the structure of formula (ID):
  • M 1 and M 2 are each independently selected from -NR 4 -, -NR 4 C(0)- or - C(0)NR 4 -;
  • R 1 and R 2 are each independently selected from an alkyl, alkenyl, cycloalkyl, and, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, eycloalkylalkyi, ary!a!kyi, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarydaikyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaiyi, and heterocyclyl portion is optionally substituted with one or more R 1 ;
  • R 4 is selected from an alkyl, alkenyl, cycloalkyl, and, biphenyl, heterocyclyl heterocycloalkyl, heteroaiyi, eycloalkylalkyi, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarydaikyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 7 :
  • R 4 is each independently H or C1-C3 alkyl
  • R 5 and R 7 are each independently selected from I, Br, Cl, F, -CH2F, -CHF2, - CFs, -Ci-Cfi alkyl, aikynyl, -CN, -(C1-C3 alkylene)-CN, -NH2, -NO2, -Ns, -OH, -OCF3, - OMe, -NMe?., -NEt 2 , or CiO ⁇ OiCi-( ⁇ . alkyl); [376] wherein at least one of R 1 and R 2 is a phenyl substituted with at least one of - CoCH or -Ns.
  • M 1 and M 2 are each -NR 4 C(Q) ⁇
  • -M ⁇ R 1 is -NR 4 C(0)R 1 .
  • -M 2 R 2 is -NR 4 C(0)R 2 .
  • -M ⁇ R 1 is -NR 4 C(0)R 1 and -M 2 R 2 is -NR 4 C(0)R 2 .
  • At least one of R 1 and R 2 is a phenyl substituted with at least one of -CoCH or -Ns and the other one of R ! and R 2 is a phenyl or pyridyl, optionally substituted with one or more R 5 .
  • R 3 is phenyl optionally substituted with one or more R 7 .
  • R 5 and R 7 is each selected from I, Br, Cl, F, -CH 2 F, -CHF 2 , ⁇ CF 3 , -OCF 3 , -N 3 , -CN, -OH, methyl, ethyl, propyl, -CoCH, -CN, -Ntb, -NO’.
  • -N 3 -OH, -0( ⁇ ! ⁇ ;. -OMe, -NMer, or -NEt 2 .
  • the compound of formula (I) has the structure of formula (IE):
  • M 1 and M 2 are each independently selected from -NR 4 -, -NR 4 C(0) ⁇ , -C(0)NR 4 ⁇ , or ⁇ S(0)mNR 4 -;
  • R 1 and R 2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkyialkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroaryl alkenyl, or heteroary!a!kyny!, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 5 ;
  • R 3 is selected from an aryl or heteroaryl, wherein aryl and heteroaryl is optionally substituted with one or more R 7 ;
  • R 4 is each independently H or Ci-Ch alkyl
  • R 5 and R 7 are each independently selected from I, Br, Cl, F, -CH 2 F, -CHF2, - CF 3 , -Ci-Ce alkyl, alkynyl, -CN, -(C1-C3 alkyiene)-CN, -NH 2 , -NO2, -Ns, -OH, -OCF 3 , - OMe, -NMe 2 , -NEt 2 , or -C(0)0(Ci-Ce alkyl); [388] wherein when M 1 and M 2 are both -NR 4 C(())-, at least one of R 1 and R 2 is
  • M 1 and M 2 are both - S(0)mNR 4 -. In another embodiment, M 1 and M 2 are both -C(0)NR 4 -. In one embodiment of the compound of formula (IE), -M 1_ R l is -NR 4 C(0)R l . In one embodiment of the compound of formula (IE), -M 2 R 2 is -NR 4 C(0)R 2 . In one embodiment of the compound of formula (IE) -IVE R 1 is -NR 4 C(0)R 1 and -M 2 R 2 is -NR 4 C(0)R 2 .
  • R 1 and R 2 are a phenyl or pyridyl, optionally substituted with one or more R ⁇ 1 .
  • R 1 and R 2 is phenyl, optionally substituted with one or more R 5 .
  • at least one of R 1 and R 2 is a phenyl or pyridyl, optionally substituted with one or more R ⁇ 1 .
  • R 1 and R 2 is phenyl, optionally substituted with one or more R 5 .
  • at least one of R 1 and R 2 is a phenyl or pyridyl, optionally substituted with one or more R ⁇ 1 .
  • R 1 and R 2 is phenyl, optionally substituted with one or more R 5 .
  • At least one of R is a phenyl or pyridyl, optionally substituted with one or more R 7
  • R 3 and R 7 is each selected from I, Br, Cl, F, -CH 2 F, -CHF?., -CFS, -OCFS, -NS, -CN, -OH, methyl, ethyl, propyl, -CoCH, -CN, -NH2, -NO ⁇ - -N3, -OH, -on-.. -OMe, -NMez, or -NEt 2 .
  • the compound is not
  • the compound of formula (I) has the structure of formula (IF):
  • M 1 is selected from -NR 4 -, ⁇ NR 4 C(0) ⁇ or ⁇ C(Q)NR 4 -;
  • R 1 and R 2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocydyl heterocycloalkyl, 5-6 membered heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroary!alkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocydyl portion is optionally substituted with one or more R 5 ;
  • R' is selected from an alkyl, alkenyl, cycloalkyl, and, biphenyl, heterocydyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arydalkyl, arydalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocydyl portion is optionally substituted with one or more R 7 ;
  • R 4 is each independently H or Ci-Cs alkyl
  • R 5 and R 7 are each independently selected from 1, Br, Cl, F, -CEbF, -CHF 2 , - CFi, -C1-C6 alkyl, alkynyl, -CN, -(C1-C3 alkylene)-CN, -NFI2, -NO2, -N3, -OH, -OCF3, - OMe, -NM62, -NEt2, or -C(G)0(CI ⁇ C6 alkyl).
  • -IVE R 1 is -NR 4 C(0)R 1 .
  • R 1 and R 2 are each
  • R 2 is phenyl optionally
  • R 2 is
  • R 3 is cycloalkyl, aryl, heterocycly], or heteroaryl, each optionally substituted with one or more R 7 .
  • R 3 is phenyl optionally substituted with one or more R 7 .
  • the compound is selected from Table 1 below, or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of the present disclosure is selected from Table 2, below, or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of formula (I), excludes compounds of Table A.
  • the compound of formula (I), (G), (IA), (IB), ( IB ' ⁇ . (IC), (ID), (IE), or (IF) excludes compounds of Table A.
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound of any one of formula (I), (G), (IA), (IB), (IB'), (IC), (ID), (IE), or (IF).
  • a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound of any one of formula (I), (G), (IA), (IB), (IB'), (IC), (ID), (IE), or (IF).
  • the pharmaceutical composition comprises , pharmaceutically acceptable salt thereof.
  • the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound of Table 2. In one embodiment, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a
  • the present disclosure provides a pharmaceutical composition as disclosed herein comprises one additional therapeutically active agent.
  • M 1 and M 2 are each independently selected from a bond, -NR 4 -, or -NR 4 C(0) , -C(0)NR 4 -;
  • R 1 and R 2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyL wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 5 ;
  • R 1 is cycloalkylalkyl, heterocyclylalkyl, arylalkyl, or heteroarylalkyl, wherein cycloalkyl, and, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 5 ;
  • R 2 is cycloalkylalkyl, heterocyclylalkyl, arylalkyl, or heteroarylalkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 5 ;
  • R 4 is selected from an alkyl, alkenyl, cycloalkyl, and, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarydalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R :
  • R 4 is each independently H, alkyl, wherein each alkyl is optionally substituted with one or more R 5 ;
  • R 5 is each independently I, Br, Cl, F, -CH2F, -P IF. ⁇ . -CF3, -OCFs, -CN, - alkyl-CN, -CONHa, -CONHR 6 , -CQNR 6 R 6 , -COOH, -M l ⁇ . -NHR 6 , -NO2, -NR 6 R 6 , -Ns, - OH, OR 6 , -COOR 6 , -OSOsR 6 , oxo, R 6 , -SH, -SO2R 6 , -SOsH, -SOsR 6 , or -SR 6 ;
  • R 6 is each independently alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl; or alternatively two R 6 on the same N atom can together form a 3-6 membered N-heteroeyciyl; and
  • R 7 is each independently I, Br, Cl, F, -CH?.F, -CHF2, -CFs, -OCFs, -CN, - alkyl-CN, -CONH2, -CONHR 6 , -CONR 6 R 6 , -COOH, -M ! ⁇ .
  • the compound is not /V-benzyl-7V-(5-(benzylamino)-l-phenyl-li/- l,2,4- ⁇ riazol-3-yl)acetamide, A r -(5-((2-clilorobeiizyd)amino)-i -phenyl- Ii7- 1,2, 4-tnazol-3- yl)-2-fluorobenzamide and /V 3 ,AP-bis(4-methylbenz ⁇ d)-l -phenyl- IH- 1 ,2, 4-triazole-3, 5- diamine.
  • At least one of -Mti R 1 and -M 2 R 2 is -NR 4 -(CI-CJ alk lene)-cyc]oalkyl, -NR 4 -(CI-C 3 alkylene) ⁇ heterocyclyl, -NR 4 - ⁇ Ci-C 3 alkylene)-aryl, or -NR 4 -(CI-C3 alkylene)-heteroaryl; wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl is each optionally substituted with one or more R 5 .
  • At least one of -M 1_ R ] and -M 2 R 2 is -NR 4 -(CI-C3 alkylene)-phenyl, or -NR 4 -(CI ⁇ C alkyl ene)-pyridyl, wherein phenyl and pyridyl is each optionally substituted with one or more R 5 .
  • at least one of -IVti R 1 and -M 2 R 2 is -NR 4 -CH 2 -phenyl, -NR 4 -CH 2 CH 2 -phenyl, -NR 4 -CH 2 -pyridyl, -NR 4 -
  • pyridyl is each optionally substituted with one or more R 5
  • -M 3 R ! and -M 2 R 2 are each selected from -NR 4 -CH 2 -phenyl, -NR 4 -CH 2 CH 2 -phenyl, -NR 4 -CH 2 -
  • -IVF R 1 is -NR 4 C(0)R ! .
  • -M 2 R 2 is -NR 4 C(0)R 2 .
  • R 1 and R 2 are each
  • one of M 1 and M 2 is a bond.
  • R 1 and R 2 are each
  • R 1 and R 2 are each independently selected from phenyl, azetidinyl, pyrro!idinyi, piperidiny!, imidazo!y!, isoxazolyl, oxazolyl, thiazoiyl, pyndyl, pyndazinyl, pyrazmyl, pynmidinyl, pyridinoneor, or pyridine N-oxide, each optionally substituted with one or more R 3 .
  • M 1 is a bond and R 1 is pyridyl, optionally substituted with one or more Rf
  • M 2 is a bond and R 2 is pyridyl, optionally substituted with one or more R 5 .
  • M 1 is a bond and M 2 is -NR 4 - or -NR 4 C(0)-.
  • M 2 is a bond and SVI ! is -NR 4 - or -NR '( ⁇ ())-.
  • R 3 is phenyl, optionally substituted with one or more R 7 ; and R 7 is each independently I, Br, Cl, F, -CH?.F, -CHF2, - CF 3 , -OCFJ, -CN, -NS, -OH, methyl, ethyl, propyl, -CoCH; -CN, -NH 2 , -NO2, -Ns, -OH, - OCF3, -OMe, -NM62, or -NEt 2 .
  • R 5 and R 7 are each independently I, Br, Cl, F, -CH?.F, -CHF2, - CF 3 , -OCFJ, -CN, -NS, -OH, methyl, ethyl, propyl, -CoCH; -CN, -NH 2 , -NO2, -Ns, -OH, - OCF3, -OMe, -NM62, or -NEt 2 .
  • R 4 is each independently H or C1-C3 alkyl
  • the compound of formul a (P) has the structure of formula (II A) :
  • R 1 and R 2 are each independently selected from an cycioalky!, aryl, biphenyl, heterocyclyl, or heteroaryl, each optionally substituted with one or more R 5 ;
  • R 3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryi, cycloalkylalkyl, arylalkyi, arylalkenyl, aiylalkynyl, heterocydylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 7 ;
  • R 4 is each independently H, alkyl, wherein each alkyl is optionally substituted with one or more R 3 ;
  • R 5 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CFs, -OCF3, -CN, - alkyl -CN. -CONH2, -CONHR 6 , -CONR 6 R 6 , -COOH, -M l '. M IR' . -NO2, -NR 6 R 6 , -Ns, - OH, OR 6 , -COOR 6 , -OSOsR 6 , oxo, R 6 , -SH, -SO2R 6 , -SOsH, -SOsR 6 , or -SR 6 ;
  • R 6 is each independently alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl; or alternatively two R 6 on the same N atom can together form a 3-6 membered N -heterocyclyl;
  • R 7 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CFs, -OCF3, -CN, - alkyl-CN, -COME, -CONHR 6 , -CONR 6 R 6 , -COOH, -M l ⁇ . -M I ' . -NO-..
  • R 1 is aryl, optionally substituted with one or more R 5 .
  • R 1 is phenyl, optionally substituted with one or more R 5 .
  • 5 is 5-6 membered heteroaryl, optionally substituted with one or more R 5 .
  • R 1 is pyridyl, optionally substituted with one or more R 5 .
  • R 2 is phenyl optionally
  • R 2 is
  • R 3 is cycloalky!, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more R 7 .
  • R 3 is phenyl optionally substituted with one or more R 7 .
  • R 5 is I, Br, Cl, F, -CH2F, - C! !l x -CF3, -C1-C6 alkyl, alkynyl, -CN, -(C1-C3 alkylene)-CN, -NH? register -NO2, -N3, -OH, - OCF3, -OMe, -NMe?., -NEte, or -C(0)0(Ci-C6 alkyl).
  • R 5 and R 7 are each
  • the compound of formula (II) and (II A) excludes die compounds of Table C.
  • the compound is selected from Table 3A below, or a pharmaceutically acceptable salt or solvate thereof.
  • L 1 , L 2 and L 3 are each independently selected from a bond, aikylene, or alkenylene;
  • R 1 and R 2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkyialkyl, arylalkyl, ary!aikenyl, arylalkynyl, heterocyclylalkyL heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 5 ;
  • R 3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heteroeycly!alky!, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R 7 ;
  • R 4 is each independently H, alkyl, wherein each alkyl is optionally substituted with one or more R 5 ;
  • R 5 is each independently I, Br, Cl, F, -CH?.F, -CHF?, -CFs, -OCFs, -CN, - alkyl-CN, -CONH2, -CON HR ". ⁇ CONR 6 R 6 , -COR 6 , -COO! I. -M l ⁇ . -NHR 6 , -NO ⁇ .
  • R 6 is each independently alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl; or alternatively two R 6 on the same N atom can together form a 3-6 membered N-heterocy cly! ;
  • R 7 is each independently I, Br, Cl, F, -CH2F, -CHF?, -CF , -OCF3, -CN, - alkyl-CN, -CONH2, -CONHR 6 , ⁇ CONR 6 R 6 , -COOH, -NH2, -NHR 6 , -NO2, -NR 6 R 6 , -N3, - OH, OR 6 , -COOR 6 , -OSQ3R 6 , oxo, R 6 , -SH, -SO2R 6 , -SO3H, -SO3R 6 , -SR 6 , cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more Ry
  • m is 0, 1, or 2;
  • the compound of formula (III) has the structure of formula (III A):
  • M 1 and M 2 are each independently selected from -NR 4 -, -NR 4 C(0)- or - C(0)NR 4 -, provided that M 1 and M 2 are not both -NR 4 -;
  • R 1 and R 2 are each independently phenyl, optionally substituted with one or more R 5 :
  • alkylene NHCO(Ci-Cio alkyl) or -(Ci-Ce alkylene)N(Ci-C3 alkyl)CO(Ci-Cio alkyl);
  • F, -CHF? represent -CF: -Ci-Ce alkyl, alkynyl, -CN, -(C1-C3 alkylene)-CN, -NH 2 , -NO2, -N3, -OH, -OCFj, -OMe, -NMer, -NEt 2 , C(0)0(Ci-C6 alkyl), -CO(Ci-Cio alkyl), -NHCO(Ci-Cio alkyl), -N(Ci-C?
  • alkyl CO(Ci- C10 alkyl), -(Ci-Ce alky lene)NHCO(C 1 -C 10 alkyl), or -(Ci-Ce alkylene)N(Ci-C 3 alkyl)CO(C]-Cio alkyl);
  • R 7a , R 71 ', R 7e , and R 7e is each independently H, I, Br, Cl, F, -CH2F, -CHF2, - CF 3 , -OCF3, -N3, -CN, -OH, methyl, ethyl, propyl, C1-C3 haloalkyl, C1-C3 alkoxy, or Ci- Cs haloalkoxy; and
  • R 7c is H, I, Br, Cl, F, -CH 2 F, -CHF2, -CFs, -OCF3, -Ns, -CN, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, 4-6 membered heterocyclyl, or 5-6 membered heteroaiyl, wherein the heterocyclyl and heteroaryl is optionally substituted with one or more R 5 .
  • the compound of formula (III) has the structure of formula (MB):
  • M 1 and M 2 are each independently selected from -NR 4 -, -NR 4 C(0)- or - C(0)NR 4 -, provided that M 1 and M 2 are not both -NR 4 -;
  • R 1 and R 2 are each independently phenyl, optionally substituted with one or more R " :
  • R 3 is phenyl, substituted with one or more R 7 ;
  • R 4 is each independently H or C3-C3 alkyl
  • R 5 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CF3, -Ci-Ce alkyl, alkynyl, -CN, -(C1-C3 alkylene)-CN, -NH2, -NO2, -Ns, -OH, -OCFs, -OMe, -NMe 2 , -NEte, -C(0)0(Ci-C 6 alkyl), -CO(Ci-Cio alkyl), -NHCO(Ci-Cio alkyl), -N(Ci-Cs alkyl)CO(Ci- C10 alkyl), -(Ci-Ce alkylene)NHCO(Ci-Cio alkyl), or -(Ci-Ce alkylene)N(Ci-C3 alkyl)CO(Ci-Cio alkyl); and
  • R 7 is heterocyciyl substituted with -CO(Ci-Cio alkyl), which is optionally further substituted with one or more R 5 .
  • At least one of R 1 or R 2 is substituted with -(C1-C3 alkylene)NHCO(Ci-C8 alkyl) or -(C1-C3 alkyl ene)N(Ci-Cs alkyi)CO(Ci-C8 alkyl).
  • at least one of R 5 or R 2 is substituted with - CH 2 NHCO(CI-C8 alkyl) or -CH 2 N(Ci-C3 alkyl)CO(Ci-C8 alkyl).
  • R f is phenyl substituted with -(C1-C3 alkylene)NHCO(C]-Cs alkyl) or -(C1-C3 alkylene)N(Ci-C3 alkyl)CO(Ci-Cs alkyl).
  • R ! is phenyl substituted with -CIRNHCO/Ci- Cs alkyl) or -CH2N(CI-C3 alkyl)CO(Ci-Ce alkyl).
  • R 1 is phenyl substituted with CH2NHC 0(C4-C 8 alkyl) or -CH2N(CI-C3 alkyl)CO(C4-C8 alkyl).
  • R 2 is phenyl substituted with -(C1-C3 alkyleneiNHCOiCi-Cs alkyl) or -(C1-C3 alkylene)N(Ci-C3 alkyl)CO(Ci-Cg alkyl).
  • R 2 is phenyl substituted with -CH 2 NHCO(CI- Cs alkyl) or -CH 2 N(Ci-C3 alkyl)CO(Ci-Cs alkyl).
  • R 2 is phenyl substituted with CI FN!
  • R 7a , R 7b , R 7c , R 7e , and R 7e is each independently H, I, Br, Cl, F, -CH2F, -CHF2, -CF3, -OCF3, -N 3 , -CN, -OH, methyl, ethyl, propyl, -CoCH; -CN, -NH2, -NO2, -Ns, -OH, -OCFs, -OMe, -NMe 2 , or -NEte.
  • R 7a , R 7b , R 7e , and R 7e is each independently H.
  • R 3 is phenyl, substituted with 6-membered heterocyclyl and wherein the 6-membered heterocyclyl is substituted with -COCCi-Cho alkyl).
  • R 3 is phenyl substituted with a R 3 is phenyl, substituted with 6-membered heterocyclyl comprising one or two heteroatoms selected from O, N, and S, and wherein the 6-membered heterocyclyl is substituted with -CO(Ci-Cio
  • R 3 is phenyl substituted with a piperidine or a piperazine, wherein the piperidine or the piperazine is substituted with -CO(Ci-Cio alkyl).
  • R 3 is phenyl substituted with a piperidine or a piperazine, wherein the piperidine or the piperazine is substituted with -CO(C 4 - Cio alkyl).
  • R ’! and R are each independently phenyl, optionally substituted with one or more substitutent selected fro I, Br, Cl, F, -CHzF, -CHF 2 , -CF 3 , -OCFB, -N3, -CN, -OH, methyl, ethyl, propyl, -Co €H; -CN, -NH2, -NO?., -Ns, -OH, -OCFs, -OMe, -NMe?., or -NEts.
  • the compound of formul a (III) excludes compounds of Table A. In one embodiment, the compound of formula (III), excludes compounds of Table B.
  • various embodiments disclosed herein for formula (I), (G), (IA), (IB), (IB 1 ), (IC), (ID), (IE), and/or (IF) can be applied to the compounds of formula (III), (IIIA), and/or (IIIB).
  • the compound is selected from Table 3B below, or a pharmaceutically acceptable salt or solvate thereof.
  • the compound of the invention excludes compounds in Tables A- D.
  • the compound of formula (I), (III), (G), (IA), (IB), (IB'), (IC), (ID), (IE), and (IF) excludes compounds in Table A.
  • the compound of formula (I), (III) (G), (IA), (IB), (IB'), (IC), (ID), (IE), and (IF) excludes compounds in Table A.
  • the compounds described above may have particular functional characteristics.
  • the compound may have an oral bioavailability of about 10% to about 70% in a patient.
  • the compound may have an oral bioavailability of about 10% to about 50%.
  • the compound may have an oral bioavailability of about 10% to about 30%.
  • the compound may have an oral bioavailability greater than about 20%.
  • the compound may have an oral bioavailability in a patient with any of the ranges above when administered in the assay as in Example 6.
  • the compound when administered orally, may have a Tmax of about 0.2 hrs to about 2 hrs in a patient. In another embodiment, the compound may have a Tmax of about 0.3 hrs to about 1 hr m a patient. In another embodiment, the compound may have a Tmax of about 0.4 hrs to about 0.6 hr in a patient. In another embodiment, the compound may have a Tmax in a patient with any of the ranges above when admini stered in the assay as in Example 6.
  • the compound when administered orally, may have a Cmax of about 100 ng/'mL to about 1 ,000 ng/'niL in a patient. In another embodiment, when admini stered orally, the compound may have a Cmax of about 150 ng/mL to about 500 ng/'mL in a patient. In another embodiment, when administered orally, the compound may have a Cmax of about 200 ng/mL to about 400 ng/mL in a patient. In another embodiment, the compound may have a Cmax in a patient with any of the ranges above when administered in the assay as in Example 6
  • the compound may have a half-life in human liver microsomes greater than about 100 minutes. In another embodiment, the compound may have a half-life in human liver microsomes greater than about 300 minutes. In another embodiment, the compound may have a half-life in human liver microsomes greater than about 500 minutes. [499] In another embodiment, the compound may have half-life in human liver microsomes of about 100 minutes to about 1 ,000 minutes. In another embodiment, the compound may have half-life in human liver microsomes of about 200 minutes to about 800 minutes. In another embodiment, the compound may have half-life in human liver microsomes of about 500 minutes to about 700 minutes.
  • the compound may have a half-life in rat liver microsomes greater than about 100 minutes. In another embodiment, the compound may have a half-life in rat liver microsomes greater than about 300 minutes. In another embodiment, the compound may have a half-life in rat liver microsomes greater than about 500 minutes.
  • the compound may have half-life in rat liver microsomes of about 100 minutes to about 1,000 minutes. In another embodiment, the compound may have half-life in rat liver microsomes of about 200 minutes to about 800 minutes. In another embodiment, the compound may have half-life in rat liver microsomes of about 500 minutes to about 700 minutes.
  • the compound with any of the functional characteristics as described above may be a compound of formula (I), (G), (IA), (IB), (IB'), (IC), (ID), (IE), (IF), (III), (Hi A), (PIB), (II) and/or (I ⁇ A), or a pharmaceutically acceptable salt or solvate thereof.
  • the compound with the functional characteristics as described above may from Table I , Table 2, Table 3A and-' or Table 3B.
  • Ubiquitination is crucial for a plethora of physiological processes, including cell survival and differentiation and innate and adaptive immunity. Proteins are built-up to cater for the structural and biochemical requirements of the cell and they are also broken-down in a highly-regulated process serving more purposes than just destruction and space management. Proteins have different half-lives, determined by the nature of the amino acids present at their N-termini. Some will be long-lived, while other will rapidly be degraded. Proteolysis not only- enables the cell to dispose of misfolded or damaged proteins, but also to fine-tune the concentration of essential proteins within the cell, such as the proteins involved in the cell cycle. Tliis rapid, highly specific degradation can be achieved through the addition of one to several ubiquitin molecules to a target protein. The process is called ubiquitination.
  • Ubiquitin-protein (E3) ligases are a large family of enzymes that select various proteins for uhiquitination. These ubiquitin ligases, called“Ub ligases” are known to have a role in various diseases and conditions, including but not limited to, cancer, inflammation and infectious diseases
  • Parkin ligase is a component of a multiprotein “E3” ubiquitin ligase complex, which in turn is part of the ubiquitin-proteasome system that mediates the targeting of proteins for degradation.
  • E3 multiprotein “E3” ubiquitin ligase complex
  • Parkin ligase is a component of a multiprotein “E3” ubiquitin ligase complex, which in turn is part of the ubiquitin-proteasome system that mediates the targeting of proteins for degradation.
  • Parkin ligase is not known, mutations in Parkin ligase are linked to various diseases, such as Parkinson’s disease, cancer and mycobacterial infection. Parkin ligase is thus an attractive target for therapeutic intervention.
  • ligases there are various known methods for regulating ligases known m the art. Many ligases, particularly ligases involved m the Uhiquitin-Proteasome Pathway System (UPS), are known to have Zinc Finger (ZnF) domains that stabilize critical protein binding regions in that ligase.
  • UPS Uhiquitin-Proteasome Pathway System
  • ZnF Zinc Finger
  • ZnF domains coordinate zinc ions and this coordination stabilizes functional activity of the protein.
  • the functional activity provided by proteins with ZnF domains can include the regulation of important cellular signaling pathways, such as recognizing ubiquitms, regulation of DNA, such as transcription and repair, and acting as cellular redox sensors.
  • the binding of zinc to ZnF domains, or simply just regulating how zinc interacts with the ZnF domains, are essential to ligases involved in the UPS.
  • Parkin ligase is known to have one or more ZnF domains.
  • the present disclosure focuses on two different strategies for modulating ZnF domains in Parkin ligase.
  • One strategy of the present disclosure includes using chelatin compounds that bind to the ZnF domains and thus disallowing the binding of zinc, or causing the dissociation of zinc, such as Zn, or Zn 2+ , from the ZnF domain.
  • Another strategy' of the present disclosure includes using compounds that bind or react with a cysteine amino acid residue in the ZnF domain.
  • One or more cysteine residues are essential in ZnF domains for binding to and/or coordinating to the zinc ion.
  • the zinc ion (usually Zn 2 ) can coordinate with multiple cysteine or histidine residues.
  • This flexibility in the ZnF domains of Parkin ligase is thought to allow the domain to he reversible, and is thus is one possible mechanism for regulating Parkin ligase.
  • efforts directed to this approach are disclosed in U.S. Patent Application No. 14,961,285; U.S. Provisional Application No. 62/237,400; U.S. Provisional Application No. 62/222,008, and U.S. Provisional Application No. 62/087,972, all of which are hereby incorporated by reference in their entirety.
  • the present disclosure relates to the use of one or more agents or one or more compounds of formula (I), (G), (IA), (IB), (IB'), (1C), (ID), (IE), and (IF), (111), (IPA), and (IIIB), or (II) and (HA), or a pharmaceutically acceptable salt or solvate thereof, which have electrophilic, chelation or both electrophilic and chelation properties that can interact with the zinc ion and/or the cysteine residue(s) in a Parkin ligase.
  • compounds of the present disclosure modulate Parkin ligaseA activity.
  • the present disclosure is thus directed to a method for activating or modulating Parkin ligase by the chelation of Zn followed by its removal from the ZnF domain, or through electrophilic attack at the cysteine amino acid(s) that holds the Zn in place.
  • a method of modulating or activating a Parkin ligase comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of formula (I), (T'), (IA), (IB), (IB 1 ), (IC), (ID), (IE), and (IF), (III), ( II I A) and (IIIB), or (II) and (PA), or a pharmaceutically acceptable salt or solvate thereof, is disclosed.
  • a method of modulating or activating a Parkin ligase comprising administering to a subject m need thereof a therapeutically effective amount of one or more compounds of formula (I), (G), (TA), (IB), (IB'), (IC), (ID), (IE), and (IF), (III), (PIA), and (IIIB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof, that disrupt at least one Parkin ligase zinc finger is disclosed.
  • a method of activating a Parkin ligase comprising administering to a subject two or more compounds that disrupt at least one Parkin ligase zinc finger, wherein at least one of the compound is selected from a compound of formula (I), (G), (IA), (IB), (IB 1 ), (IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof.
  • the present disclosure relates to the use of one or more agents or one or more compounds of formula (I), (G), (IA), (IB), (IB 1 ), (IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (IT) and (IIA), or a pharmaceutically acceptable salt or solvate thereof to promote parkin E3 ligase enzyme activity.
  • the compounds of the present disclosure can be an electrophile or a chelator.
  • the compounds of the present disclosure can function as both an electrophile and as a chelator.
  • the compounds of the present disclosure can include multiple functional groups wherein at least one functional group has chelating properties and at least one other functional group has electrophilic properties.
  • the compound useful for methods in modulating or activating Parkin iigase as disclosed herein is selected from Tables 1-3, or a pharmaceutically acceptable salt or sol vate thereof.
  • the compound of the present disclosure is useful in a method to increase the Parkin iigase reaction with the Activity-based Ubiquitin vinyl su!fone probe. See e.g., Example 2.
  • the one or more compounds of the present disclosure can coordinate with a Zn ion, and/or bind or react with one or more cysteine residues.
  • the Zn ion may be either a Zn l or a Zn 2+ ion.
  • the compound can coordinate to a Zn ion is a monodentate, bidentate, or tridentate ligand.
  • the compound of the present disclosure can bind and/or react with a thiol group in more than one cysteine residues. In another embodiment, the compound can bind and/or react with a thiol group m two cysteine residues. In another embodiment, the compound can hind and/or react with a thiol group in three cysteine residues. In another embodiment, the compound can bind and/or react with a thiol group m four cysteine residues.
  • the compound can bind or react with one or more cysteine residues in one or more domains selected from the group consisting amino acids 141 -225, amino acids 238-293, amino acids 313-377, and amino acids 418-449 of human Parkin Iigase. See http://www.uniprot.org/uniprot/O60260.
  • the methods of the present disclosure also include activating auto-ubiquitinization of a Parkin Iigase by administering to a subject in need thereof a therapeutically effective amount of one or more compounds of formula (I), (F), (I A), (IB), (IB 1 ), (IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof.
  • the one or more compounds of the present disclosure can disrupt at least one Parkin Iigase zinc finger.
  • Phospho Ubiquitin (pUB) an endogenous cellular regulator of Parkin
  • Parkin Iigase an endogenous cellular regulator of Parkin
  • one or more compounds can be administered to a subject in need thereof that acts synergistically with Phospho Ubiquitin (pUB) in activating the Parkin Iigase. See, e.g., Example 3.
  • the one or more compounds that acts synergistically with pUB in activating the Parian ligase is a compound of formula (I), (F), (IA), (IB), (IB’), (IC), (ID), (IE), and (IF), (III), (PIA), and (IPB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof.
  • one or more compounds of the present disclosure can be administered with pUB to synergistically increase the activation of Parkin ligase and/or its auto-ubiquitinization.
  • the activation of the Parkin ligase treats or reduces the incidence of one or more diseases or ailments selected from the group consisting of Alzheimer's Dementia, Parkinson’s disease, Huntington Disease, Amyotrophic Lateral Sclerosis (ALS), Freidreich’s ataxia.
  • diseases or ailments selected from the group consisting of Alzheimer's Dementia, Parkinson’s disease, Huntington Disease, Amyotrophic Lateral Sclerosis (ALS), Freidreich’s ataxia.
  • a method of treating Parkinson’s disease comprising administering to a subject need thereof a therapeutically effective amount of one or more compounds of formula (I), (G), (IA), (IB), (IB'), (IC), (ID), (IE), and (IF), (III), (III A), and (PIB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof
  • Parkinson’s disease loss of dopamine neurons are believe to lead to Parkinson’s disease, which can be caused by damaged mitochondria. Damaged mitochondria leads to dopamine neuron loss across etiologies in Parkinson’s Disease patients. In a normal dopamine neurons, Parkin is activated in response to damaged mitochondria leading to their removal via mitophagy (e.g., mitochondrial autophagy).
  • mitophagy e.g., mitochondrial autophagy
  • Park2 mutations are responsible for 50% of autosomal recessive early onset of Parkinson’s, thus, without bound to any theory, Parkin enzyme is believed to play a key role in maintenance of dopamine neuron health. Accordingly, restoring Parkin function can delay or prevent dopamine neuron loss.
  • the compound of formula (I), i f). (IA), (IB), (IB 1 ), (IC), (ID), (IE), and (IF), (III), (IIIA), and (MB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof slows the progression of Parkinson’s Disease in a subject in need thereof, comprising administering a therapeutically effective amount of the compound to the subject.
  • the slowing of the progression is in genetic and sporadic Parkinson ’ s Disease.
  • the compound of formula (I), (T'), (IA), (IB), (IB 1 ), (IC), (ID), (IE), and (IF), (III), (IIIA), and (MB), or (II) and (HA), or a pharmaceutically acceptable salt or solvate thereof promotes removal of damaged mitochondria in a subject in need thereof, comprising administering a therapeutically effective amount of the compound to the subject.
  • the compound of formula (I), (G), (IA), (IB), (IB 1 ), (IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (11) and (HA), or a pharmaceutically acceptable salt or solvate thereof enhances mitophagy a subject in need thereof.
  • the bacterial infection is Mycobacterium infection.
  • the viral infection is HIV, Hepatitis B infection or Hepatitis C infection.
  • Another embodiment of the present invention includes methods of treating and/or reducing the incidence of cancer, specifically comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds that disrupt at least one Parkin ligase zinc finger and induces Parkin ligase activity.
  • the activated Parkin ligase suppresses the growth of one or more tumors and/or prevents metastasis of one or more tumors.
  • the cancer may be selected from one or more of the group consisting of Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, AIDS-Related Cancers, Kaposi Sarcoma, Lymphoma, Anal Cancer, Appendix Cancer, Astrocytomas, Childhood Atypical Teratoid/Rhabdoid Tumor, Basal Cell Carcinoma, Skin Cancer (Nonmelanoma), Childhood Bile Duct Cancer, Extraliepatic Bladder Cancer, Bone Cancer, Ewing Sarcoma Family of Tumors, Osteosarcoma and Malignant Fibrous Histiocytoma, Brain Stem Glioma, Brain Tumors, Embryonal Tumors, Germ Cell Tumors, Craniopharyngioma, Ependymoma, Bronchial Tumors, Burkitt Lymphoma (Non-Hodgkin Lymphoma), Carcinoid Tumor,
  • Macrog!obu!inemia Waldenstrom, Male Breast Cancer, Malignant Fibrous Histiocytoma of Bone and Osteosarcoma, Melanoma, Intraocular (Eye) Cancer, Merkel Cell Carcinoma, Mesothelioma, Malignant, Metastatic Squamous Neck Cancer with Occult Primary', Midline Tract Carcinoma Involving NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndromes, My elody splash c/My el oproliferative Neoplasms, Myelogenous Leukemia, Chronic, Myeloid Leukemia, Acute, Myeloma Multiple, Chronic Myeloproliferative Neoplasms, Nasal Cavity' and Paranasal Sinus Cancer, Nasopharyngeal Cancer,
  • Neuroblastoma Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Lip and Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Epithelial Cancer, Low Malignant Potential Tumor, Pancreatic Cancer, Pancreatic Neuroendocrine Tumors (Islet Cell Tumors), Papillomatosis, Paraganglioma, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, Pituitary Tumor, Plasma Cell Neoplasm/Multiple Myeloma, Pleuropulmonary Blastoma, Primary Central Nervous System Lymphoma, Rectal Cancer, Renal Cell (Kidney) Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary' Gland Cancer, Sarcoma, Ewing Cancer, Kaposi Cancer, Osteosarcoma (Bone Cancer), Soft
  • the cancer is glioblastoma, small cell lung carcinoma, breast cancer and/or prostate cancer.
  • the administration of the Parkin !igase suppresses one or more tumors in the subject.
  • the compound eliminates damaged mitochondria, increases cell viability during cellular stress, decreases tumor transformation and/or mitigates alpha-synuclein in cells.
  • the methods of the present disclosure include treating and/or reducing the incidence of Parkinson’s disease, specifically by administering to a subject in need thereof a therapeutically effective amount of one or more compounds that disrupt at least one Parkin hgase zinc finger and induces Parkin ligase activity, wherein the compound can coordinate with a Zn ion and/or react with a thiol group in a cysteine(s).
  • the compound that disrupts at least one Parkin ligase zinc finger and incudes Parkin ligase activity' in the above mentioned method is selected from compound of formula (I), (G), (1A),
  • the one or more compounds eliminate damaged mitochondria, increases cell viability during cellular stress and/or mitigates alpha-synuclein in cells.“Somatic Mutations of the Parkinson’s disease- associated gene PARK2 in glioblastoma and other human malignancies” ⁇ Nature Genetics Jan 2010 42(1)77-82).
  • the compound that eliminate damaged mitochondria, increase cell viability during cellular stress and/or mitigates alpha-synuclein in cells in the above mentioned method is a selected from compound of formula (I), (G), (IA), (IB), (IB 1 ),
  • the Parkin ligase activation alters ubiquitination.
  • the alteration of ubiquitination is caused by the ability of Parkin to modify a substrate protein by covalent attachment of Ubiquitin, a substrate protein being Parkin itself, or another protein such as Mitofusion 1 or 2, FBW7, or other publicly reported substrates of Parkin ligase.
  • Furth er embodiments of the present disclosure relate to meth ods of treating, preventing, or ameliorating one or more symptoms associated with neurological diseases or disorders including but not limited to Alzheimer’s Dementia, Parkinson’s disease, Huntington Disease, Amyotrophic Lateral Sclerosis (ALS), Freidreich’s ataxia, Spinocerebellar Ataxia, Multiple Systems Atrophy, PSP, Tauopathy, Diffuse Lewy Body Disease, Lewy Body dementia, any disorder characterized by abnormal accumulation of a-synuclem, disorders of the aging process, and stroke.
  • neurological diseases or disorders including but not limited to Alzheimer’s Dementia, Parkinson’s disease, Huntington Disease, Amyotrophic Lateral Sclerosis (ALS), Freidreich’s ataxia, Spinocerebellar Ataxia, Multiple Systems Atrophy, PSP, Tauopathy, Diffuse Lewy Body Disease, Lewy Body dementia, any disorder characterized by abnormal accumulation of a-synuclem, disorders of the aging process, and stroke
  • Other embodiments of the present discl osure relate to methods of treating, preventing, or ameliorating one or more symptoms associated with hut not limited to mental retardation, deafness, blindness, diabetes, obesity, cardiovascular disease, and autoimmune diseases such as multiple sclerosis, Sjogrens syndrome, lupus, glaucoma, including pseudoexfoliation glaucoma, Leber's Hereditary Optic Neuropathy, and rheumatoid arthritis.
  • autoimmune diseases such as multiple sclerosis, Sjogrens syndrome, lupus, glaucoma, including pseudoexfoliation glaucoma, Leber's Hereditary Optic Neuropathy, and rheumatoid arthritis.
  • the methods of the present disclosure include treating and/or reducing the incidence of cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), (F), (I A), (IB), (IB 1 ), (IC), (ID),
  • the compound of the present disclosure can disrupts at least one Parkin ligase zinc finger and induces Parkin ligase activity, wherein the compound can coordinate with a zinc ion and/or bind or react with a cysteine.
  • the Parkin ligase suppresses the growth of one or more tumors and/or prevents metastasis of one or more tumors.
  • the cancer is glioblastoma, small cell lung carcinoma, breast cancer or prostate cancer.
  • the cancer is lymphoma.
  • the cancer is mantle cell lymphoma.
  • the cancer is colon cancer, lung cancer, and/or ovarian cancer.
  • the methods of the present disclosure include treating and/or reducing the incidence of Parkinson’s disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), (I s ), (IA), (IB), (IB'), (IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof that disrupts at least one Parkin ligase zinc finger and induces Parkin ligase activity, wherein the compound can coordinate with a zinc ion and/or bind or react with a cysteine.
  • the compound of the present disclosure eliminates damaged mitochondria, increases cell viability during cellular stress and/or mitigates alpha-synuclein in cells.
  • the methods of the present disclosure excludes administration of compounds disclosed in " fable A or " fable C.
  • a pharmaceutical composition comprises one or more compounds of formula (I), (G), (IA), (IB), (IB'), (IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof.
  • a pharmaceutical composition comprises a therapeutically effective amounts of one or more compounds of formula (I), (G), (IA), (IB), (IB'), (IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (II) and (II A), or a pharmaceutically acceptable salt or solvate thereof.
  • a pharmaceutical composition as described herein, comprises one or more compounds selected from Table 1, or a pharmaceutically acceptable salt or solvate thereof.
  • a pharmaceutical composition as described herein comprise one or more compounds selected from Table 2, or a pharmaceutically acceptable salt or solvate thereof.
  • a pharmaceutical composition as described herein comprise one or more compounds selected from Table 3A, or a pharmaceutically acceptable salt or solvate thereof.
  • a pharmaceutical composition as described herein comprise one or more compounds selected from Table 3B, or a pharmaceutically acceptable salt or solvate thereof.
  • a pharmaceutical composition described herein does not contain a compound disclosed in Table A or Table C.
  • a pharmaceutical composition as described herein, comprising one or more compounds of formula (I), (G), (IA), (IB), (IB'), (IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (II) and (PA), or a pharmaceutically acceptable salt or solvate thereof, further comprises one or more additional therapeutically active agents.
  • one or more additional therapeutically active agents are selected from therapeutics useful for treating cancer, neurological disease, a disorder characterized by abnormal accumulation of a- synuclein, a disorder of an aging process, cardiovascular disease, bacterial infection, viral infection, mitochondrial related disease, mental retardation, deafness, blindness, diabetes, obesity, autoimmune disease, glaucoma, Leber's Hereditary Optic Neuropathy, and rheumatoid arthritis.
  • a pharmaceutical composition comprising one or more compounds of formula (I), (G), (IA), (IB), (IB'), (IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or adjuvant is provided.
  • the pharmaceutically acceptable excipients and adjuvants are added to the composition or formulation for a variety of purposes.
  • a pharmaceutical composition comprising one or more compounds of formula (I), (G), (IA), (IB), (IB' l, (IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (II) and (HA), or a pharmaceutically acceptable salt or solvate thereof, further comprises a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier includes a pharmaceutically acceptable excipient, binder, and/or diluent.
  • suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the pharmaceutical compositions of the present disclosure may additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels.
  • the pharmaceutical compositions may contain additional, compatible, pharmaceuticaily-active materials such as, for example, antipruritics, astringents, local anesthetics or anti-inflammatory agents, or may contain additional materials useful in physically formulating various dosage forms of the compositions of the present invention, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers.
  • additional materials useful in physically formulating various dosage forms of the compositions of the present invention such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers.
  • such materials when added, should not unduly interfere with the biological activities of the components of the compositions of the present invention.
  • the formulations can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the oligonucleotide(s) of the formulation.
  • auxiliary agents e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the oligonucleotide(s) of the formulation.
  • the compounds of the present disclosure can be formulated for administration by a variety of means including orally, parenterally, by inhalation spray, topically, or rectalJy in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety' of infusion techniques.
  • Intraarterial and intravenous injection as used herein includes administration through catheters.
  • the compounds disclosed herein can be formulated in accordance with the routine procedures adapted for desired administration route. Accordingly, the compounds disclosed herein can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formu!atory agents such as suspending, stabilizing and/or dispersing agents. Tire compounds disclosed herein can also be formulated as a preparation for implantation or injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt).
  • suitable polymeric or hydrophobic materials e.g., as an emulsion in an acceptable oil
  • ion exchange resins e.g., as sparingly soluble derivatives (e.g., as a sparingly soluble salt).
  • the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen- free water, before use.
  • a suitable vehicle e.g., sterile pyrogen- free water
  • suitable formulations for each of these methods of administration can be found, for example, in Remington: The Science and Practice of Pharmacy , A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, PA.
  • a pharmaceutical composition of the present disclosure is prepared using known techniques, including, but not limited to mixing, dissolving, granulating, dragee-makmg, levigating, emulsifying, encapsulating, entrapping or tableting processes
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), (G), (IA), (IB), (IB'), (IC), (ID), (IE), and (IF), (III), (IIIA), and (I ⁇ B), or (II) and (PA), or a pharmaceutically acceptable salt or solvate thereof, as disclosed herein, combined with a pharmaceutically acceptable carrier.
  • suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions.
  • Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably Q.05M phosphate buffer or 0.814 saline. Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions.
  • non-aqueous solvents suitable for use in the present application include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers suitable for use in the present application include, but are not limited to, water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media.
  • Oral carriers can be elixirs, syrups, capsules, tablets and the like.
  • Liquid earners suitable for use m the present application can be used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compounds.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic sol v ent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • Liquid carriers suitable for use in the present application include, but are not limited to, water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyi cellulose solution), alcohols (including monohydrie alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
  • the carrier can also include an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are useful in sterile liquid form comprising compounds for parenteral administration.
  • the liquid carrier for pressurized compounds disclosed herein can be halogenated hydrocarbon or other pharmaceutically acceptable propellent.
  • Solid carriers suitable for use in the present application include, but are not limited to, inert substances such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like.
  • a solid carrier can further include one or more substances acting as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material.
  • the carrier can be a finely divided solid which is in admixture with the finely divided active compound.
  • the active compound is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the active compound.
  • suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, poly vinylpyrrolidine, low melting waxes and ion exchange resins.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing m a suitable machine the active ingredient m a free flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • Parenteral carriers suitable for use in the present application include, but are not limited to, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils.
  • Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose and the like.
  • Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.
  • Carriers suitable for use in the present application can be mixed as needed with dismtegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art.
  • the carriers can also be sterilized using methods that do not deleteriously react with the compounds, as is generally known in the art.
  • Diluents may be added to the formulations of the present invention. Diluents increase the hulk of a solid pharmaceutical composition and/or combination, and may make a pharmaceutical dosage form containing the composition and/or combination easier for the patient and care giver to handle.
  • Diluents for solid compositions and-' or combinations include, for example, microcrystalline cellulose (e.g., AVICEL), microf e cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tnbasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, poly methacrylates (e.g., EUDRAGTT(r)), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.
  • microcrystalline cellulose e.g., AVICEL
  • microf e cellulose e.g., lactose
  • starch e.g., pregelatinized starch
  • calcium carbonate calcium sulfate
  • sugar dextrates
  • dextrin dextrin
  • a pharmaceutical composition of the present invention is a solid (e.g., a powder, tablet, a capsule, granulates, and/or aggregates).
  • a solid pharmaceutical composition comprising one or more ingredients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, lubricants, binders, and disintegrating agents.
  • Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression.
  • Binders for solid pharmaceutical compositions and/or combinations include acacia, alginic acid, carbomer (e.g., carbopol), carboxymethyicellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, gum tragacanth, hydrogenated vegetable oil, hydroxy ethyl cellulose, hydroxypropyl cellulose (e.g., KLUCEL), hydroxypropyl methyl cellulose (e.g., METHOCEL), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g., KOLLIDON, PLASDONE), pregelatinized starch, sodium alginate, and starch.
  • carbomer e.g., carbopol
  • the dissolution rate of a compacted solid pharmaceutical composition m the patient’s stomach may be increased by the addition of a disintegrant to the composition and/or combination.
  • Disintegrants include alginic acid, carboxymethyicellulose calcium, carboxymethyicellulose sodium (e.g., AC-DI-SOL and PRIMELLOSE), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., KOLLIDON and POLYPLASDONE), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacnlin potassium powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycoiate (e.g., EXPLOTAB), potato starch, and starch.
  • a disintegrant include alginic acid, carboxymethyicellulose calcium, carboxymethyicellulose sodium (e.g., AC-DI-SOL and PRIMELLOSE), colloidal silicon dioxide, croscar
  • Glidants can be added to impro ve the fiowahility of a non-compacted solid composition and/or combination and to improve the accuracy of dosing.
  • Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
  • a dosage form such as a tablet is made by the compaction of a powdered composition
  • the composition is subjected to pressure from a punch and dye.
  • Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities.
  • a lubricant can be added to the composition and/or combination to reduce adhesion and ease the release of the product from the dye.
  • Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
  • Flavoring agents and flavor enhancers make the dosage form more palatable to the patient.
  • Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition and/or combination of the present invention include rnaltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl ma!tol, and tartaric acid.
  • Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
  • a pharmaceutical composition of the present invention is a liquid (e.g., a suspension, elixir and/or solution).
  • a liquid pharmaceutical composition is prepared using ingredients known in the art, including, but not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
  • Liquid pharmaceutical compositions can be prepared using compounds of formula (1), (!'), (IA), (IB), (IB 1 ), (IC), (ID), (IE), and (IF), (III), (IIIA), and (MB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof, and any other solid excipients where the components are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
  • a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
  • formulations for parenteral administration can contain as common excipients sterile water or saline, po!yalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
  • biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene- poly oxy propylene copolymers can be useful excipients to control the release of active compounds.
  • Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes.
  • Formulations for inhalation administration contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-auryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally.
  • Formulations for parenteral administration can also include glycocholate for buccal administration, methoxysa!icylate for rectal administration, or citric acid for vaginal administration.
  • Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition and/or combination an active ingredient or other excipient that is not soluble m the liquid carrier.
  • Emulsifying agents that may be useful m liquid compositions and/or combinations of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, earbomer, cetosteaiyl alcohol, and cetyl alcohol.
  • Liquid pharmaceutical compositions can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract.
  • a viscosity enhancing agent include acacia, alginic acid bentonite, earbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyi cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum.
  • Sweetening agents such as aspartame, lactose, sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve the taste.
  • Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
  • a liquid composition can also contain a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
  • a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate, or sodium acetate.
  • a pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.).
  • a pharmaceutical composition comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer.
  • other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives).
  • injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like.
  • compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.
  • Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • such suspensions may also contain suitable stabilizers or agents that increase the solubility of the pharmaceutical agents to allow for the preparation of highly concentrated solutions.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentera!ly acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophiiized powder.
  • a non-toxic parentera!ly acceptable diluent or solvent such as a solution in 1,3-butane-diol or prepared as a lyophiiized powder.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile fixed oils may conventionally be employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid may likewise be used in tire preparation of injectables.
  • Formulations for intravenous administration can comprise solutions in sterile isotonic aqueous buffer. Where necessary', the formulations can also include a solubilizing agent and a local anesthetic to ease pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophiiized powder or water free concentrate in a hermetically sealed container such as an ampule or sachet indicating the quantity' of active agent.
  • the compound is to be administered by infusion, it can be dispensed in a formulation with an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose/water.
  • an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
  • Suitable formulations further include aqueous and non- aqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes that render the formulation isotonic with the bodily fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents.
  • a pharmaceutical composition of the present invention is formulated as a depot preparation. Certain such depot preparations are typically longer acting than non-depot preparations. In certain embodiments, such preparations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. In certain embodiments, depot preparations are prepared using suitable polymeric or hydrophobic materials (for example an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • suitable polymeric or hydrophobic materials for example an emulsion in an acceptable oil
  • ion exchange resins for example an emulsion in an acceptable oil
  • sparingly soluble derivatives for example, as a sparingly soluble salt.
  • a pharmaceutical composition of the present invention comprises a delivery system.
  • deliver' systems include, but are not limited to, liposomes and emulsions.
  • Certain deliver systems are useful for preparing certain pharmaceutical compositions including those comprising hydrophobic compounds.
  • certain organic solvents such as dimethylsulfoxide are used.
  • a pharmaceutical composition of the present invention comprises a co-solvent system.
  • co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • co-solvent systems are used for hydrophobic compounds.
  • VPD co-solvent system is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80 and 65% w/v polyethylene glycol 300.
  • co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics.
  • identity' of co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
  • a pharmaceutical composition of the present invention comprises a sustained-release system
  • a sustained-release system is a semi-permeable matrix of solid hydrophobic polymers.
  • sustained-release systems may, depending on their chemical nature, release pharmaceutical agents over a period of hours, days, weeks or months.
  • Appropriate pharmaceutical compositions of the present disclosure can he determined according to any clinically-acceptable route of administration of the composition to the subject. The manner in which the composition is administered is dependent, in part, upon the cause and/or location. One skilled in the art will recognize the advantages of certain routes of administration.
  • the method includes administering an effective amount of the agent or compound (or composition comprising the agent or compound) to achieve a desired biological response, e.g., an amount effective to alleviate, ameliorate, or prevent, in whole or in part, a symptom of a condition to be treated, e.g., oncology and neurology disorders.
  • a desired biological response e.g., an amount effective to alleviate, ameliorate, or prevent, in whole or in part, a symptom of a condition to be treated, e.g., oncology and neurology disorders.
  • the route of administration is systemic, e.g., oral or by injection.
  • the agents or compounds, or pharmaceutically acceptable salts or derivatives thereof are administered orally, nasally, transdermal!y, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, intraportal !y, and parenteral!y.
  • the route of administration is local, e.g., topical, intra-tumor and peri-tumor.
  • the compound is administered orally.
  • a pharmaceutical composition of the present disclosure is prepared for oral administration.
  • a pharmaceutical composition is formulated by combining one or more agents and pharmaceutically acceptable carriers. Certain of such carriers enable pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject.
  • Suitable excipients include, but are not limited to, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • such a mixture is optionally ground and auxiliaries are optionally added.
  • pharmaceutical compositions are formed to obtain tablets or dragee cores.
  • disintegrating agents e.g., cross-linked polyvinyl pyrrolidone, agar, or algimc acid or a salt thereof, such as sodium alginate are added.
  • dragee cores are provided with coatings.
  • concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to tablets or dragee coatings.
  • pharmaceutical compositions for oral administration are push- fit capsules made of gelatin.
  • Such push-fit capsules comprise one or more pharmaceutical agents of the present invention in admixture with one or more filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • pharmaceutical compositions for oral administration are soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • one or more pharmaceutical agents of the present invention are be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added.
  • compositions are prepared for buccal administration. Certain of s uch pharmaceutical compositions are tablets or lozenges formulated in conventional manner.
  • a pharmaceutical composition is prepared for transmucosal administration.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • a pharmaceutical composition is prepared for administration by inhalation.
  • Certain of such pharmaceutical compositions for inhalation are prepared the form of an aerosol spray in a pressurized pack or a nebulizer.
  • Certain of such pharmaceutical compositions comprise a propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • the dosage unit may be determined with a valve that delivers a metered amount.
  • capsules and cartridges for use in an inhaler or insufflator may be formulated.
  • Certain of such formulations comprise a powder mixture of a pharmaceutical agent of the invention and a suitable powder base such as lactose or starch.
  • the compound of the present disclosure are administered by the intravenous route.
  • the parenteral administration may be provided in a bolus or by infusion.
  • a pharmaceutical composition is prepared for rectal administration, such as a suppository or retention enema.
  • Certain of such pharmaceutical compositions comprise known ingredients, such as cocoa butter and/or other glycerides.
  • a pharmaceutical composition is prepared for topical administration.
  • Certain of such pharmaceutical compositions comprise bland moisturizing bases, such as ointments or creams.
  • suitable ointment bases include, but are not limited to, petrolatum, petrolatum plus volatile silicones, and lanolin and water in oil emulsions.
  • suitable cream bases include, but are not limited to, cold cream and hydrophilic ointment
  • the therapeutically effective amount is sufficient to prevent, alleviate or ameliorate symptoms of a disease or to prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art
  • one or more compounds of formula (I), (G), (1A), (IB), (IB'), (IC), (ID), (IE), and (IF), (III), ( ⁇ IA), and (HIB), or (II) and (DA), or a pharmaceutically acceptable salt or solvate thereof are formulated as a prodrug.
  • a prodrug upon in vivo administration, is chemically converted to the biologically, pharmaceutically or therapeutically more active form.
  • prodrugs are useful because they are easier to administer than the corresponding active form. For example, in certain instances, a prodrug may be more bioavailable (e.g., through oral administration) than is the corresponding active form.
  • a prodrug may have improved solubility' compared to the corresponding active form.
  • prodrugs are less water soluble than the corresponding active form.
  • such prodrugs possess superior transmittal across cell membranes, where water solubility is detrimental to mobility'.
  • a prodrug is an ester.
  • the ester is metabolically hydrolyzed to carboxylic acid upon administration.
  • the carboxylic acid containing compound is the corresponding active form.
  • a prodrug comprises a short peptide (polyaminoaeid) bound to an acid group.
  • the peptide is cleaved upon administration to form the corresponding active form
  • a prodrug is produced by modifying a pharmaceutically active compound such that tire active compound will be regenerated upon in vivo administration.
  • the prodrug can be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity', to improve the flavor of a drug or to alter other characteristics or properties of a drag.
  • the amount of the compound of formula (I), (G), (IA), (IB), (IB 1 ), (IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof, or compounds disclosed in Tables 1, 2, 3.4 and/or 3B, or a pharmaceutically acceptable salt or solvate thereof, can be administered at about 0.001 mg/kg to about 100 mg/kg body weight (e.g., about 0.0! mg/kg to about 10 mg/kg or about 0.1 mg/kg to about 5 mg/kg).
  • the concentration of a disclosed compound in a pharmaceutically acceptable mixture will vary depending on several factors, including the dosage of the compound to be administered, the pharmacokinetic characteristics of the compound(s) employed, and the route of administration.
  • the agent may be administered in a single dose or in repeat doses.
  • the dosage regimen utilizing the compounds of the present invention is selected m accordance with a variety 7 of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. Treatments may be administered daily or more frequently depending upon a number of factors, including the overall health of a patient, and the formulation and route of administration of the selected compound(s). An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
  • compositions of the present disclosure may be manufactured and/or administered in single or multiple unit dose forms.
  • ABP Activity-Based Probe
  • ABP consists of a ubiquitin moiety with an epitope tag (e.g. HA tag) at the N-terminus, and a reactive group at the C-terminus.
  • the activity of Parkin-RBR (w/o the RO inhibitory domain) is significantly higher than the activity of Parkin-RORBR or the activity of full-length Parkin.
  • TR-FRET Time Resolved Fluorescence Resonance Energy Transfer
  • Example 2 Activity-Based Probe Assay using an Ubiquitin vinyl sulfone probe
  • Ubiquitin vinyl sulfone probe can be used that irreversibly binds to the active site cysteine of Parkin ligase. Covalent attachment of the probe to the Parkin can be monitored by TR-FRET.
  • Candidate activator compounds can be identified by increasing the activity of Parkin ligase due to an increase in TR-FRET signal. Screening for activating compounds can be distinguished from the controls as follows:
  • 100% activation signal Heat activated Parkin + 100 nM control activator in DMSO.
  • 0% activation signal ::: Heat activated Parkin + DMSO only.
  • Parkin activators can be identified by an increase of the 0% activation signal TR-FRET signal.
  • Assay Plate White 384 well plate (Coming 3572)
  • Reaction Buffer 50 mM HEPES (pH 8.5), 150 mM NaCl, 0.01% Tween 20, 0.1% BSA Detection Buffer: 50 mM HEPES (pH 8 5), 150 mM NaCl, 0.01 % Tween 20, 0.1 % BSA,
  • Detection Reagent A 2 6 nM Anti-6HTS-Eu crypiate and 40 nM Anii-HA-XL665 in detection buffer
  • Eu cryptate Anti-6HIS-Eu cryptate (CisBio 61HISKLA)
  • XL665 Anti-HA-XL665 (CisBio 610HAXLA)
  • reaction buffer 500 m ⁇ /1 5 ml tube: Eppendorf Thermomixer 5 minutes, 400 rpm at 58 °C and put on ice until needed).
  • 2nd Emission Filter Europium 615 EM (Bar code 203) Read 655 nm (channel 1) and 615nm (channel 2) wavelengths on Envision®
  • the Data can be read in CSV files. There are two tables in those CSV files, which are the values of 655nm (channel i) and 615nm (channel 2) wavelengths respectively. The data is converted to an HTRF Ratio ::: (Channel 1 / Channel 2) *10,000
  • the % Activation of compound titration can then he used to find activation EC50 or highest % activation if less than 75% activation is seen for the candidate compound.
  • a Parkin pUB Auto-ubiquitinylation Assay is used to evaluate a compound’s potency to activate Parkin’s ability to Auto-ubiquitinylate itself.
  • Parkin activators can be identified by an increase of the 0% activation signal TR-FRET signal.
  • Assay Plate White 384 well plate (Coming 3572)
  • Enzyme 1 El (Ubiquitin-activating enzyme/UBEl Boston Biochem E-305)
  • Enzyme 2 E2 (UBcH7/Ube2L3 Boston Biochem E2-640)
  • Enzyme 3 Parkin-His tagged 203 mM (10.5 mg/ml)
  • DMSO DMSO (Sigma-34869-2.5L)
  • Reaction Buffer 50 niM HEPES, 50 mM NaCl, 1 mM MgC , 0.005% Tween 20, 0 1%
  • Detection Buffer 50 mM HEPES, 50 mM NaC!, 800 mM KF, 5 mM EDTA, 0.005%
  • Detection Reagent Z 13.4 nM Anti-6His-d2 in detection buffer
  • the % Activation of compound titration can then be used to find activation EC50 or highest % activation if less than 75% acti vation is seen for the candidate compound.
  • XLFIT5 model 205 was applied for the data analysis.
  • phenaceiin for CYP1A2, diclofenac for CYP2C9, omeprazole for CYP2C19, dextromethorphan for CYP2D6 and midazolam for CYP3A4 were added to a separate tube with the final substrate concentrations of 1 mM (1% DMSO) for evaluating the enzyme activities in the liver rnicrosornes.
  • 1% DMSO 1% DMSO
  • an aliquot of 15 m L reaction mixtures were removed and 200 pL of methanol (with internal standard of 25 ng/mL propranolol) was added to quench the reaction. The resulting mixture was centrifuged and supernatant was used for LC-MS/MS analysis.
  • Compound 42 was evaluated for in vivo therapeutic efficacy the treatment of subcutaneous HCT-116 (colon cancer) xenograft model in nude mice.
  • Each mouse was inoculated subcutaneously at the flank region with either HCT-l 16 cells (1.0 x 106) in 0.1 ml of IxPBS mixed with Main gel (1 : 1) for tumor development and xenotransplantation.
  • Group 1 is for mice administered with a vehicle negative control
  • Group 2 is mice treated with Compound F at 25 nig/kg daily for up to 26 days
  • Group 3 is mice treated with 1 mg/kg of Compounds 42 daily for up to 26 days
  • Group 4 is mice treated with 5 mg/kg of Compound 42 daily for up to 26 days.
  • the vehicle with or without drug is administered to the mouse by intrapentoneal injection.
  • the formulation with respective drug is as follow-s:
  • mice were assigned into groups using randomized block design as following: First, the experimental animals were divided into homogeneous blocks based on their tumor volume. Secondly, within each block, randomization of experimental animals to different groups were conducted. By using randomized block design to assign experimental animals, we ensured that each animal had the same probability of being assigned to any given treatment groups and therefore systematic error was minimized.
  • Figure 1 sho 's the xenograft study result for Compound 42.
  • Compound 42 at 5 mg/kg reduced tumor size by greater than 50%.

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Abstract

The present disclosure is directed to asymmetric triazole benzamide compounds of formula (I) and formula (II), pharmaceutical compositions thereof and methods for modulating or activating a Parkin ligase The present disclosure is also directed to methods of treating and/or reducing the incidence of diseases or conditions related to the activation of Parkin ligase. R1, R2, R3, M1, M2, M3, L1, L2, and L3 are as defined herein.

Description

ASYMMETRIC TRIAZOLE BENZAMIDE DERIVATIVES AND THE COMPOSITIONS AND METHODS OF TREATMENT REGARDING THE SAME
CROSS-REFERENCE TO RELATED APPLICATIONS
[1] This application claims priority to U.S. Provisional Application No. 62/593,582, filed December 1, 2017, the disclosures of which are hereby incorporated by reference in their entireties for all purposes.
FIELD OF TFIE INVENTION
[2] The present invention relates to asymmetric tri azole benzamide compounds and their derivatives as well as methods of modulating Parkin ligase or methods of treating various diseases and conditions with the triazole benzamide compounds and their derivatives.
BACKGROUND OF THE INVENTION
[3] Ubiquitin-Proteasome Pathway System (UPS) is a critical pathway that regulates key regulator proteins and degrades misfolded or abnormal proteins. UPS is central to multiple cellular processes, and if defective or imbalanced, it leads to pathogenesis of a variety of diseases. Posttranslational modification of proteins by ubiquitin is a fundamental cellular mechanism that regulates protein stability and activity and underlies a multitude of functions, from almost ever)' aspect of biology. The covalent attachment of ubiquitin to specific protein substrates is achieved through the action of E3 ubiquitin ligases. These !igases comprise over 500 different proteins and are categorized into multiple classes defined by the structural element of their E3 functional activity. Specifically, both HECT and RING ligases transfer an activated ubiquitin from a thioester to the e-amino acid group of a lysine residue on a substrate; however, HECT ligases have an active site cysteine that forms an intermediate thioester bond with ubiquitin, while RI G ligases function as a scaffold to allow direct ubiquitin transfer from the E2 to substrate. Recent evidence suggests that a subfamily of RING ligases, the RING- between-RING (RBR) family, may contain a catalytic cysteine residue 1,2 in addition to a canonical RING domain. (Riley et al. 2013. Nat Commun. 4: 1982,“Riley et al.”), which is herein incorporated by reference in its entirely.
[4] Deubiquitinating proteins and ubiquitin-specific proteases (DIJBs and USPs) and E3 Ligases play a vital role in the UPS. These proteins are supported by flexible Zinc Finger (ZnF) domains which stabilize the binding of ubiquitin (Ub) for specialized functions.
[5] Parkin is a RING-between-RING E3 ligase that functions in the covalent attachment of ubiquitin to specific substrates, and mutations in Parkin are linked to Parkinson’s disease, cancer and mycobacterial infection. The individual RING domains for Parkin have been the subject of much debate, in regards to the specific residues that coordinate Zn ions, as well as their relationship to canonical RING crossbrace structures defining classical E2-bindmg domains. RO is a novel domain structure, but is more similar to Zn-finger domains than to E3 RING domains (Riley et al. 2013. Nat Comrnun. 4: 1982)
[6] While many drug discovery' programs focus on the UPS, few have been successful due to the lack of selectivity and direct access to enzymatic protein active sites. The present invention is directed towards a novel approach of disrupting Zn-finger domains that pro vide a therapeutic benefit for various diseases and disorders, including oncology' and neurology' disorders.
SUMMARY OF THE INVENTION
m The compounds of the present disclosure can modulate or active Parkin ligase and may be useful in treating various diseases and conditions as disclosed herein. In one embodiment, the present disclosure provides compounds comprising the structure of formula (I):
Figure imgf000004_0001
[8] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[9] L1, L2 and L3 are each independently selected from a bond, alkylene, or alkenylene;
[10] M1 and M2 are each independently selected from -NR4-, -NR4C(0)-, -
N(C(0)R])-, -C(0)NR4-, -NR4C(0)NR4-, -('{OK -C(=NR4)-, -C(=NOR4)-, -()( «>}-·. - 1 (0)0-. -()( {())()-. -0C(0)NR4-, -NR4C(0)0-, -S(0)m-, -S(0)mNR4-, or -NR4S(0)m-, provided that M1 and M2 are not both -NR4-;
[11] R1 and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryd, cydoalkylalkyl, arylalkyl, ar lalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroary alkenyl, or lieteroarylalkynyL wherein each eycloalkyl, aryl, heteroaryd, and heterocyclyl portion is optionally substituted with one or more R5; [12] R3 is selected from an alkyl alkenyl, cycloalkyl, aryl, biphenyl, heterocyciyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroaryl alkyl, heteroary!alkenyl, or heteroaiylalk nyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyciyl portion is optionally substituted with one or more R7;
[13] R4 is each independently H, alkyl, wherein each alkyl is optionally substituted with one or more R5;
[14] R5 is each independently I, Br, Cl, F, -CFI;F, -Cl si ;. -CFs, -OCF3, -CN, - alkyl -CN, -CON H r -CONHR6, -CONR6R6, -COOH, -M i ·. -M IR". -NO;, -NR6R6, -Ns, - OH, OR6, -COOR6, -OSOsR6, oxo, R6, -SH, -SQ2R6, -SOiH, -SOsR6, or -SR6;
[15] R6 is each independently alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl; or alternatively two R6 on the same N atom can together form a 3-6 membered N-heterocycly!;
[16] R7 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CFs, -OCFs, -CN, - alkyl-CN, -CONH2, -CONHR6, -CONR6R6, -COOH, -XI I w -NHR6, -NO2, -NR6R6, -Ns, - OH, OR6, -COOR6, -OSOsR6, oxo, R6, -SH, -SO2R6, -SOsH, -SOsR6, -SR6, cycloalkyl, heterocyciyl, and, or heteroaryl, wherein each cycloalkyl, heterocyciyl, aryl, and heteroaryl is optionally substituted with one or more R5;
[17] m is 0, 1 , or 2; and
[18] wherein the compound is not L JV'~(1 -phenyl-1/7-1 ,2,4-triazole-3,5- diyl)dibenzamide, 7V-(3-benzamido- 1 -phenyl- \H~ 1 ,2,4-triazol-5-yl)furan-2-carboxamide, A-(5-cinnamamido-l-phenyl-l//-l,2,4-triazoI-3-yl)benzamide, ¥-(1 -phenyl-5 -
(pheny lamino)- i If- 1 ,2,4-tri az.ol -3 -y 1 )benzami de, 4-fluoro- ¥-(5 -(4-methoxy benzami do)- 1 - phenyl- \H~\, 2, 4-triazol-3-yl)benzamide, AC¥'~(l -pheny!-l//~l ,2,4-triazole~3,5-diyi)bis(4~ methylbenzamide), iV-(5-((2-chlorobenzyl)amino)-l-phenyl-li -l,2,4-triazol-3-yl)-2- fluorobenzamide, /V-(3-benzamido-l-phenyl-li/-l,2,4-triazol-5-yl)-4-fluorobenzamide, ;V-(3-benzamido- 1 -phenyl- 1 H- 1 ,2,4-triazol-5-yl)-4-nitrobenzamide, ;V-(3-benzamido- 1 - phenyl- IH-l ,2,4-triazol-5-yl)-3-nitrobenzamide, and 4-((3-benzamido- 1 -phenyl- 1 H- 1 ,2,4-triazol-5-yl)carbamoyi)benzoic acid.
[19] In one embodiment of the compound of formula (I), I,1, L2 and IF are each independently a bond.
[20] In one embodiment of the compound of formula (I), M1 and M2 are each
independently selected from -NR4-, -NR4C(0)-, -CiOlNR4-, -N(C(0)Ri)-, or -NR4S(0)m- In one embodiment, M] and M2 are each independently selected from -NR4-, -NR4C(0)- or - C(0)NR4~.
[21] in one embodiment of the compound of formula (I), R4 at each occurrence is independently H or Ci-Cs alkyl.
[22] In one embodiment of the compound of formula (I), U is a bond and R3 is an aryl or a heteroaryl, optionally substituted with one or more R7.
[23] In one embodiment of the compound of formula (1), R3 is a phenyl or phenyl fused bicy cle, optionally substituted with one or more R7. In another embodiment, R3 is heteroaryl selected from imidazolyl or pyrazolyl, optionally substituted with one or more R7.
[24] In one embodiment of the compound of formula (I), R7 is each independently I, Br,
Cl, F, -CH?F, -CHF, -CF, -OCRs, -CN, -MR, -NMe?, -NO?., -Ns, -OH, OR6, R6, -SH, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R5.
[25] In one embodiment of the compound of formula (1), R3 is a phenyl substituted with a
4-6 membered heterocyclyl, which is optionally substituted with one or more R7.
[26] In one embodi ent of the compound of formula (I), R’! and R2 are each independently selected from phenyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, phenyl-(Ci-Cs alkyl)-, phenyl -(C -C3 alkenyl)-, 5-6 membered heteroaryl -(Ci- Cs alkyl)-, or heteroaryl-(C?-C3 alkenyl)-, wherein each cycloalkyl, aryl, heteroaryl portion is optionally substituted with one or more R3. In some embodiments, the 6-10 membered aryl or
5-10 membered heteroaryl is a bicyclic ring.
[27] In one embodiment of the compound of formula (I), R3 is selected from I, Br, Cl, F, Ci-Ce alkyl, alkynyl, -CN, -(Ci-Cs alkyleneVCN, -NH?, -NO?, -Ns, -OH, -OCF3, -OMe, - NMe?, or -NEt?.
[28] In one embodiment of the compound of formula (I), at least one of R1, R2, and R3 is phenyl and substituted with at least one of methyl, ethyl, -CºCH, I, Br, Cl, F, -CF3, -CN, - CH?CN, -CH2CH2CN, -NΉ?, -NO?, -Ns, -OH, -OCFs, -OMe or -NMe? In some
embodiments, at least two of R1, R2, and R3 is phenyl and substituted with at least one of methyl, ethyl, -C CI L I, Br, Cl, F, -CF :. -CN, -CH?CN, -CH?CH?CN, -M l·. -NO?, -N3, -OH, -OCF3, -OMe or -NMe?. In another embodiment, at least one of R1, R2, and 3 is pyridyl, optionally substituted with one or more of methyl, ethyl, -CºCH, I, Br, Cl, F, -CF3, -CN, - (Ί 1 ·('\.-( ! K ! l C\. -M l?. -NO?, -Ns, -OH, -OCFs, -OMe or -NMe?..
[29] In one embodiment, the compound of formula (I) has the structure of formula (F):
Figure imgf000007_0001
[30] or a pharmaceutically acceptable salt or solvate thereof, wherein L3, M1, M2, R1, R2, and R3 are as defined for formula (1).
[31] In one embodiment of the compound of formula (G), M1 and M2 are each independently selected from -NR4-, -NR4C(0)-, -C(0)NR4-, -N(C(Q)Rfj-, or -NR4S(0)m-.
[32] In one embodiment of the compound of formula (G), R1 and R2 are each
independently selected from phenyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, phenyl-(Ci-C3 alkyl)-, phenyl-(C2-C3 alkenyl)-, 5-6 membered heteroaryl-(Ci-C3 alkyl)-, or heteroaryl-(C2-C3 alkenyl)-, wherein each cycloalkyl, and, heteroaryi portion is optionally substituted with one or more R5; and R3 is an aryl or a heteroaryl, optionally substituted with one or more R7.
[33] In one embodiment, the compound of formula (I) has the structure of formula (IA):
Figure imgf000007_0002
34] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[35] M1 and M2 are each independently selected from -NR4C(0)- or -C(0)NR4-;
[36 R1 and R2 are each
[3 / R3 is selected from
Figure imgf000007_0003
[38] R4 is each independently H or C -Cr alkyl; and
[39] R7a, R7b, R7e, and R7e is each independently H, I, Br, Cl, F, -CH2F, -CHFz, - CF¾, -OCF3, -N3, -CN, -OH, methyl, ethyl, propyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C C3 haloa!koxy; [40] R7c is H, I, Br, Cl, F, -( I FF. -d l l ·. -CFs, -OCFs, -N3, -CN, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, 4-6 membered heterocyclyl, or 5-6 membered heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one or more R5;
[41] R5 is I, Br, Cl, F, -CH2F, -CHF ·. -CF3, -Ci-Ce alkyl, alkynyl, -CN, -(C1-C3 alkylene)-CN, -NH2, -NO2, -Ns, -OH, -OCF3, -OMe, -NMe2, -NEt2, or -C(0)0(Ci-Ce alkyl);
[42] wherein at least one of R7a, R7b, R7c, R7e, and R7eis not FI.
[43] In one embodiment of the compound of formula (IA), 5 is selected from R3 is
Figure imgf000008_0001
[44] In one embodiment of the compound of formula (I A), four of R7a, R71*, R7c, R7e, and R7eis H. In another embodiment, three of R/a, R7b, R7c, R7e, and R7eis H. In some
embodiments, R7a, R7b, R7c, R7e, and R7e is each independently H, I, Br, Cl, F, -Cl i d . -CHF2, C F ·.. -OCF3, -N3, -CN, -OH, methyl, ethyl, propyl, -CºCH; -CN, -M l··. -NO2, -N3, -OI L - OCF3, -OMe, -NMe2, or -NEt2.
[45] In one embodiment of the compound of formula
Figure imgf000008_0002
some embodiments, R7c is I, Br, -CFI2F, -CHF2, -CF3, methyl, ethyl, propyl, -CºCH; -CN, -NH2, - NO2, -Ns, -OH, -OCF3, -OMe, -NMe2, or -NEt2. In other embodiments, R7c is I, Br, -CH2F, - CHF2, -CFS, -OCF3, or -OMe. In one embodiment, R7c is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or pyrazolyl, each optionally substituted with one or more R5.
[46] In one embodiment, the compound of formula (I) has the structure of formula (IB):
Figure imgf000008_0003
[47] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[48] M3 and M2 are each independently selected from -NR4-, -NR4C(0)- or -
C(0)NR4-; [49] R1 and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyi, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or
heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
[50] wherein one of -V R1 and -Vi’R ' is ~NR4~(cycloalkylalkyl), -NR4- (heterocyclylalkyl), -NR4-(arylalkyl), or -NR4-(heteroarylalkyl), wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
[51] R3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaxyl, and heterocyclyl portion is optionally substituted with one or more R7;
[52] R4 is each independently H or C1-C3 alkyl;
[53] R5 is I, Br, Cl, F, -CH2F, -CHF2, -CFs, -Ci-Ce alkyl, alkynyl, -CN, -(C1-C3 alkyl ene)-CN, -NH2, -NO2, -Ns, -OH, -OCF3, -OMe, -NMe2, -NEt2, or -C(0)0(Ci-Ce alkyl); and
[54] R7 is each independently I, Br, Cl, F, -CH2F, -CHF?„ -CF3, -OCF3, -CN, - alkyl-CN, -CONH2, -CON HR ". -CONR6R6, -COOH, -NH2, -NHR6, -NO2, -NR6R6, -N3, - OH, OR6, -CQQR6, -OSO3R6, oxo, R6, -SH, -SO2R6, -SO3H, -SO3R6, -SR6, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more Rk
[55] In one embodiment of the compound of formula (IB), one of -MF R1 and -M2 R2 is - NR4-(C I-C3 a!ky!ene)-cycloa!kyl, -NR4-(CI-C3 alkylene)-heterocyclyl, -NR4-(CI-C3 alkylene)-aryl, or -NR4-(CI -C3 alkylene)-heteroaryl; wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl is each optionally substituted with one or more R5 In some embodiments, one of -M! Rf and ~M2 RZ is -NR4-(Ci-C3 aikyiene)-phenyl, or -NR4-(CI-C3 alkylenej-pyridyl, wherein phenyl and pyridyl is each optionally substituted with one or more Rk In other embodiments, one of -M1_R! and -M2 R2 is -NR4-CH2-phenyl, -NR4-CH2CH2-phenyl, -NR4-
CH2-pyridyl, -NR4-CH2CH2-pyridyl,
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000010_0002
; wherein phenyl and pyridyl is each optionally substituted with one or more R5.
[56] In one embodiment of the compound of formula (IB), R1 and R2 are each
independently selected from phenyl or pyridyl, each optionally substituted with one or more
R
[57] In one embodiment of the compound of formula (IB), one of -Mf R1 and -M R2 is - NR4-(Ci-C3 a!ky!ene)-pheny!, or -NR4-(CI-CJ alkyl ene)-pyridyl, and the other one of -M^R1 and -M2 R2 is -NR4C(0)-phenyl, -NR4C(0)-pyridyl, -C(0)NR4-phenyl, or -C(0)NR4-pyridyJ; wherein each phenyl and pyridyl is optionally substituted with one or more R’. In some embodiments, one of -M! Rf and -M2 R is -NR4-(CI-CJ alkylene)-phenyl, or -NR4-(CI-C3 alkylene)-pyridyl, wherein each phenyl and pyridyl is optionally substituted with one or more
R5. and the other one
Figure imgf000010_0003
O O
Figure imgf000010_0004
In other embodiments, one of -M^R1 and ~M2 R2 is -
NR4-(CI-C3 a!ky!ene)-phenyl, or -NR4-(CI-C3 alkyl ene)-pyridyl, wherein each phenyl and pyridyl is optionally substituted with one or more R5, and the other one of -iVB R1 and -M2 R2
Figure imgf000010_0005
[58] In one embodiment of the compound of formula (IB), R3 is phenyl, optionally substituted with one or more R7; and R7 is each independently I, Br, Cl, F, -CHzF, -CHFz, - CFs, -OCFs, -CN, -Ns, -OH, methyl, ethyl, propyl, -CºCH; -CN, -NH2, -NO2, -Ns, -OH, - OCFs, -OMe, -NMez, or -NEtz.
[59] In one embodiment of the compound of formula (IB), R5 is selected from I, Br, Cl, F, -CHzF, -CHFz, -CFs, -OCFs, -Ns, -CN, -OH, methyl, ethyl, propyl, -CºCH; -CN, -NHz, - NOz, -Ns, -OH, -OCFs, -OMe, -NMez, or -NEtz.
ent of the compound of formula (IB), the compound is not
Figure imgf000011_0001
[61] In one embodiment, the compound of formula (I) has the structure of formula (IB1):
Figure imgf000011_0002
[62] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[63] R1 is cycloalkyl alkyl, heteroeyclylalky!, ary!alkyl, or heteroarylalkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
[64] R is selected from cycloalkyl, aryl, biphenyl, heterocyclyl, or heteroaryl, wherein each optionally substituted with one or more R5;
[65] R3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocycly!a!kyl, heteroarylalkyl, heteroarylalkenyl, or heteroaryl alkyny!, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R7;
[66] R4 is each independently H or Ci-Cs alkyl;
[67] R5 is I, Br, Cl, F, -CH2F, -CHF2, -CF3, -Ci-Ce alkyl, alkynyl, -CN, -(C1-C3 alkylene)-CN, -NH2, -NO2, -Ns, -OH, -OCFs, -OMe, -NMez, -NEtz, or -C(0)0(Ci-Ce alkyl); and [68] R7 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CFs, -OCF3, -CN, - alkyl -CN, -CONH2, -CONHR6, -CONR6R6, -COOH, -M l·. -M IR". -NO2, ~NR6R6, -Ns, - OH, OR6, -COOR6, -OSOsR6, oxo, R6, -SH, -SO2R6, -SOsH, -SO3R6, -SR6, cycloalkyl, heterocyciyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R5.
[69] In one embodiment of the compound of formula (IB!), R1 is -C1-C3 alkyl ene- cycloalkyl, -C1-C3 alkylene-heterocyclyl, -C1-C3 alkylene-aryl, or -C1-C3 alkylene-heteroaryl; wherem cycloalkyl, aryl, heteroaryl, and heterocyclyl is each optionally substituted with one or more R5. In some embodiments, R3 is -C1-C3 alkylene-phenyl or -C1-C3 alkylene-pyridyl, wherein phenyl and pyridyl is each optionally substituted with one or more R5. In another embodiment, R1 is -CF -phenyl, -CHaCHz-phenyl, -CHz-pyridyl, -CHzCHa-pyridyl,
Figure imgf000012_0001
; wherein phenyl and pyridyl is each optionally substituted with one or more
Figure imgf000012_0002
[70] In one embodiment of the compound of formula { IB'}. R2 is aryl or 5-6 membered heteroaryl, each optionally substituted with one or more R5. In another embodiment, R2 is
phenyl optionally substituted with one or more Rk In some embodiments, R2 is
Figure imgf000012_0003
71] In one embodiment of the compound of formula (IB'), R3 is phenyl, optionally substituted with one or more R7; and R7 is each independently I, Br, Cl, F, -CH2F, -CHF2, -
CFs, -OCF3, -CN, -Ns, -OH, methyl, ethyl, propyl, -CºCH; -CN, -\ϋ ·. -NO2, -Ns, -OH, - OCFs, -OMe, -NMey or -NEts. [72] In one embodiment of the compound of formula (IB1), 4 is selected from I, Br, Cl, F, - CH2F, -CFIF2, -CFs, -OCFs, -Ns, -CN, -OH, methyl, ethyl, propyl, -CºCH; -CN, -NH2, -NO2, -Ns, -OH, -OCFs, -OMe, -NMe2, or -NEts.
173] In one embodiment, the compound of formula (I) has the structure of formula (IC):
Figure imgf000013_0001
[74] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[75] M1 and M2 are each independently selected from -NR4-, -NR4C(0)- or -
C(0)NR4-;
[76] R1 and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocydyl heterocycloalkyl, 5-6 membered heteroaryl, cycloalkylalkyl, arylalkyl, axylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, and, heteroaryl, and heterocydyl portion is optionally substituted with one or more R5;
[77] wherein at least one of -Mk R1 and -M2 R2 is -NR4-(4-6 membered heterocydyl), -NR4-(5-6 membered heteroaryl), or -NR4-naphthalenyl, wherein 4-6 membered heterocydyl, 5-6 membered heteroaryl, and naphtha!enyl is each optionally substituted with one or more R5;
[78] R3 is selected phenyl, optionally substituted with one or more R7;
[79] R4 is each independently H or C1-C3 alkyl; and
[8Q] R5 and R7 are each independently selected from I, Br, Cl, F, -CH2F, -CHF2, -
CFs, -Ci-C6 alkyl, alkynyl, -CN, -(C1-C3 a!kylene)-CN, -NH2, -NO2, -Ns, -OH, -OCFs, - OMe, -NMer, ~NEt2, or -C(0)0(Ci-C6 alkyl).
[81] In one embodiment of the compound of formula (IC), at least one of -Md R1 and -M2~ R2 is -NR4-azetidinyl, -NR4-pyrrohdinyl, -NR4-piperidinyl, -NR4-imidazoIyl, -NR4- isoxazolyl, -NR4~oxazolyl, -NR4-thiazolyl, -NR4-thiophenyl, -NR4-pyridyl, -NR4-pyridazinyl, ~NR4~pyrazinyl, -NR4-pyrimidinyl, or -NR4-pyridinone, wherein each of azetidinyl, pyrrolidinyl, piperidinyl, imidazolyl, isoxazolyl, oxazolyl, tlnazolyl, pyridyl, pyridazinyl, pyrazinyi, pyrimidmyl, or pyridmone is optionally substituted with one or more R5. In other embodiments, at least one of -M’tR1 and ~M2 R2 is -NR4 -pyridyl, wherein pyridyl is optionally substituted with one or more Rk In some embodiments, -M^R1 and ~M2 R2 are each -NR4-pyridyl, wherein pyridyl is optionally substituted with one or more R3. In other embodiments, one of -M1_R! and -M2 R2 is -NR4-azetidinyi, -NR4-pyrrolidinyl, -NR4- piperidinyl, -NR4 -imidazolyl, -NR4-isoxazolyl, ~NR4~oxazolyl, -NR4-thiazolyl, -NR4- thiophenyl, -NR4-pyridyl, -NR4-pyridazinyl, -NR4-pyrazinyl, -NR4-pyrimidinyl, or -NR4- pyridinone, wherein each of azetidinyi, pyrrolidinyl, pipendinyl, imidazolyl, isoxazolyi, oxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, or pyridinone is optionally
O substituted with one or more R5, and the other one of -M’R1 and ~M2 R2 is
Figure imgf000014_0001
Figure imgf000014_0002
In one embodiment of the compo und of formula (IC), one of -MF R1 and -M2 R2 is-
NR4-azetidinyl, -NR4-pyrrolidinyl, -NR4-piperidinyl, -NR4-imidazolyl, -NR4 -isoxazolyi, - NR4-oxazolyl, -NR4-thiazolyl, -NR4-thiophenyl, -NR4~pyridyl, -NR4~pyridazinyl, -NR4- pyrazinyl, -NR4 -pyrimidinyl, or -NR4-pyridinone, wherein each of azetidinyi, pyrrolidinyl, pipendinyl, imidazolyl, isoxazolyi, oxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, or pyridinone is optionally substituted with one or more R5, and the other one of
Figure imgf000014_0003
[83] In one embodiment of the compo und of formula (IC), R5 and R7 is each selected from I, Br, Cl, F, -CH2F, -CHF2, ~CF3, -OCFJ, -Ns, -CN, -OH, methyl, ethyl, propyl, -CºCFI; -CN, -NH2, -NO '. -N3, -OH, -0CF3, -OMe, -NMei, or -NEti.
|84] In one embodiment of the compound of formula (IC), the compound is not
Figure imgf000014_0004
Figure imgf000015_0001
ent, the compound of formula (I) has the structure of formula (ID):
Figure imgf000015_0002
[86] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[87] M1 and M2 are each independently selected from -NR4-, -NR4C(0)- or - C(0)NR4-;
[88] R1 and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, aryla!kyl, arylalkenyl, arylalkynyl, heterocyclyl alkyl, heteroarylalkyl, heteroaryl alkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more Rs:
[89] R3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalky 1, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R7;
[90] R4 is each independently H or C1-C3 alkyl; and
[91] R5 and R7 are each independently selected from I, Br, Cl, F, -CH2F, -CHF2, - CFs, -Ci-Ce alkyl, alkynyl, -CN, -(C1-C3 alkylene)-CN, -NFL·, -NO2, -Ns, -OH, -OCF3, - OMe, -NMe2, -NEt2, or -C(0)0(Ci-C6 alkyl);
[92] wherein at least one of R1 and R2 is a phenyl substituted with at least one of - ( C! i or -N3.
[93] In one embodiment of the compound of formula (ID), M1 and M2 are each -NR4C(0)-.
[94] In one embodiment of the compound of formula (ID), at least one of R1 and R2 is a phenyl substituted with at least one of -CºCH or -N3 and the other one of R1 and R2 is a phenyl or pyridyl, optionally substituted with one or more R5.
[95] in one embodiment of the compound of formula (ID), R3 is phenyl optionally substituted with one or more R7. [96] In one embodiment of the compound of formula (ID), R3 and R7 is each selected from I, Br, Cl, F, -CH2F, -CHF2, -CF3, -OCF3, -Ns, -CN, -OH, methyl, ethyl, propyl, -CºCH, -CN, -NH2, -NO '. -N3, -OH, -0CF3, -OMe, ~NMe2, or -NEt2.
[97] In one embodiment, the compound of formula (I) has the structure of formula (IE):
Figure imgf000016_0001
98] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[99] M1 and M2 are each independently selected from -NR4-, -NR4C(0)-, -C(0)NR4- , or -S(0)mNR4-;
[100] R1 and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocydyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocydyl portion is optionally substituted with one or more R5;
[101] R2 is selected from an aryl or heteroaryl, wherein aryl and heteroaryl is optionally substituted with one or more R7;
[102] R4 is each independently H or Ci-C3 alkyl; and
[103] R5 and R7 are each independently selected from I, Br, Cl, F, -CH2F, -CHF2, - CF3, -Ci-Ce alkyl, alkynyl, -CN, -(Ci-C3 aIkylene)-CN, -NH2, -N02, -N3, -OH, -OCF3, - OMe, -NMe2, -NEC, or -C(0)0(Ci-C6 alkyl);
[104] wherein when M1 and M2 are both -NR4C(0)-, at least one of R1 and R2 is
Figure imgf000016_0002
[105] In one embodiment of the compound of formula (IE), M1 and M2 are both - S(0)mNR4-. In another embodiment, M3 and M2 are both -C(0)NR4-.
[106] In one embodiment of the compound of formula (IE), at least one of R1 and R2 is a phenyl or pyndyi, optionally substituted with one or more R5. In some embodiments, R3 and R2 is phenyl, optionally substituted with one or more R5. In other embodiments, at least one
Figure imgf000017_0003
[107] In one embodiment of the compound of formula (IE), at least one of R* is a phenyl or pyridyl, optionally substituted with one or more R7.
[108] In one embodiment of the compound of formula (IE), R5 and R7 is each selected from I, Br, Cl, F, -CH2F, -CHF2, -CFS, -OCFJ, -NS, -CN, -OH, methyl, ethyl, propyl, -CºCH, -CN, -NH2, -NO2, -Ns, -OH, -OCF3, -OMe, -NMe2, or -NEt2.
109] In one embodiment of the compound of formula (IE), the compound is not
Figure imgf000017_0001
[110] In one embodiment, the compound of formula (I) has the structure of formula (IF):
Figure imgf000017_0002
[111] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[112] M3 is selected from -NR4-, -NR4C(0)- or -C(0)NR4-;
[113] R1 and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyi heterocycloalkyl, 5-6 membered heteroaryl, cycioa!kylalkyl, arylalkyl, aryl alkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroaryl alkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyi portion is optionally substituted with one or more R5;
[114] R3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyi heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R :
[115] R4 is each independently H or CJ -CT alkyl; and
[116] R5 and R7 are each independently selected from I, Br, Cl, F, -CT-fcF, -CHF2, - CF3, -C1-C6 alkyl, alkyny!, -CN, -(C1-C3 alkylene)-CN, -NH2, -NO2, -Ns, -OH, -OCF3, - OMe, -NMe?., -NEt2, or -C(0)0(C]-C6 alkyl).
[117] In one embodiment of the compound of formula (IF), R1 and R2 are each
independently selected from aryl or 5-6 membered heteroaryl, each optionally substituted with one or more R5.
[118] In one embodiment of the compound of formula (IF), R2 is phenyl optionally
substituted with one or more R5. In another embodiment, R2 is
Figure imgf000018_0001
[119] In one embodiment of the compound of formula (IF), R3 is cycloalkyl, aryl, heterocy clyl, or heteroaryl, each optionally substituted with one or more R7. In another embodiment, R3 is phenyl optionally substituted with one or more R'.
[120] In one embodiment of the compound of formula (I), (G), (IA), (IB), (1B!), (IC), (ID), (IE), or (IF) the compound is selected from Table 1. In one embodiment, the compound of
formula (
Figure imgf000018_0002
pharmaceutically acceptable salt thereof. In
other embodiments, the compound of formula (
Figure imgf000018_0003
pharmaceutically acceptable salt thereof
[121] In one embodiment, the compound of the present disclosure is selected from Table 2.
[122] In one embodiment, the compound of formula (I), excludes compounds of Table A. In one embodiment, the compound of formula (I), (G), (IA), (IB), (ΊB'), (IC), (ID), (IE), or (IF) excludes compounds of "fable A. [123] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound of any one of formula (I), (I'), (I A), (IB), (ΪB
one embodiment, the pharmaceutical composition comprises
Figure imgf000019_0001
Figure imgf000019_0004
eutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound of Table 1. In one embodiment, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable earner or a pharmaceutically acceptable excipient and a compound of Table 2. In one embodiment, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and
Figure imgf000019_0002
pharmaceutically acceptable salt thereof. In one embodiment of the pharmaceutical composition, the compounds of Table A are excluded.
[125] In one embodiment, the present disclosure provides a pharmaceutical composition as disclosed herein comprises one additional therapeutically active agent.
[126] In one embodiment, the present disclosure provides compounds comprising the structure of formula (II):
Figure imgf000019_0003
] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[128] M3 and M2 are each independently selected from a bond, -NR4-, or -NR4C(0)- , -C(0)NR4-;
[129] R! and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, axylalkyl, aryl alkenyl, ary!a!kynyl, heterocydylalkyl, heteroaryialkyl, heteroaryl alkenyl, or
heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
[130] wherein at least one of M1 and M2 is a bond or -NR4-;
[131] wherein when M3 is -NR4-, then R1 is cycloalkylalkyl, heterocydylalkyl, arylalkyl, or heteroaryialkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
[132] wherein when M2 is -NR4-, then R2 is cycloalkylalkyl, heterocydylalkyl, arylalkyl, or heteroaryialkyl, wherein cycloalkyl, a ryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
[133] R3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaiyl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkyny!, heterocydylalkyl, heteroaryialkyl, heteroarylalkenyi, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R7;
[134] R4 is each independently H, alkyl, wherein each alkyl is optionally substituted with one or more R5;
[135] R5 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CF3, -OCF3, -CN, - a!kyl-CN, -CONH?, -CONHR6, -CONR6R6, -COGH, -M l ·. -M I ' . -NO-.. -NR6R6, -N3, - OH, OR6, -CQOR6, -QSQ3R6, oxo, R6, -SH, -SQ2R6, -SO3H, -SO3R6, or -SR6;
[136] R6 is each independently alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl; or alternatively two R6 on the same N atom can together form a 3-6
membered N -heterocyclyl; and
[137] R7 is each independently I, Br, Cl, F, -CFHF, -C l li e. -CFs, -OCF3, -CN, - alkyl -CN, -CONH2, -CONHR6, -CONR6R6, -COOH, - l ·. -NHR6, -NO2, -NR6R6, -N3, - OH, OR6, -COOR6, -OSO3R6, oxo, R6, -SH, -SO2R6, -SO3H, -SO3R6, -SR6, cycloalkyl, heterocyclyl, aryl, or heteroaiyl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R5; [138] wherein the compound is not /V-benzyl-7V-(5-(benzylamino)-l-phenyJ-li/- l ,2,4-triazol-3-yl)acetamide, jV-(5-((2-chlorobenzyl)amino)-l -phenyl- Iff- 1,2, 4-triazol-3- y!)~2~fluorobenzamide and /V3 iV5-bis(4-methylbenzyl)-l-phenyl-lff-l,2,4-triazole-3,5- diamine.
[139] In one embodiment of the compound of formula (II), at least one of -M1_R] and -M2 R2 is -NR4-(CI-C3 alkylene)~eycloalkyl, -NR4-(CI-C3 alkylene)-heterocyclyl, -NR4-(CI-C3 alkylene)-aryl, or -MR4-(CI-C3 alkylene)-heteroaryl; wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl is each optionally substituted with one or more R5.
[140] In one embodiment of the compound of formula (II), at least one of
Figure imgf000021_0001
and -M2 R2 is -NR4-(CI-C alkyiene)~phenyl, or -NR4-(Ci-C3 alkylene)-pyridyl, wherein phenyl and pyridyl is each optionally substituted with one or more R5. In other embodiments, at least one of -M^R1 and -M2 R2 is -NR4-CH2-phenyl, -NR4-CH2CH2-phenyl, -NR4-CH2-pyridyl, -NR4-
Figure imgf000021_0002
and pyridyl is each optionally substituted with one or more R5. In some embodiments, -M^R1 and -M2 R2 are each selected from -NR4-CH?-phenyl, -NR4-CH2CH2-phenyl, -NR4-CH2-
Figure imgf000021_0003
Figure imgf000022_0001
Figure imgf000022_0002
; wherein phenyl and pyridyl is each optionally substituted with one or more R5.
[141] In one embodiment of the compound of formula (11), R1 and R2 are each
independently selected from phenyl or pyridyl, each optionally substituted with one or more R5.
[142] in one embodiment of the compound of formula (II), one of M1 and M2 is a bond.
[143] In one embodiment of the compound of formula (II), R1 and R2 are each
independently selected from phenyl or 5-6 membered heteroaryl, each optionally substituted with one or more R5. In other embodiments, R3 and R2 are each independently selected from phenyl, azetidinyl, pyrrolidinyl, pipendinyl, imidazolyl, isoxazolyl, oxazolyi, thiazolyl, pyridyl, pyridazinyl, pyrazinyi, pyrimidmyl, pyridinoneor, or pyridine N-oxide, each optionally substituted with one or more R5.
[144] in one embodiment of the compound of formula (II), M1 is a bond and R3 is pyridyl, optionally substituted with one or more R3.
[145] In one embodiment of fte compound of formula (II), M2 is a bond and R2 is pyridyl, optionally substituted with one or more R\
[146] In one embodiment of the compound of formula (11), M1 is a bond and M2 is -NR4- or -NR4C(0)-.
[147] In one embodiment of the compound of formula (TT), M2 is a bond and M1 is -NR4- or ~NR4C(G)~.
[148] In one embodiment of the compound of formula (II), R3 is phenyl, optionally substituted with one or more R7; and R7 is each independently I, Br, Cl, F, -CFFF, -CHF?„ - CF , -OCF3, -CN, -N , -OH, methyl, ethyl, propyl, -CºCH; -CN, -NH2, -NO2, -N3, -OH, - OCFs, -OMe, -NMe2, or -NEta. [149] In one embodiment of the compound of formula (II), R5 and R7 are each
independently selected from I, Br, Cl, F, -CH2F, -CHF2, -CF3, -OCF3, -N3, -CN, -OH, methyl, ethyl, propyl, -CºCH; -CN, -NH2, -NO2, ~N3, -OH, -OCF3, -OMe, ~NMe2, or -NEt2.
[150] In one embodiment of tire compound of formula (II), R4 is each independently H or C1-C3 alkyl
[151] In one embodiment , the compound of formul a (P) has the structure of formula (II A) :
Figure imgf000023_0001
[152] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[153] R1 and R2 are each independently selected from an cycioalky!, aryl, biphenyl, heterocyclyl, or heteroaryl, each optionally substituted with one or more R5;
[154] R3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryi, cycloalkylalkyl, arylalkyi, arylalkenyl, aiylalkynyl, heterocydylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R7;
[155] R4 is each independently H, alkyl, wherein each alkyl is optionally substituted with one or more R3;
[156] R5 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CFs, -OCF3, -CN, - alkyl -CN. -CONH2, -CONHR6, -CONR6R6, -COOH, -M l '. M IR' . -NO2, -NR6R6, -Ns, - OH, OR6, -COOR6, -OSOsR6, oxo, R6, -SH, -SO2R6, -SOsH, -SOsR6, or -SR6;
[157] R6 is each independently alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl; or alternatively two R6 on the same N atom can together form a 3-6 membered N -heterocyclyl;
[158] R7 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CFs, -OCF3, -CN, - alkyl-CN, -CONH2, -CONHR6, -CONR6R6, -COOH, -M l ·. -M I ' . -NO.-.. ~NR6R6, -N3, - OH, OR6, -COOR6, -OSO3R6, oxo, R6, -SH, -SO2R6, -SO3H, -SO3R6, -SR6, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R5.
[159] In one embodiment of the compound of formula (IIA), R1 is aryl, optionally substituted with one or more R5. In another embodiment, R1 is phenyl, optionally substituted with one or more R5. In some embodiments, 5 is 5-6 membered heteroaryl, optionally substituted with one or more R5. In other embodiments, R1 is pyridyl, optionally substituted with one or more R5.
[160] In one embodiment of the compound of formula (IIA), R2 is phenyl optionally
substituted with one or more R5. In some embodiments, R2 is
Figure imgf000024_0001
[161] In one embodiment of the compound of formula (IIA), R3 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more R7. In some embodiments, R3 is phenyl optionally substituted with one or more R7.
[162] In one embodiment of the compound of formula (IIA), R5 is I, Br, Cl, F, -CH2F, -
Ci li x -CT\ -Ci-Ce alkyl, alkynyl, -CN, -(C 1-C3 alkylene)-CN, -NH?„ -NO2, -Ns, -OH, - OCF3, -OMe, -NMe?., -NEt?, or -C(0)0(Ci-Ce alkyl).
[163] In one embodiment of the compound of formula (IIA), R5 and R7 are each
independently selected from I, Br, Cl, F, -CH2F, -CHF?, -CF3, -OCF3, -N3, -CN, -OH, methyl, sthyl, propyl, -CºCH; -CN, -Nth, -NO2, -Ns, -OH, -OCF3, -OMe, -NMe?., or -NEt:
[164] In one embodiment, the compound of formula (II) or (PA) excludes the compounds of Table C.
[165] In one embodiment of the compound of formula (II) or (IIA), the compound is selected from Table 3A.
[166] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound of formula (II) or (IIA). In other embodiments, the pharmaceutical composition further comprising one additional therapeutically active agent. In one embodiment of the pharmaceutical composition, the compounds of Table C are excluded.
[167] In one embodiment, the present disclosure provides compounds comprising the structure of formula (III):
Figure imgf000024_0002
[168] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[169] L!, L2 and L3 are each independently selected from a bond, alkylene, or a!kenylene; [170 M] and M2 are each independently selected from -NR4-, -NR4C(G)-, - S(C{0)\V }-. -C(0)NR4-, -NR4C(0)NR4-, -C(O)-, -C(=NR4)-, -C(=NOR4)-, -()( {())-. - C(0)0-, -0C(0)0-, -0C(0)NR4-, -NR4C(0)0-, -S(0)m- -S(0)mNR4-, or -NR4S(0)m-, provided that M1 and M2 are not both -NR4-;
[171] R! and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aiyl, biphenyl, heterocyc!yi heterocycloalkyl, heteroaiyl, cycloalkylalkyl, arylalkyl, aiylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
[172] R3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, aryla!kenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, and, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R7;
[173[ R4 is each independently H, alkyl, wherein each alkyl is optionally substituted with one or more R5;
[174] R5 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CFs, -OCFs, -CN, - alkyl-CN, -CONH2, -CONHR6, -CONR6R6, -COR6, -COOH, -M l;. -NHR6, -NO2, - NR6R6, ~NR6COR6, -<alkyiene)NR6COR6, -NJ, -OH, OR6, -COOR6, -OSO3R6, oxo, R6, - SH, -SQ2R6, -SO3H, -SO3R6, or -SR6;
[175] R6 is each independently alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl; or alternatively two R6 on the same N atom can together form a 3-6 rnembered N-heterocy cly 1 ;
[176] R7 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CFs, -OCF3, -CN, - alkyl-CN, -CONH2, -CONHR6, -CONR6R6, -COOH, -NH2, -NHR6, -NO2, -NR6R6, -N3, - OH, OR6, -COOR6, -OSO3R6, oxo, R6, -SH, -SO2R6, -SO3H, -SO3R6, -SR6, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and
heteroaryl is optionally substituted with one or more R5;
[177] m is 0, 1, or 2: and
[178] wherein the compound is not L ^'-(1 -phenyl- 1//-1, 2, 4~lriazole-3,3~
diyl)dibenzamide, .¥-(3-benzami do- 1 -phenyl- SH- 1 ,2,4-triazol-5~y l)furan-2-carboxamide, 7V-(5-cinnamamido- 1 -phenyl- IH- 1 ,2,4-tnazol-3 -yl)benzamide, N~( 1 -pheny 1-5 -
(pheny lamino)- 1 H- 1 ,2,4-triazol-3 -y !)benzamide, 4-fluoro-7V-(5 -(4-methoxy benzamido)- 1 - phenyl- 1//-1, 2, 4-triaz.ol-3-yl)benzamide, AyV'-(l-phenyl-l/ -l,2,4-tria?.ole-3,5-diyl)bis(4- methylbenzamide), JV-(5-((2-chlorobenzyl)amino)-l-phenyl-lii-l,2,4-triazol-3-yl)-2- fluorobenzaraide, /V-(3-benzamido-1 -phenyl-1 HA ,2,4-triazol-5-yl)~4~fluorohenz.amide, A-(3-benzamido-l-phenyl-li -l,2,4-triazol-5-yl)-4-nitrobenzamide, V-(3-benzamido-l- phenyl-l//-l,2,4-triazol-5-yT)-3-nitrobenzamide, and 4-((3-benzamido-l-phenyl-l//- 1 ,2,4-triazol-5-y ])carbamoyl)benzoic acid.
[179] In one embodiment , the compound of formul a (III) has the s tructure of formula (III A):
Figure imgf000026_0001
[180] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[181] M1 and M2 are each independently selected from -NR4-, -NR4C(0)- or - C(0)NR4-, provided that M1 and M2 are not both -NR4-;
[182] R1 and R2 are each independently phenyl, optionally substituted with one or more R":
[183] wherein at least one of R1 or R2 is substituted with -(C1-C6
alkylene)NHCO(Ci-Cio alkyl) or -(Ci-Ce alkylene)N(Ci-C3 alkyl)CO(Ci-Cio alkyl);
Figure imgf000026_0002
[185] R4 is each independently H or C1-C3 alkyl;
[186] R5 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CF3, -Ci-Ce alkyl, alkynyl, -CN, -(C1-C3 alkylene)-CN, -NH2, -NO2, -Ns, -OH, -OCR. -OMe, -NMe2, -NEt2, -C(0)0(Ci-C6 alkyl), -CQ(Ci-Cio alkyl), -NHCO(Ci-Cio alkyl), -N(CI-C3 alkyl)CO(Ci- C10 alkyl), -(Ci-Ce alkylene)NHCO(Ci-Cio alkyl), or -(Ci-Ce alkylene)N(Ci-C3 a!kyl)CO(Ci-Cio alkyl);
[187] R7a, R7**, R7e, and R7e is each independently H, I, Br, Cl, F, -CH2F, -CHF2, - CF3, -OCF3, -N3, -CN, -OH, methyl, ethyl, propyl, C1-C3 haloalkyl, C1-C3 alkoxy, or Ci- C3 haloalkoxy; and
[188] R7c is H, 1, Br, Cl, F, -CH2F, -CHF2, -CFs, -OCFs, -N3, -CN, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, 4-6 membered heterocydyl, or 5-6 membered heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one or more R5
[189] In some embodiment of the compounds of formula (111) and/or (IPA), R1 is phenyl substituted with -(C1-C3 alkylene)NHCO(Ci-C8 alkyl) or -(C1-C3 alkylene)N(Ci-C:<
alkyl)CO(Ci-C8 alkyl). In some embodiments, R1 is phenyl substituted with -CH2NHCO(CI- Cs alkyl) or -CH2N(CI-C3 alkyl)CO(Ci-Cg alkyl).
[190] In some embodiment of the compounds of formula (III) and/or (IIIA), R7a, R71’, R7c, R7e, and R7e is each independently H, I, Br, Cl, F, -CH2F, -CHF2, -CFs, -OCFs, -Ns, -CN, -OH, methyl, ethyl, propyl, -CºCH; -CN, -NH2, -NO2, -N3, -OH, -OCFs, -OMe, -NMe2, or -NEt2, In some embodiments, R7a, R75, R7e, and R7e is each independently H.
[191] In one embodiment, the compound of formula (III) and/or (IIIA), is
Figure imgf000027_0001
or ; or a pharmaceutically acceptable salt thereof.
[192] In one embodiment , the compound of formula (III) has the structure of formula (IIIB):
Figure imgf000027_0002
[193] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[194] M1 and M2 are each independently selected from -NR4-, -NR4C(G)- or - C(0)NR4~, provided that M1 and M2 are not both -NR4-;
[195] R1 and R2 are each independently phenyl, optionally substituted with one or more R5:
[196] R3 is phenyl, substituted with one or more R7;
[197] R4 is each independently H or Ci-Cs alkyl;
[198] R5 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CF3, -Ci-Cs alkyl, alkynyl, -CN, -(C1-C3 alkylene)-CN, -NH2, -NO2, -Ns, -OH, -OCFs, -OMe, -NMe2, -NEfc, -C(0)0(Ci-C6 alkyl), -CO(Ci-Cio alkyl), -NHCO(Ci-Cio alkyl), -N(Ci-Cs alkyl)CO(Ci- Cio alkyl), -(Ci-Ce alkylene)NHCO(Ci-Cio alkyl), or -(Ci-Ce alkylene)N(Ci-C3 alkyl)CO(Ci-Cio alkyl); and
[199] wherein at least one R7 is heterocyclyl substituted with -CO(Ci-Cio alkyl), which is optionally further substituted with one or more R5.
[200] In some embodiment of the compounds of formula (III) and/or (IIIB), R3 is phenyl, substituted with 6-membered heterocyclyl and wherein the 6-membered heterocyclyl is substituted with -CO(Ci-Cio alkyl). In some embodiment of the compounds of formula (III) and/or (IIIB), R3 is phenyl substituted with a piperidine or a piperazine, wherein the piperidine or the piperazine is substituted with -CO(Ci-Cio alkyl).
[201] In some embodiment of the compounds of formula (III) and/or (IIIB), R1 and R2 are each independently phenyl, optionally substituted with one or more substitutent selected from I, Br, Cl, F, -CtfcF, -CHF2, -CFs, -OCFs, -Ns, -CN, -OH, methyl, ethyl, propyl, -CºCH; -CN, -NHz, -NO’. -Ns, -OH, -OCF s, -OMe, -NMes, or -NEtz.
[202] In some embodiment of the compounds of formula (III) and/or (IIIB), the compound is
Figure imgf000028_0001
pharmaceutically acceptable salt thereof.
[203] In one embodiment, the compound of formula (III), excludes compounds of Table A. In one embodiment, the compound of formula (III), excludes compounds of Table B.
[204] In one embodiment of the present disclosure, a method of modulating a Parkin ligase is provided comprising administering to a subject in need thereof an effective amount of a compound of (I), (F), (IA), (IB), (IB1), (IC), (ID), (IE), (IF), (III), (III A), (IIIB), (II) and/or (IIA), or a pharmaceutically acceptable salt thereof. .
[205] In one embodiment of the present disclosure, a method of treating a disease or a condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of (I), (G), (IA), (IB), (IB’), (IC), (ID), (IE), (IF), (III), (IIIA), (IIIB), (II) and/or (IIA), or a pharmaceutically acceptable salt thereof is provided. In some embodiments, the disease or the condition is cancer. In some embodiments, the cancer is colon cancer, lung cancer, or ovarian cancer. [206] In one embodiment of the present disclosure, a method of treating Parkinson’s Disease is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound
Figure imgf000029_0001
(II) and/or (IIA), or a pharmaceutically acceptable salt thereof.
[207] In one embodiment of the present disclosure, a method of slowing the progression of Parkinson’s Disease is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of (I), (G), (IA), (IB), (IB'), (IC), (ID), (IE), (IF), (III), (III A), (IIIB), (II) and/or (IIA), or a pharmaceutically acceptable salt thereof.
[208] In one embodiment of the present disclosure, a method of restoring dopamine neuronal balance in a subject in need thereof is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of (I), (I'), (I A), (IB), (IB'), (IC), (ID), (IE), (IF), (III), (IPA), (IIIB), (II) and/or (IIA), or a pharmaceutically acceptable salt thereof
[209] In one embodiment of the present disclosure, a method of delaying or preventing dopamine neuron loss in a subject in need thereof is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of (I), (G), (IA), (IB), (IB'), (IC), (ID), (IE), (IF), (III), (III A), (IIIB), (II) and/or (IIA), or a pharmaceutically acceptable salt thereof.
[210] In one embodiment of the present disclosure, a method of increasing mitophagy of damaged mitochondria m a subject in need thereof is provided, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of (I), (G), (IA), (IB), (IB1), (IC), (ID), (IE), (IF), (III), (1IIA), (IIIB), (II) and/or (IIA), or a pharmaceutically acceptable salt thereof.
[211] In one embodiment of any one of the methods disclosed herein, the compound is Compound 42 or a pharmaceutically acceptable salt thereof. In one embodiment of any one of the methods disclosed herein,
[212] In one embodiment of any one of the methods disclosed herein, a compound selected from Table 1 , 2, 3A and/or 3B is administered to a subject in need thereof In another
embodiment of the methods disclosed herein.
Figure imgf000029_0002
a pharmaceutically acceptable salt thereof is administered to a subject in need thereof. [213] In some embodiments of any one of the methods disclosed herein, a compound selected from Tables A and C are excluded.
BRIEF DESCRIPTION OF THE FIGURES
[214] Figure 1 shows a Xenograft study testing Compound 42 efficacy to delay subcutaneous HCT-116 tumor growth. Compound 42, Compound F or control were administered daily (IP). Group 1 = Vehicle Control, Group 2 = Compound F (25 mg/kg). Group 3 = Compound 42 (1 mg/kg), Group 4 = Compound 42 (5 mg/kg)
[215] Figure 2 shows the % inhibition of cancer cell line proliferation with Compound 42
[216] Figure 3 shows mean plasma concentration of Compound 42 in mice after IV, IP, and PC) administration.
[217] Figure 4 show's mitophagy by Compound 42 treated with CCCP (carbonyl cyanide m- chloroph eny 1 hy drazine) .
DETAILED DESCRIPTION
[218] All publications, patents and patent applications, including any drawings and appendices therein are incorporated by reference in their entirety for all purposes to the same extent as if each indi vidual publication, patent or patent application, drawing, or appendix was specifically and individually indicated to be incorporated by reference in its entirety for all purposes.
DEFINITIONS
[219] While the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to facilitate explanation of the presently disclosed subject matter
[220] Throughout the present specification, the terms‘about” and/or“approximately” may be used in conjunction with numerical values and/or ranges. The term“about” is understood to mean those values near to a recited value. For example,“about 40 [units]” may mean within ± 25% of 40 (e.g., from 30 to 50), within ± 20%, ± 15%, ± 10%, ± 9%, ± 8%, ± 7%, ± 6%, ± 5%, ± 4%, ± 3%, ± 2%, ± 1%, less than ± 1 %, or any other value or range of values therein or therebelowi Furthermore, the phrases“less than about [a value]” or“greater than about [a value]” should be understood in view of the definition of the term“about” provided herein. The terms“about” and“approximately” may be used interchangeably. [221] Throughout the present specification, numerical ranges are provided for certain quantities. It is to be understood that these ranges comprise all subranges therein. Thus, the range“from 50 to 80” includes all possible ranges therein (e.g., 51-79, 52-78, 53-77, 54-76, 55-75, 60-70, etc.). Furthermore, all values within a given range may be an endpoint for the range encompassed thereby (e.g., the range 50-80 includes the ranges with endpoints such as 55-80, 50-75, etc.).
[222] The term“a” or“an” refers to one or more of that entity7; for example,“a kinase inhibitor” refers to one or more kinase inhibitors or at least one kinase inhibitor. As such, the terms“a” (or“an”). “one or more” and“at least one” are used interchangeably herein. In addition, reference to“an inhibitor” by the indefinite article“a” or“an” does not exclude the possibility that more than one of the inhibitors is present, unless the context clearly requires that there is one and only one of the inhibitors.
[223] As used herein, the verb“comprise” as is used in this description and in the claims and its conjugations are used in its non-limiting sense to mean that items following the word are included, but items not specifically mentioned are not excluded. The present invention may suitably“comprise”,“consist of’, or“consist essentially of’, the steps, elements, and/or reagents described in the claims.
[224] 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 connection with the recitation of claim elements, or the use of a "negative" limitation.
[225] The term“pharmaceutically acceptable salts” include those obtained by reacting the active compound functioning as a base, with an inorganic or organic acid to form a salt, for example, salts of hydrochloric acid, sulfuric acid, phosphoric acid, methanesuifonic acid, camphorsulfonic acid, oxalic acid, maleic acid, succinic acid, citric acid, formic acid, hydrobromic acid, benzoic acid, tartaric acid, fumaric acid, salicylic acid, mandelic acid, carbonic acid, etc. Those skilled in the aid will further recognize that acid addition salts may be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
[226] The term "treating" means one or more of relieving, alleviating, delaying, reducing, reversing, improving, or managing at least one symptom of a condition in a subject. The term "treating" may also mean one or more of arresting, delaying the onset (i.e., the period prior to clinical manifestation of the condition) or reducing the risk of developing or worsening a condition. [227] An "effective amount" means the amount of a formulation according to the invention that, when administered to a patient for treating a state, disorder or condition is sufficient to effect such treatment. The "effective amount" will vary' depending on the active ingredient, the state, disorder, or condition to be treated and its severity', and the age, weight, physical condition and responsiveness of the mammal to be treated.
[228] The term "therapeutically effective" applied to dose or amount refers to that quantity of a compound or pharmaceutical formulation that is sufficient to result in a desired clinical benefit after administration to a patient in need thereof.
[229] All weight percentages (i.e., "% by weight" and "wt. %" and w/w) referenced herein, unless otherwise indicated, are measured relative to the total weight of the pharmaceutical composition.
[230] As used herein, "substantially" or "substantial" refers to the complete or nearly complete extent or degree of an action, characteristic, properly, state, structure, item, or result. For example, an object that is "substantially" enclosed would mean that the object is either completely enclosed or nearly completely enclosed. The exact allowable degree of deviation from absolute completeness may in some cases depend on the specific context. However, generally speaking, the nearness of completion will be so as to have the same overall result as if absolute and total completion were obtained. The use of "substantially" is equally applicable when used in a negative connotation to refer to the complete or near complete lack of action, characteristic, property, state, structure, item, or result. For example, a composition that is "substantially free of' other active agents would either completely lack other active agents, or so nearly completely lack other active agents that the effect would be the same as if it completely lacked other active agents. In other words, a composition that is "substantially free of an ingredient or element or another active agent may still contain such an item as long as there is no measurable effect thereof
[231] As used herein, the“alignment” of two or more protem/amino acid sequences may be performed using the alignment program ClustalW2, available at wwwvebi. ac.uk/Toois/insa' elustalw2/. The following default parameters may be used for Pairwise alignment: Protein Weight Matrix = Gonnet; Gap Open = 10; Gap Extension = 0.1.
[232] “Ubiquitin Proteasorne Pathway System (UPS)” as used herein relates to the ubiquitin proteasome pathway, conserved from yeast to mammals, and is required for the targeted degradation of most short-lived proteins in the eukaryotic cell. Targets include cell cycle regulator ' proteins, whose timely destruction is vital for controlled cell division, as well as proteins unable to fold properly within the endoplasmic reticulum. Ubiquitin modification is an ATP-dependent process carried out by three classes of enzymes. An“ubiquitin activating enzyme” (El) forms athio-ester bond with ubiquitin, a highly conserved 76-amino acid protein. This reaction allows subsequent binding of ubiquitin to a '‘ubiquitin conjugating enzyme” (E2), followed by the formation of an isopeptide bond between the carboxy-terminus of ubiquitin and a lysine residue on the substrate protein. The latter reaction requires a“ubiquitin ligase” (E3). E3 ligases can be single- or multi-subunit enzymes. In some cases, the ubiquitin-binding and substrate binding domains reside on separate polypeptides brought together by adaptor proteins or culling. Numerous E3 ligases provide specificity in that each can modify only a subset of substrate proteins. Further specificity is achieved by post-translational modification of substrate proteins, including, but not limited to, phosphorylation. Effects of mono ubiquitination include changes in subcellular localization. However, multiple ubiquitination cycles resulting in a polyubiquitin chain are required for targeting a protein to the proteasome for degradation. The multisubunit 26S proteasome recognizes, unfolds, and degrades polyubiquitinated substrates into small peptides. The reaction occurs within the cylindrical core of the proteasome complex, and peptide bond hydrolysis employs a core threonine residue as the catalytic nucleophile. It has been shown that an additional layer of complexity, in the form of multiubiquitin chain receptors, may lie between the poly ubiquitination and degradation steps. These receptors react with a subset of polyubiquitinated substrates, aiding in their recognition by the 26S proteasome, and thereby promoting their degradation. This pathway is not only important in cellular homeostasis, but also in human disease. Because ubiquitin/proteasome-dependent degradation is often employed in control of the cell division cycle and cell growth, researchers have found that proteasome inhibitors hold some promise of being dev eloped into potential cancer therapeutic agents.
[233] Protein degradation through the ubiquitin-proteasome system is the major pathway of non-lysosomal proteolysis of intracellular proteins. It plays important roles m a variety7 of fundamental cellular processes such as regulation of cell cycle progression, division, development and differentiation, apoptosis, cell traffi cking, and modulation of the immune and inflammatory responses. The central element of this system is the covalent linkage of ubiquitin to targeted proteins, which are then recognized by the 26S proteasome, an adenosine triphosphate-dependent, multi-catalytic protease. Damaged, oxidized, or misfolded proteins as well as regulatory proteins that control many critical cellular functions are among the targets of this degradation process. Aberration of this system leads to the dysregulation of cellular homeostasis and the development of multiple diseases (Wang et al. Cell Mol Immunol. 2006 Aug; 3 (4) : 255-61). [234] ‘‘Parkin ligase” or“Parkin” as used herein relates to a protein which in humans is encoded by the PARK2 gene. ( Kitada T, Asakawa S, Hattori N, Maisumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N ( April 1998). "Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism". Nature 392 (6676): 605-608. doi: 10.1038/33416. PMID 9560156. Matsumine H, Yamamura Y, Hattori N, Kobayashi T, Kitada T, Yoritaka A, Mizuno Y (April 1998). "A microdeletion of D6S305 in a family of autosomal recessive juvenile parkinsonism (PARK2)". Genomics 49 (1): 143-146. doi: l0.1006/geno.1997.5196. PMID 9570960. The protein is a component of a multiprotein E3 ubiquitin ligase complex which in turn is part of the ubiquitin-proteasome system that mediates the targeting of proteins for degradation. Mutations in the PARK2 gene are known to cause a familial form of Parkinson's disease known as autosomal recessive j uvenile Parkinson's disease (AR-JP).
[235] “Ligase” as used herein, is an enzyme that can catalyze the joining of two or more compounds or biomolecules by bonding them together with a new chemical bond. The “ligation” of the two usually with accompanying hydrolysis of a small chemical group dependent to one of the larger compounds or biomolecules, or the enzyme catalyzing the linking together of two compounds, e.g., enzymes that catalyze joining of groups C-O, OS, C- N, etc. Ubiquitin-protein (E3) ligases are a large family of highly di verse enzymes selecting proteins for ubiquitination.
[236] “Ub Ligases” are involved in disease pathogenesis for oncology, inflammation & infectious disease. E3 ligase belonging to the RING-between-RTNG (RBR) family of E3 ligases containing both canonical RING domains and a catalytic cysteine residue usually restricted to HECT E3 ligases; termed‘RING/TIECT hybrid' enzymes. Mutations in Parkin linked to Parkinson’s disease, cancer and mycobacterial infection. Parkin is recognized as a neuroprotective protein with a role in mitochondrial integrity. Human genetic data implicate loss of Parkin activity as a mechanism for pathogenesis of Parkinson’s disease (PD).
[237] “Zinc Finger (ZnF) Domain” as used herein relates to a protein structure characterized by coordinating zinc ions to stabilize the functional activity. ZnF stabilize the binding of Ub, Deubiquitinating Enzymes (DUBs), and Ligases (E3) in the UPS.
[238] “Ligands” as used herein bind to metal via one or more atoms in the ligand, and are often termed as chelating ligands. A ligand that binds through two sites is classified as bidentate, and three sites as tridentate. The "bite angle" refers to the angle between the two bonds of a bidentate chelate. Chelating ligands are commonly formed by linking donor groups via organic linkers. A classic bidentate ligand is ethylenedi amine, which is derived by the
J2 linking of two ammonia groups with an ethylene (-CH2CH2-) linker. A classic example of a polydentate ligand is the hexadentate chelating agent EDTA, which is able to bond through six sites, completely surrounding some metals. The binding affinity of a chelating system depends on the chelating angle or bite angle. Many ligands are capable of binding metal ions through multiple sites, usually because the ligands have lone pairs on more than one atom. Some ligands can bond to a metal center through the same atom but with a different number of lone pairs. The bond order of the metal ligand bond can be in part distinguished through the metal ligand bond angle (M-X-R). This bond angle is often referred to as being linear or bent with further discussion concerning the degree to which the angle is bent. For example, an imido ligand in the ionic form has three lone pairs. One lone pair is used as a sigma X donor, the other two lone pairs are available as L type pi donors. If both lone pairs are used in pi bonds then the M- N-R geometry is linear. However, if one or both of these lone pairs are non-bonding then the M-N-R bond is bent and the extent of the bend speaks to how much pi bonding there may be. It was found that few heteroatoms, such as nitrogen, oxygen, and sulfur atoms, interacted with zinc, ideal distances between the zinc and these heteroatoms were identified. Whereas carboxyl ales bound to the zinc via both rnonodentate and bi den late interactions, the hydroxamates bound dominantly in a bi dentate manner. These results aid in the design of new inhibitors with the potential to interact with zinc in the target protein. Virtually every molecule and ever' ion can serve as a ligand for (or "coordinate to") metals. Monodentate ligands include virtually all anions and all simple Lewis bases. Thus, the halides and pseudohalides are important anionic ligands whereas ammonia, carbon monoxide, and water are particularly common charge-neutral ligands. Simple organic species are also very common, be they anionic (RO and RCCh-) or neutral (R2O, R2S, R3 XNHX, and R3P). Complexes of polydentate ligands are called chelate complexes. They tend to be more stable than complexes derived fro monodentate ligands. This enhanced stability , the chelate effect, is usually attributed to effects of entropy, which favors the displacement of many ligands by one polydentate ligand. When the chelating ligand forms a large ring that at least partially surrounds the central atom and bonds to it, leaving the central atom at the center of a large ring. The more rigid and the higher its denticity, the more inert will be the macrocyciic complex.
[239] “Chelator” as used herein relates to a binding agent that suppresses chemical activity by forming a chelate (a coordination compound in which a metal ato or ion is bound to a ligand at two or more points on the ligand, so as to form, for example, a heterocyclic ring containing a metal atom).
00 [240] ‘‘Chelation” as used herein relates to a parti cul ar way that ions and molecul es bind metal ions. According to the International Union of Pure and Applied Chemistry (IUPAC), chelation involves the formation or presence of two or more separate coordinate bonds between a poly dentate (multiple bonded) ligand and a single central atom. Usually these ligands are organic compounds, and are called chelants, chelators, chelating agents, or sequestering agents.
[241] “Electrophile” as used herein relates to species that is attracted to an electron rich center. In chemistryg an electrophile is a reagent attracted to electrons. It participates in a chemical reaction by accepting an electron pair in order to bond to a nucleophile. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carries a partial positive charge, or have an atom that does not have an octet of electrons.
[242] The terms below, as used herein, have the following meanings, unless indicated otherwise:
[243] “Amino” refers to the -NH2 radical.
[244] “Cy ano” refers to the -CN radical.
[245] “Halo” or“halogen” refers to hromo, chloro, fluoro or iodo radical.
[246] “Hydroxy” or“hydroxyl” refers to the -OH radical.
[247] “Imrno” refers to the =NH substituent.
[248] “Nitro” refers to the -NO2 radical .
[249] “Qxo” refers to the =0 substituent.
[250] “Thioxo” refers to the =S substituent.
[251] “Alkyl” or“alkyl group” refers to a fully saturated, straight or branched hydrocarbon chain radical having from one to twelve carbon atoms, and which is attached to the rest of the molecule by a single bond. Alkyls comprising any number of carbon atoms from 1 to 12 are included. An alkyl comprising up to 12 carbon atoms is a C1-C12 alkyl, an alkyl comprising up to 10 carbon atoms is a C1-C10 alkyl, an alkyl comprising up to 6 carbon atoms is a Ci-Ce alkyl and an alkyl comprising up to 5 carbon atoms is a C1-C5 alkyl. A Ci-Cs alkyl includes C5 alkyls, C4 alkyls, C3 alkyls, C2 alkyls and Ci alkyl (i.e., methyl). A CVCe alkyl includes all moieties described above for C1-C5 alkyls but also includes Ce alkyls. A C1-C10 alkyl includes all moieties described above for C1-C5 alkyls and Ci-Ce alkyls, but also includes C7, Ce, C9 and Cio alkyls. Similarly, a C1-C12 alkyl includes all the foregoing moieties, but also includes C11 and C12 alkyls. Non-limiting examples of Ci-Ci 2 alkyl include methyl, ethyl, «-propyl, /-propyl, sec-propyl, «-butyl, /-butyl, sec-butyl, ί-butyl, «-pentyl, /-amyl, «-hexyl, n-heptyl, «-octyl, «- nonyl, w-decyl, n-undecyl, and ra-dodecyl. Unless staled otherwise specifically in the specification, an alkyl group can be optionally substituted.
[252] “Alkylene” or“alkylene chain” refers to a fully saturated, straight or branched divalent hydrocarbon chain radical, and having from one to twelve carbon atoms. Non-limiting examples of C1-C12 alkylene include methylene, ethylene, propylene, «-butylene, ethenylene, propenylene, «-butenylene, propynylene, «-butynylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkylene chain can be optionally substituted.
[253] “Alken l” or“alkenyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Each alkenyl group is attached to the rest of the molecule by a single bond. Alkenyl group comprising any number of carbon atoms from 2 to 12 are included. An alkenyl group comprising up to 12 carbon atoms is a C2-C12 alkenyl, an alkenyl comprising up to 10 carbon atoms is a C2-C10 alkenyl, an alkenyl group comprising up to 6 carbon atoms is a C2-C6 alkenyl and an alkenyl comprising up to 5 carbon atoms is a C2-C5 alkenyl. A C2-C5 alkenyl includes Cs alkenyls, Cs alkenyls, Cs alkenyls, and C2 alkenyls. A C2-C0 alkenyl includes all moieties described above for C2-C5 alkenyls but also includes C0 alkenyls. A C2-C10 alkenyl includes all moieties described above for C2-C5 alkenyls and C2-C6 alkenyls, but also includes C?, Cs, C9 and Cio alkenyls. Similarly, a C2-C12 alkenyl includes all the foregoing moieties, but also includes Cn and C12 alkenyls. Non-limiting examples of C2-C12 alkenyl include ethenyl (vinyl), 1 -propenyl, 2-propenyl (ally!), iso-propenyl, 2-methyl-l-propenyl, l-butenyl, 2-butenyl, 3- hutenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pen tenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4- hexenyl, 5-hexenyl, l-heptenyl, 2-heptenyl, 3-heptenyl, 4-heptenyl, 5-heptenyl, 6-heptenyl, 1- octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl, 7-octenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 4-nonenyl, 5-nonenyl, 6-nonenyl, 7-nonenyl, 8-nonenyl, i-decenyl, 2-decenyl, 3- decenyi, 4-deeenyl, 5-decenyl, 6-decenyl, 7-decenyl, 8-decenyl, 9-decenyl, 1 -undecenyl, 2- undecenyl, 3-undecenyl, 4-undecenyl, 5-undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, 1 -dodecenyl, 2-dodecenyl, 3-dodecenyl, 4-dodecenyl, 5- dodecenyl, 6-dodecenyl, 7-dodecenyl, 8-dodecenyl, 9-dodecenyl, 10-dodecenyl, and 11- dodecenyl. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted. [254] “Alkenylene” or “alkenylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon double bonds. Non-limiting examples of C2-C12 alkenylene include ethene, propene, butene, and the like. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkenylene chain can be optionally substituted.
[255] “Alkynyl” or“alkynyl group” refers to a straight or branched hydrocarbon chain radical having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Each alkynyl group is attached to the rest of the molecule by a single bond. Alkynyl group comprising any number of carbon atoms from 2 to 12 are included. An alkynyl group comprising up to 12 carbon atoms is a C2-C12 alkynyl, an alkynyl comprising up to 10 carbon atoms is a C2-C10 alkynyl, an alkynyl group comprising up to 6 carbon atoms is a CVCe alkynyl and an alkynyl comprising up to 5 carbon atoms is a C2-C5 alkynyl. A C2-C5 alkynyl includes Cs alkynyls, Cfi alkynyls, C3 alkynyls, and C2 alkynyls. A C2-C6 alkynyl includes all moieties described above for C2-C5 alkynyls but also includes Ce alkynyls. A C2-Cio alkynyl includes all moieties described above for C2-C5 alkynyls and C2-C6 alkynyls, but also includes CT, Cs, C9 and C 10 alkynyls. Similarly, a C2-C 12 alkynyl includes all the foregoing moieties, but also includes C11 and C12 alkynyls. Non-limiting examples of C2-C12 alkenyl include ethyny!, propynyl, butynyl, pentynyl and the like. Unless stated otherwise specifically in the specification, an alkyl group can be optionally substituted.
[256] “Alkynyl ene” or “alkynylene chain” refers to a straight or branched divalent hydrocarbon chain radical, having from two to twelve carbon atoms, and having one or more carbon-carbon triple bonds. Non-limiting examples of C2-C12 alkynylene include ethynylene, propargylene and the like. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group can be through one carbon or any two carbons within the chain. Unless stated otherwise specifically in the specification, an alkynylene chain can be optionally substituted.
[257] “Alkoxy” refers to a radical of the formula -ORa where Ra is an alkyl, alkenyl or alkny! radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, an alkoxy group can be optionally substituted. [258] “Alkylamino” refers to a radical of the formula -NHRa or -NRaRa where each Ra is, independently, an alkyl, alkenyl or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically m the specification, an alkylamino group can be optionally substituted.
[259] “Alkylcarbonyl” refers to the -C(=::0)Ra moiety, wherein Ra is an alkyl, alkenyl or alkynyl radical as defined above. A non-limiting example of an alkyl carbonyl is the methyl carbonyl (‘acetal’) moiety . Alkylcarbonyl groups can also be referred to as“Cw-Cz acyl” where w and z depicts the range of the number of carbon in Ra, as defined above. For example, “Cl-Cio acyl” refers to alkylcarbonyl group as defined above, where Ra is Ci-Cio alkyl, Ci-Cio alkenyl, or Ci-Cio alkynyl radical as defined above. Unless stated otherwise specifically in the specification, an alkyl carbonyl group can be optionally substituted.
[260] “Ary 1” refers to a hydrocarbon ring system radical comprising hydrogen, 6 to 18 carbon atoms and at least one aromatic ring. For purposes of this invention, the aryl radical can be a monocyclic, bicyclie, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems. Aryl radicals include, but are not limited to, aryl radicals derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, x-indacene, indane, indene, naphthalene, phena!ene, phenanthrene, pleiadene, pyrene, and triphenylene. Unless stated otherwise specifically m the specification, the term“aryl” is meant to include aryl radicals that are optionally substituted.
[261] “Aralkyl” or“arylalky!” refers to a radical of the formula -Rb-Rc where ¾ is an alkyl ene group as defined above and Rc is one or more aryl radicals as defined above, for example, benzyl, diphenylmethyl and the like. Unless stated otherwise specifically in the specification, an aralkyl group can be optionally substituted.
[262] “Aralkenyl” or“aryla!keny!” refers to a radical of the formula -Rb-Rc where Rt> is an alkenylene o group as defined above and Rc is one or more aryl radicals as defined above. Unless stated otherwise specifically in the specification, an aralkenyl group can be optionally substituted.
[263] “Aralkynyl” or“aiylalkynyl” refers to a radical of the formula -Rb-Rc where Rb is an alkynylene group as defined above and Rc is one or more aryl radicals as defined above. Unless stated otherwise specifically in the specification, an aralkynyl group can be optionally substituted.
[264] “Carbocyelyl,”“carbocyclic ring” or“carbocycle” refers to a rings structure, wherein the atoms which form the ring are each carbon. Carbocyclic rings can comprise from 3 to 20 carbon atoms in the ring. Carbocyclic rings include aryls and cycloalkyl cycloalkenyl and cydoalkynyl as defined herein. Unless stated otherwise specifically in the specification, a carbocyclyl group can be optionally substituted.
[265] “Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclic fully saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecul e by a single bond. Monocyclic cycloalkyl radicals include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cydoheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norhornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2. l ]heptanyl, and the like. Unless otherwise stated specifically in the specification, a cycloalkyl group can be optionally substituted.
[266] “Cycloalkenyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon double bonds, which can include fused or bridged ring systems, having from three to twenty' carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cycloalkenyl radicals include, for example, cyclopentenyl, cyclohexeny!, cycloheptenyl, cycloctenyl, and the like. Polycyclic cycloalkenyl radicals include, for example, bicycloj 2.2.1 ]hept-2-enyi and the like. Unless otherwise stated specifically in the specification, a cycloalkenyl group can be optionally substituted.
[267] “Cydoalkynyl” refers to a stable non-aromatic monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, having one or more carbon-carbon triple bonds, which can include fused or bridged ring systems, having from three to twenty carbon atoms, preferably having from three to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. Monocyclic cydoalkynyl radicals include, for example, cycloheptynyl, cyclooetynyl, and the like. Unless otherwise stated specifically in the specification, a cydoalkynyl group can be optionally substituted.
[268] “Cycloalkyl alkyl” refers to a radical of the formula -Rh-Ra where R* is an alky!ene, alkenylene, or alkynylene group as defined above and Rd is a cycloalkyl, cycloalkenyl, cydoalkynyl radical as defined above. Unless stated otherwise specifically m the specification, a cycloalky lalkyl group can be optionally substituted.
[269] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-diiluoroethyl, 3-bromo-2-fluoropropyl, 1 ,2-dibromoethyl, and the like. Unless stated otherwise specifically in the specification, a haloaikyi group can be optionally substituted.
[270] “Haloalkenyl” refers to an alkenyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., 1-fluoropropenyl, 1,1-difluorobutenyl, and the like. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted .
[271] “Haloalkynyl” refers to an alkynyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., l-fluoropropynyJ, 1-fluorobutynyl, and the like. Unless stated otherwise specifically in the specification, a haloalkenyl group can be optionally substituted.
[272] “Heterocyclyl,” “heterocyclic ring” or “heterocycle” refers to a stable 3- to 20-membered non-aromatic, partially aromatic, or aromatic ring radical which consists of two to twelve carbon atoms and from one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. Heterocyclycl or heterocyclic rings include heteroaryls as defined below. Unless stated otherwise specifically in the specification, the heterocyclyl radical can be a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heterocyclyl radical can be optionally oxidized; the nitrogen atom can be optionally quaternized; and the heterocyclyl radical can be partially or fully saturated. Examples of such heterocyclyl radicals include, but are not limited to, dioxolany!, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazoiiny!, imidazolidmyi, isothiazolidmyl, isoxazolidmyi, morpholinyl, oetahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyi, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryi, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholmyl, and 1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in the specification, a heterocyclyl group can be optionally substituted.
[273] “Heterocyclylalkyl” refers to a radical of the formula -Rb-Re where Rb is an a!ky!ene group as defined above and Re is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocycloaiky!alkyi group can he optionally substituted.
[274] “Heterocyclylalkenyl” refers to a radical of the formula ~Rb~Re where Rb is an alkenyiene group as defined above and Re is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocycloalkylalkenyl group can be optionally substituted . [275] “Heterocyclylalkynyl” refers to a radical of the formula -Rb-Re where R¾ is an alkynylene group as defined above and Rs is a heterocyclyl radical as defined above. Unless stated otherwise specifically in the specification, a heterocycloalky !aikynyl group can be optionally substituted.
[276] 'W-heierocyclyr’ refers to a heterocyclyl radical as defined above containing at least one nitrogen and where the point of attachment of the heterocyclyl radical to the rest of the molecule is through a nitrogen atom in the heterocyclyl radical. Unless stated otherwise specifically in the specification, a.Y-heterocyclyl group can be optionally substituted.
[277] “Heteroaryl” refers to a 5- to 20-rnemhered ring system radical comprising hydrogen atoms, one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, and at least one aromatic ring. For purposes of this invention, the heteroaryl radical can he a monocyclic, bicyclic, tricyclic or tetracyclic ring system, which can include fused or bridged ring systems; and the nitrogen, carbon or sulfur atoms in the heteroaryl radical can be optionally oxidized; the nitrogen atom can be optionally quatemized. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyi, benzindolyl, benzodioxolyl, benzofuranyl, henzooxazolyl, benzothiazolyi, benzothiadiazolyl, benzofb] [1 ,4]dioxepinyl, 1 ,4-benzodioxanyl, benzonaphthofuranyi, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzoihiophenyl), benzoiriazoly 1, henzo[4,6]imidazo[ 1 ,2~a]pyridinyl, carbazo!y!, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isomdoiyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyi, 1- oxidopyridinyl, 1-oxidopyrimidinyl, i-oxidopyrazinyl, 1-oxidopyridazinyl, 1 -phenyl- lif-pyrrolyl, phenazinyl, phenothiazinyl, phenoxaziny!, phtha!azinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidmyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl group can be optionally substituted.
[278] ‘ -heteroaryU refers to a heteroaryl radical as defined above containing at least one nitrogen and where the point of attachment of the heteroaryl radical to the rest of the molecule is through a nitrogen atom in the heteroaryl radical . Unless stated otherwise specifically in the specification, an L-heteroaryi group can be optionally substituted. [279] “Heteroaiylalkyl” refers to a radical of the formula -Rb-Rr where Rb is an alkylene chain as defined above and Rf is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroary!alkyl group can be optionally substituted.
[280] “Heteroaiylalkeny P’ refers to a radical of the formula -Rb-Rf where Rb is an alkenylene, chain as defined above and Rr is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkeny! group can be optionally substituted.
[281] “HeteroarylalkynyF’ refers to a radical of the formula -Rb-Rr where Rb is an alkynylene chain as defined above and Rr is a heteroaryl radical as defined above. Unless stated otherwise specifically in the specification, a heteroarylalkynyl group can be optionally substituted.
[282] “Thioalkyl” refers to a radical of the formula -SRa where Ra is an alkyl, alkenyl, or alkynyl radical as defined above containing one to twelve carbon atoms. Unless stated otherwise specifically in the specification, a thioalkyl group can be optionally substituted.
[283] The term‘"substituted” used herein means any of the above groups (/. e., alkyl, alkylene, alkenyl, alkenylene, alkynyl, alkynylene, alkoxy, alkylamino, aikylcarbonyl, thioalkyl, aryl, aralkyl, carbocyclyl, cycloalkyl, cycloalkenyl, cycloalkynyl, cydoalkylaikyl, haloalkyl, heterocyclyl, /V-heterocyclyl, heterocyclylalkyl, heteroaryl, /V-heteroaiyl and'or heteroaiydalkyl) wherein at least one hydrogen atom is replaced by a bond to a non-hydrogen atoms such as, but not limited to: a halogen atom such as F, Cl, Br, and 1; an oxygen atom in groups such as hydroxy] groups, alkoxy groups, and ester groups; a sulfur atom in groups such as thiol groups, thioalkyl groups, sulfone groups, sulfony! groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylammes, arylammes, alkyiarylamines, diarylamines, N-oxides, imides, and enamines; a silicon atom in groups such as trialky Isilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various other groups.“Substituted” also means any of the above groups in which one or more hydrogen atoms are replaced by a higher-order bond (e.g., a double- or triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups; and nitrogen in groups such as i ines, oximes, hydrazones, and nitriles. For example, “substituted” includes any of the above groups in which one or more hydrogen atoms are replaced
with -NRgRh, -NRgC(=0)Rh, -NlUCi ())\ R,Ri·. -NR,( i ())()Ri, -NRgS02Rh, -()('{ ())\ R, Rh, -ORg, -SRg, -SORg, -S02Rg, -GSChRg, -S020Rg, =NS02Rg, and -SChNRgRh.“Substituted also means any of the above groups in which one or more hydrogen atoms are replaced with -C(=O)Rg, ~C(=O)ORg, -C(=0)NRgRh, -CFUSCbRg, -CH2S02NRgRh In the foregoing, Rg and Rh are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycioalkynyl, cydoalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, iV-heterocyclyl, heterocyclylalkyl, heteroaiyl, /V-heteroaryl and/or heteroarylalkyl.“Substituted” further means any of the above groups in which one or more hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkenyl, alkynyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, cycioalkynyl, cydoalkylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclyl, iV-heterocydyl, heterocyclylalkyl, heteroaryl, Y-heteroaiyl and/or heteroaryialkyl group. In addition, each of the foregoing substituents can also be optionally substituted with one or more of the above substituents.
As used herein, the symbol“ 1 ” (hereinafter can be referred to as“a point of attachment bond”) denotes a bond that is a point of attachment between two chemical entities, one of which is depicted as being attached to the point of attachment bond and the other of
XyJL which is not depicted as being attached to the point of attachment bond. For example,“ ϊ
” indicates that the chemical entity“XY” is bonded to another chemical entity via the point of attachment bond. Furthermore, the specific point of attachment to the non-depicted chemical entity can be specified by inference. For example, the compound CH3-R3, wherein R3 is H or“
Figure imgf000044_0001
” infers that when R3 is‘‘XY”, the point of attachment bond is the same bond as the bond by which R3 is depicted as being bonded to CHs.
[285] The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed inventions, or that any publication specifically or implicitly referenced is prior art.
Compounds of the Present Disclosure
[286] The compound of the present disclosure can be useful for modulating Parkin hgase. Further, the compound of the present disclosure can be useful for treating various diseases and conditions including, but not limited to, cancer, neurological disease, a disorder characterized by abnormal accumulation of a-synuclein, a disorder of an aging process, cardiovascular disease, bacterial infection, viral infection, mitochondrial related disease, mental retardation, deafness, blindness, diabetes, obesity, autoimmune disease, glaucoma, Leber's Hereditary Optic Neuropathy, and rheumatoid arthritis.
[287] In one embodiment, the present disclosure provides compounds comprising the structure of formula (I):
Figure imgf000045_0001
[288] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[289] L3, L2 and L3 are each independently selected from a bond, alkyl ene, or alkenylene:
[29Q] M! and M2 are each independently selected from -NR4-, -NR4C(0)-, -
N(C(0)R3)~, -C(0)NR4-, -NR4C(0)NR4-, -( {())-. -C(=NR4)-, -C(=NOR4)-, -OC (OK - C(0)0-, -0C(0)0-, -0C(0)NR4-, -NR4C(0)0-, -S(0),„-, -S(Q)™NR4-, or -NR4S(0)m-, provided that M! and M2 are not both -NR4-;
[291] R1 and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, and, biphenyl, heterocyclyl heterocycloalkyl, heteroar l, eycloalkylalkyl, ary!a!kyl, andalkenyl, arylalkynyl, heterocyclylalkyl, lieteroaiydaikyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalky!, aryl, heteroaiyi, and heterocyclyl portion is optionally substituted with one or more R5;
[292] R3 is selected from an alkyl, alkenyl, cycloalkyl, and, biphenyl, heterocyclyl heterocycloalkyl, heteroaiyi, eycloalkylalkyl, arylaikyi, ary!alkenyi, arylalkynyl, heterocyclylalkyl, heieroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, a yl, heteroaiyi, and heterocyclyl portion is optionally substituted with one or more R7:
[293] R4 is each independently H, alkyl, wherein each alkyl is optionally substituted with one or more R5; [2941 R5 is each independently I, Br, Cl, F, -CFFF, -CHF2, -CFs, -OCF3, -CN, - alkyl -CN, -CONH2, -CONHR6, -CONR6R6, -COOH, -M l·. -M IR". -NO2, ~NR6R6, -Ns, - OH, OR6, -COOR6, -OSOsR6, oxo, R6, -SH, -SO2R6, -SO3H, -SQ3R6, or -SR6;
[295] R6 is each independently alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl; or alternatively two R6 on the same N atom can together form a 3-6
membered N-heterocyclyl;
[296] R7 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CFs, -OCFs, -CN, - alkyl-CN, -CONH2, -CONHR6, -CONR6R6, -COOH, -Ni l·. -NHR6, -NO2, -NR6R6, -N3, - OH, OR6, -COOR6, -OSOsR6, oxo, R6, -SH, -SO2R6, -SO3H, -SO3R6, -SR6, cycloalkyl, heterocyclyl, and, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R5;
[297] rn is 0, 1 , or 2; and
[298] wherein the compound is not N, N'-{\ -phenyl-!//-] ,2,4-triazoIe~3,5- diyl)dibenzamide, 7V-(3-benzamido- 1 -phenyl- 1 f/- 1 ,2,4-triazol-5-yl)furan-2-carboxamide, 7V-(5-cinnamamido-l-phenyl-L//-l,2,4-triazol-3-yl)benzamide, ¥-(1 -phenyl-5 -
(pheny lamino)- 1 I f- 1 ,2,4-tri az.ol -3 -y 1 )benzami de, 4-fluoro- ¥-(5 -(4-methoxy benzami do)- 1 - phenyl- \H-\, 2, 4-triazol-3-yl)benzamide,
Figure imgf000046_0001
-phenyl-lAT-l ,2,4-triazole-3,5-diyl)bis(4- methylbenzamide), V-(5-((2-chlorobenzyI)ammo)-l-phenyl-li/-l,2,4-triazol-3-yl)-2- fluorobenzamide, ¥-(3-benzamido-l-phenyl-li;/-l,2,4-triazoI-5-yi)-4-fluorobenzamide, /V-(3-benzamido- 1 -phenyl- 1 H- 1 ,2,4-triazol-5-yl)-4-nitrobenzamide, /V-(3-benzamido- 1 - phenyl- IH-l ,2,4-tnazol-5-yl)-3-nitrobenzamide, and 4-((3-benzamido- 1 -phenyl- 1 H- 1 ,2,4-triazol-5-yl)carbamoyi)benzoic acid.
[299] In one embodiment of the compound of formula (I), I,1, L2 and IF are each independently a bond.
[300] In one embodiment of the compound of formula (I), M1 and M2 are each
independently selected from -NR4-, -NR4C(0)-, -C(0)NR4-, -N(C(0)Ri)-, or -NR4S(0)m- In one embodiment, M1 and M are each independently selected from -NR4-, -NR4C(0)~ or - C(0)NR4-.
[301] In one embodiment of the compound of formula (I), -M^R1 is -NR4C(0)R!. In one embodiment of the compound of formula (I), -M R2 is -NR4C(0)R2. In one embodiment of the compound of formula (I), -JVF R1 is -NR4C(0)R1 and -M2 R2 is ~NR4C(0)R2.
[302] In one embodiment of the compound of formula (I), R4 at each occurrence is independently H or C1-C3 alkyl. [303] In one embodiment of the compound of formula (I), L3 is a bond and R3 is an aryl or a heieroaiyl, optionally substituted with one or more R7.
[304] in one embodiment of the compound of formula (I), R3 is a phenyl or phenyl fused bicycle, optionally substituted with one or more R7. In another embodiment, R3 is heieroaiyl selected from imidazolyl or pyrazolyl, optionally substituted with one or more R7.
[305] In one embodiment of the compound of formula (I), R7 is each independently I, Br,
Cl, F, -CH2F, -CHF, -CF, -OCF3, -CN, -NH2, -NMe2, -NO2, -N3, -OH, OR6, R6, -SH, cycloalkyl, heterocyciyl, aryl, or heieroaiyl, wherein each cycloalkyl, heteroc clyi, aryl, and heieroaiyl is optionally substituted with one or more R5.
[306] in one embodiment of the compound of formula (I), R3 is a phenyl substituted with a
4-6 membered heterocyciyl, which is optionally substituted with one or more R7.
[307] In one embodiment of the compound of formula (I), R1 and R2 are each independently selected from phenyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyi, phenyl-(Ci-C3 alkyl)-, phenyl-(C2-C3 alkenyl)-, 5-6 membered heteroaryl -(Ci- C3 alkyl)-, or heteroaryl-CCc-CN alkenyl)-, wherein each cycloalkyl, aryl, heteroaryl portion is optionally substituted with one or more R5. In some embodiments, the 6-10 membered aryl or
5-10 membered heteroaryl is a bi cyclic ring.
[308] In one embodiment of tire compound of formula (I), R5 is selected from I, Br, Cl, F, C1-C6 alkyl, alkynyl, -CN, -(C1-C3 alkylene)-CN, -NHz, -NO2, -Ns, -OH, -OCF3, -OMe, - NMe2, or -NEt2.
[309] In one embodiment of the compound of formula (1), at least one of R1, R2, and R3 is phenyl and substituted with at least one of methyl, ethyl, -GºCH, I, Br, Cl, F, -CF3, -CN, - CH2CN, -CH2CH2CN, -M l ·. -NO'. -Ns, -OH, -OCF3, -OMe or -NMe2. In some
embodiments, at least two of R1, R2, and R3 is phenyl and substituted with at least one of methyl, ethyl, -CºCH, I, Br, Cl, F, -CFs, -CN, -CH2CN, -CH2CH2CN, -NHa, -NO2, -Ns, -OH, -OCF3, -OMe or -NMe?. In another embodiment, at least one of R!, R2, and R3 is pyridyl, optionally substituted with one or more of methyl, ethyl, -CºCH, I, Br, Cl, F, -CF3, -CN, -
('! ! '( N. -CH2CH2CN, -NH2, -NO2, -Ns, -OH, -OCFs, -OMe or -NMe:
[310] In one embodiment, the compound of formula (I) has the structure of formula (G):
Figure imgf000047_0001
[311] or a pharmaceutically acceptable salt or solvate thereof, wherein L3, M1, M2, R1, R2, and R3 are as defined for formula (I).
[312] in one embodiment of the compound of formula i f ). M1 and M2 are each
independently selected from -NR4-, -NR4C(0)-, -C(0)NR4-, -N(C(0)R1)-, or -NR4S(0)m-.
[313] In one embodiment of the compound of formula (G), -Ml R’ is -NR4C(0)R1. In one embodiment of the compound of formula (G), ~M2 R2 is -NR4C(0)R2. In one embodiment of the compound of formula (G), -M^R1 is -NR4C’(0)R1 and -M2 R2 is -NR4C(0)R2.
[314] In one embodiment of the compound of formula (G), R! and R2 are each
independently selected from phenyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, phenyl-(Ci-C3 alkyl)-, phenyl-(C2-C3 alkenyl)-, 5-6 membered heteroaryl-(Ci-C3 alkyl)-, or heteroaryl-(C2-C3 alkenyl)-, wherein each cycloalkyl, aryl, heteroaryl portion is optionally substituted with one or more R5; and " is an aryl or a heteroaryl, optionally substituted with one or more R7.
[315] In one embodiment, the compound of formula (1) has the structure of formula (IA):
Figure imgf000048_0001
[316] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[317] M1 and M2 are each independently selected from -NR4C(0)~ or
Figure imgf000048_0002
[318] i1 and R2 are each independently
Figure imgf000048_0003
[319]
Figure imgf000048_0005
selected from
Figure imgf000048_0004
[32Q] R4 is each independently H or C1-C3 alkyl; and
[321] R73, R7b, R7e, and R7e is each independently H, I, Br, Cl, F, -CH2F, -CHF2, -
CFr, -OCF3, -Ns, -CN, -OH, methyl, ethyl, propyl, C1-C3 haloalkyl, C1-C3 alkoxy, or Ci-
C:< haloalkoxy;
[322] R7c is H, I, Br, Cl, F, -CFI2F, -CHF2, -CFs, -OCF3, -Nr, -CN, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, 4-6 membered heterocyclyl, or 5-6 membered heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one or more R5;
[323] R5 is I, Br, Cl, F, -C1 H-. -CHF 2, -CFs, -Ci-Ce alkyl, alkynyl, -CN, -(C1-C3 alkylene)-CN, -Ni l’. -NO?., -N3, -OH, -OCFs, -OMe, -NMe?, -NEt?, or -C(0)0(Ci-C6 alkyl);
[324] wherein at least one of R7a, R7b, R7c, R7e, and R7e is not H.
[325] In one embodiment of the compound of formula (1A), -JVF R1 is -NR4C(0)R1. In one embodiment of the compound of formula (IA), -M2 R2 is -NR4C(0)R2. In one embodiment of the compound of formula (IA), -M^R1 is -NR^ OjR1 and -M2 R2 is -NR4C(0)R2.
[326] in one embodiment of the compound of formula (I A), R3 is selected from R3 is
Figure imgf000049_0001
[327] in one embodiment of the compound of formul a (IA), four of R7a, R71', R/c, R7e, and R7e is H. In another embodiment, three of R7a, R7b, R7c, R7e, and R7e is H. In some
embodiments, R7a, R7b, R7c, R7e, and R7e is each independently H, I, Br, Cl, F, -CH?F, -CHF?, -CFs, -OCFS, -NS, -CN, -OH, methyl, ethyl, propyl, -CºCH; -CN, -NH?, -NO?, -Ns, -OH, - OCFs, -OMe, -NMe?, or -NEt?.
[328] In one embodiment of the compound of formula
Figure imgf000049_0002
some embodiments, R7c is I, Br, -CH?F, -CHF?, -CFs, methyl, ethyl, propyl, -CºCH; -CN, -NH?, - NO?, -N3, -OH, -OCF3, -OMe, -NMe?, or -NEt?. In other embodiments, R7c is I, Br, -CH?F, -
CHF?, -CF3, -OCF3, or -OMe. In one embodiment, R7c is azetidmyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or pyrazolyl, each optionally substituted with one or more R5.
[329] in one embodiment, the compound of formul a (I) has the structure of formula (IB):
Figure imgf000049_0003
[330] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[331] M1 and M2 are each independently selected from
Figure imgf000049_0004
-NR4C(0>- or -
C(0)NR4-; [332] R1 and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
[333] wherein one of -V R1 and -Vi’R ' is ~NR4~(cycloalkylalkyl), -NR4- (heterocyclylalkyl), -NR4-(arylalkyl), or -NR4-(heteroarylalkyl), wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
[334] R3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, ary!alkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R7;
[335] R4 is each independently H or C1-C3 alkyl;
[336] R5 is I, Br, Cl, F, -CH2F, -CHF2, -CFs, -Ci-C6 alkyl, alkynyl, -CN, -(C1-C3 alkyl ene)-CN, -NH2, -NO2, -Ns, -OH, -OCF3, -OMe, -NMe2, -NEt2, or -C(0)0(Ci-Ce alkyl); and
[337] R7 is each independently I, Br, Cl, F, -CH2F, -CHF?„ -CF3, -OCF3, -CN, - alkyl-CN, -CONH2, -CON HR ". -CONR6R6, -COOH, -NH2, -NHR6, -NO2, -NR6R6, -N3, - OH, OR6, -CQQR6, -OSO3R6, oxo, R6, -SH, -SO2R6, -SO3H, -SO3R6, -SR6, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more Rk
[338] In one embodiment of the compound of formula (IB), one of -MRR1 and -M2 R2 is - NR4-(CI~C3 alkylene)-cycloalkyl, -NR4-(CI-C3 alkylene)-heterocyclyl, -NR4-(Ci-C3 alkylene)-aryl, or -NR4-(CI-C3 alkylene)-heteroaryl; wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl is each optionally substituted with one or more R5. In some embodiments, one of -M* R! and -M2 R2 is -NR4-(CI-C3 alkylene)-phenyl, or -NR4-(CI-C3 alkylene)- pyridyl, wherein phenyl and pyridyl is each optionally substituted with one or more R5. In other embodiments, one of -VP R1 and -M2 R2 is -NR4-CH2-phenyl, -NR4-CH2CH2-phenyl, -
NR4-CH2-pyridyl, -NR4-CH2CH2-pyridyl,
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000051_0002
; wherein phenyl and pyridyl is each optionally substituted with one or more R\
[339] In one embodiment of the compound of formula (IB), -M^R1 is -NR4C(0)R1. In one embodiment of the compound of formula (IB), -M2 R2 is -NR4C(0)R2.
[340] In one embodiment of the compound of formula (IB), R1 and R2 are each
independently selected from phenyl or pyridyl, each optionally substituted with one or more R5.
[341] In one embodiment of the compound of formula (IB), one of -M! R] and -M2 R2 is - NR4-(Ci-Cs alkylene)-phenyl, or -NR4-(CI-C3 alkylenej-pyridyl, and the other one of -M3 R3 and -M R2 is -NR4C(0)-phenyi, -NR4C(0)-pyridyl, -C(0)NR4-phenyi, or -C(0)NR4-pyridyl; wherein each phenyl and pyridyl is optionally substituted with one or more Rk In some embodiments, one of -M3 R! and -M2 R2 is -NR4-(Ci-C:< alkylene)-phenyl, or -NR4-(CI-C3 alkylenej-pyridyl, wherein each phenyl and pyridyl is optionally substituted with one or more
R5, and the other one
Figure imgf000051_0003
Figure imgf000051_0004
In other embodiments, one of
Figure imgf000051_0005
and -M2 R2 is -
NR4-(C]-C3 alkylene)-phenyl, or -NR4-(Ci-Ch alkylene)-pyridyl, wherein each phenyl and pyridyl is optionally substituted with one or more R5, and the other one of -M! R] and -M2 R2
Figure imgf000052_0001
[342] In one embodiment of the compound of formul a (IB), R3 is phenyl, optionally substituted with one or more R7; and R7 is each independently I, Br, Cl, F, -CH2F, -CHF?, - CFs, -OCFS, -CN, -NS, -OH, methyl, ethyl, propyl, -C (Ί 1: -CN, -XI I w -NO?., -Ns, -OH, - OCFs, -OMe, -NMe?, or -NEt?.
[343] In one embodiment of the compound of formula (IB), R5 is selected from 1, Br, Cl, F, -CH?F, -CHF?, -CFs, -OCFs, -Ns, -CN, -OH, methyl, ethyl, propyl, -CºCH; -CN, -NH?, - NO?, -Ns, -OH, -OCFs, -OMe, -NMe?, or -NEt?.
[344] In one embodiment of the compound of formula (IB), the compound is not
Figure imgf000052_0002
345] In one embodiment, the compound of formula (I) has the structure of formula (IB'):
Figure imgf000052_0003
346] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[347] R1 is cycioalkylaikyi, heterocydyialkyl, aiylalkyl, or heteroaryl alky I, wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
[348] R2 is selected from cycloalkyl, aryl, biphenyl, heterocyclyl, or heteroaryl, wherein each optionally substituted with one or more R’;
[349] R3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyi, aiylalkyl, arylalkenyl, arylalkynyl, heterocydyialkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R7;
[350] R4 is each independently H or C1-C3 alkyl; [351 R5 is I, Br, Cl, F, -CFbF, -CHF2, -CFs, -Ci-C6 alkyl, alkynyl, -CN, -(C1-C3 alky]ene)-CN, -NH2, -NO2, -Ns, -OH, -OCF3, -OMe, -NMe2, -NEt2, or -C(0)0(Ci-Ce alkyl); and
[352] R7 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CF3, -OCFs, -CN, - alkyl-CN, -CONH2, -CON HR ". -CONR6R6, -COOH, -M b. -NHR6, -NO ·. -NR6R6, -N3, - OH, OR6, -COOR6, -OSO3R6, oxo, R6, -SH, -SO2R6, -SO3H, -SO3R6, -SR6, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, and, and heteroaryl is optionally substituted with one or more Rb
[353] In one embodiment of the compound of formula (TB'), R1 is -C1-C3 alkylene- cycloalkyl, -C1-C3 alkylene-heterocyclyl, -C1-C3 alkylene-aryl, or -C1-C3 alkylene-heteroary ; wherein cycioalkyl, aryl, heteroaryl, and heterocyclyl is each optionally substituted with one or more Rb In some embodiments, R1 is -C1-C3 alkylene-phenyl or -C1-C3 alkylene-pyridyl, wherein phenyl and pyridyl is each optionally substituted with one or more Rb In another embodiment, R1 is -CH2-phenyl, -CH2CH2-phenyl, -CH2-pyridyl, -CH2CH2-pyridyl,
Figure imgf000053_0001
; wherein phenyl and pyridyl is each optionally substituted with one or more
Figure imgf000053_0002
[354] In one embodiment of the compound of formula (IB'), R2 is aryl or 5-6 membered heteroaryl, each optionally substituted with one or more Rb In another embodiment, R2 is
phenyl optionally substituted with one or more Rb In some embodiments, R2 is
Figure imgf000053_0003
[355] In one embodiment of the compound of formula (IB'), RJ is phenyl, optionally substituted with one or more R7; and R7 is each independently I, Br, Cl, F, -CH2F, -CHF2, - CFs, -OCF3, -CN, -NJ, -OH, methyl, ethyl, propyl, -C ( 1 1; -CN, -NH2, -NO2, -Nj, -OH, - OCF3, -OMe, -NMer, or -NEt2.
[356] in one embodiment of the compound of formula (IB'), s is selected from I, Br, Cl, F, - ( i l l . -CHF2, -CFs, -OCF3, -N3, -CN, -OH, methyl, ethyl, propyl, ··( C! l; -CN, Al l·. -NO?, -N3, -OH, -OCF3, -OMe, -NMe2, or -NEt?.In one embodiment, the compound of formula (I) has the structure of formula (IC):
Figure imgf000054_0001
[357] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[358] M1 and M2 are each independently selected from -NR4-, -NR4C(0)- or - C(0)NR4-;
[359] R1 and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, and, biphenyl, heterocyclyl heterocycloalkyl, 5-6 membered heteroaiyl, cyc!oalky!alkyl, aiylalkyl, arylalkenyl, arylalkynyl, lieterocyclyialkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
[360] wherein at least one of -M^R1 and -M2 R2 is -NR4-(4-6 membered heterocyclyl), -NR4-(5-6 membered heteroaryl), or -NR4-naphthalenyl, wherein 4-6 membered heterocyclyl, 5-6 membered heteroaiyl, and naphthalenyl is each optionally substituted with one or more R5;
[361] R3 is selected phenyl, optionally substituted w ith one or more R7;
[362] R4 is each independently H or C1-C3 alkyl; and
[363] R5 and R7 are each independently selected from I, Br, Cl, F, -CH2F, -CHF?, - CF3, -C1-C6 alkyl, aikynyl, -CN, -(C1-C3 alkylene)-CN, -NH2, -NO2, -Ns, -OH, -OCF3, - OMe, -NMe?., -NEt2, or -C(0)0(Ci-Ce alkyl).
[364] In one embodiment of the compound of formula (IC), at least one of dVF R1 and -M2 R2 is -NR4-azetidinyl, -NR4~pyrrolidinyl, ~NR4~piperidinyl, -NR4-imidazolyl, -NR4- isoxazolyl, -NR4-oxazolyl, -NR4-thiazolyl, -NR4-thiophenyl, -NR4 -pyridyl, -NR4-pyridazinyl, -NR4-pyrazinyl, -NR4-pyrimidinyl, or -NR4-pyridmone, wherein each of azetidmyl, pyrrolidinyl, piperidinyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, or pyridinone is optionally substituted with one or more R5. In other embodiments, at least one of -MHl1 and -M2 R2 is -NR4 -pyridyl, wherein pyridyl is optionally substituted with one or more R5. In some embodiments, -MF R1 and -M2 R2 are each -NR4-pyridyl, wherein pyridyl is optionally substituted with one or more R3. In other embodiments, one of -M^R1 and -M2~R2 is -NR4~azetidinyl, ~NR4~pyrrolidinyl, -NR4- piperidinyl, -NR4 -imidazolyl, -NR4 -isoxazolyl, -NR4-oxazolyl, -NR4 -thiazolyl, -NR4- thiophenyl, -NR4-pyridyl, -NR4-pyridazinyl, -NR4-pyrazinyl, -NR4 -pyrimidinyl, or -NR4- pyridinone, wherein each of azetidinyl, pyrrolidinyl, piperidinyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, or pyridinone is optionally
O substituted with one or more R5, and the other one of -M1_R! and -M2 R2 is
Figure imgf000055_0001
Figure imgf000055_0002
[365] In one embodiment of the compound of formul a (IC), one of -M^R1 and -M2 R2 is- NR4-azetidinyl, -NR4-pyrrolidinyL -NR4-piperidinyl, -NR4-imidazolyl, -NR4 -isoxazolyl, -
NR4-oxazolyl, -NR4-thiazolyl, -NR4-thiophenyl, -NR4-pyridyl, -NR4-pyridazinyl, -NR4- pyrazinyl, -NR4-pyrimidinyl, or -NR4-pyridinone, wherein each of azetidinyl, pyrrolidinyl, piperidinyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, or pyridinone is optionally substituted with one or more R5, and the other one of
Figure imgf000055_0003
[366] in one embodiment of the compound of formul a (IC), -M3 R! is -NR4C(0)R1. In one embodiment of the compound of formula (IC), -M2ll2 is -NR4C(0)R2.
[367] In one embodiment of the compound of formula (IC), R5 and R7 is each selected from
I, Br, Cl, F, -CH2F, -CHF2, -CFJ, -OCFS, -Ns, -CN, -OH, methyl, ethyl, propyl, -CºCH; -CN, NH2, -NO2, -N3, -OH, -OCF3, -OMe, -NM02, or -NEt2. [368] In one embodiment of the compound of formula (IC), the compound is not
Figure imgf000056_0001
In one embodiment, the compound of formula (I) has the structure of formula (ID):
Figure imgf000056_0002
[370] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[371] M1 and M2 are each independently selected from -NR4-, -NR4C(0)- or - C(0)NR4-;
[372] R1 and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, and, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, eycloalkylalkyi, ary!a!kyi, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarydaikyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaiyi, and heterocyclyl portion is optionally substituted with one or more R1;
[373] R4 is selected from an alkyl, alkenyl, cycloalkyl, and, biphenyl, heterocyclyl heterocycloalkyl, heteroaiyi, eycloalkylalkyi, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarydaikyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R7:
[374] R4 is each independently H or C1-C3 alkyl; and
[375] R5 and R7 are each independently selected from I, Br, Cl, F, -CH2F, -CHF2, - CFs, -Ci-Cfi alkyl, aikynyl, -CN, -(C1-C3 alkylene)-CN, -NH2, -NO2, -Ns, -OH, -OCF3, - OMe, -NMe?., -NEt2, or CiO}OiCi-(\. alkyl); [376] wherein at least one of R1 and R2 is a phenyl substituted with at least one of - CºCH or -Ns.
[377] In one embodiment of the compound of formul a (ID), M1 and M2 are each -NR4C(Q)~
. In one embodiment of the compound of formula (ID), -M^R1 is -NR4C(0)R1. In one embodiment of the compound of formula (ID), -M2 R2 is -NR4C(0)R2. In one embodiment of the compound of formula (ID), -M^R1 is -NR4C(0)R1 and -M2 R2 is -NR4C(0)R2.
[378] In one embodiment of the compound of formula (ID), at least one of R1 and R2 is a phenyl substituted with at least one of -CºCH or -Ns and the other one of R! and R2 is a phenyl or pyridyl, optionally substituted with one or more R5.
[379] In one embodiment of the compound of formula (ID), R3 is phenyl optionally substituted with one or more R7.
[380] In one embodiment of the compound of formula (ID), R5 and R7 is each selected from I, Br, Cl, F, -CH2F, -CHF2, ~CF3, -OCF3, -N3, -CN, -OH, methyl, ethyl, propyl, -CºCH, -CN, -Ntb, -NO’. -N3, -OH, -0( ·!· ;. -OMe, -NMer, or -NEt2.
[381] In one embodiment, the compound of formula (I) has the structure of formula (IE):
Figure imgf000057_0001
[382] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[383] M1 and M2 are each independently selected from -NR4-, -NR4C(0)~, -C(0)NR4~ , or ~S(0)mNR4-;
[384] R1 and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkyialkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroaryl alkenyl, or heteroary!a!kyny!, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
[385] R3 is selected from an aryl or heteroaryl, wherein aryl and heteroaryl is optionally substituted with one or more R7;
[386] R4 is each independently H or Ci-Ch alkyl; and
[387] R5 and R7 are each independently selected from I, Br, Cl, F, -CH2F, -CHF2, - CF3, -Ci-Ce alkyl, alkynyl, -CN, -(C1-C3 alkyiene)-CN, -NH2, -NO2, -Ns, -OH, -OCF3, - OMe, -NMe2, -NEt2, or -C(0)0(Ci-Ce alkyl); [388] wherein when M1 and M2 are both -NR4C(())-, at least one of R1 and R2 is
Figure imgf000058_0002
[389] In one embodiment of the compound of formula (IE), M1 and M2 are both - S(0)mNR4-. In another embodiment, M1 and M2 are both -C(0)NR4-. In one embodiment of the compound of formula (IE), -M1_Rl is -NR4C(0)Rl. In one embodiment of the compound of formula (IE), -M2 R2 is -NR4C(0)R2. In one embodiment of the compound of formula (IE) -IVE R1 is -NR4C(0)R1 and -M2 R2 is -NR4C(0)R2.
[390] In one embodiment of the compound of formula (IE), at least one of R1 and R2 is a phenyl or pyridyl, optionally substituted with one or more R·1. In some embodiments, R1 and R2 is phenyl, optionally substituted with one or more R5. In other embodiments, at least one
Figure imgf000058_0001
[391] In one embodiment of the compound of formula (IE), at least one of R ; is a phenyl or pyridyl, optionally substituted with one or more R7
[392] In one embodiment of the compound of formula (IE), R3 and R7 is each selected from I, Br, Cl, F, -CH2F, -CHF?., -CFS, -OCFS, -NS, -CN, -OH, methyl, ethyl, propyl, -CºCH, -CN, -NH2, -NO ·- -N3, -OH, -on-.. -OMe, -NMez, or -NEt2. [393] In one embodiment of the compound of formula (IE), the compound is not
Figure imgf000059_0001
394] In one embodiment, the compound of formula (I) has the structure of formula (IF):
Figure imgf000059_0002
[395] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[396] M1 is selected from -NR4-, ~NR4C(0)~ or ~C(Q)NR4-;
[397] R1 and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocydyl heterocycloalkyl, 5-6 membered heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroary!alkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocydyl portion is optionally substituted with one or more R5;
[398] R' is selected from an alkyl, alkenyl, cycloalkyl, and, biphenyl, heterocydyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arydalkyl, arydalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocydyl portion is optionally substituted with one or more R7;
[399] R4 is each independently H or Ci-Cs alkyl; and
[4QQ] R5 and R7 are each independently selected from 1, Br, Cl, F, -CEbF, -CHF2, - CFi, -C1-C6 alkyl, alkynyl, -CN, -(C1-C3 alkylene)-CN, -NFI2, -NO2, -N3, -OH, -OCF3, - OMe, -NM62, -NEt2, or -C(G)0(CI~C6 alkyl).
[401] In one embodiment of the compound of formula (IF), -IVE R1 is -NR4C(0)R1.
[402] In one embodiment of the compound of formula (IF), R1 and R2 are each
independently selected from aryl or 5-6 membered heteroaryd, each optionally substituted with one or more R5. In one embodiment of the compound of formula (IF), R2 is phenyl optionally
substituted with one or more R5. In another embodiment, R2 is
Figure imgf000060_0001
[404] In one embodiment of the compound of formula (IF), R3 is cycloalkyl, aryl, heterocycly], or heteroaryl, each optionally substituted with one or more R7. In another embodiment, R3 is phenyl optionally substituted with one or more R7.
[406] In one embodiment of the compound of formula (I), (G), (IA), (IB), (IB'), (IC), (ID), (IE), or (IF), the compound is selected from Table 1 below, or a pharmaceutically acceptable salt or solvate thereof.
Figure imgf000060_0002
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
Figure imgf000069_0001
Figure imgf000070_0001
Figure imgf000071_0001
 In one embodiment, the compound of formula (
Figure imgf000072_0001
pharmaceutically acceptable salt thereof. In other embodiments, the compound of formula (I)
Figure imgf000072_0002
pharmaceutically acceptable salt thereof.
[408] In one embodi ment, the compound of the present disclosure is selected from Table 2, below, or a pharmaceutically acceptable salt or solvate thereof.
Figure imgf000072_0003
[409] In one embodiment, the compound of formula (I), excludes compounds of Table A. In one embodiment, the compound of formula (I), (G), (IA), (IB), ( IB'}. (IC), (ID), (IE), or (IF) excludes compounds of Table A.
[410] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound of any one of formula (I), (G), (IA), (IB), (IB'), (IC), (ID), (IE), or (IF). In
one embodiment, the pharmaceutical composition comprises
Figure imgf000073_0001
Figure imgf000073_0002
, pharmaceutically acceptable salt thereof.
[411] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound of Table 2. In one embodiment, the present disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier or a
pharmaceutically acceptable excipient
Figure imgf000073_0003
pharmaceutically acceptable salt thereof. In one embodiment of the pharmaceutical composition, the compounds of Table A are excluded.
[412] In one embodiment, the present disclosure provides a pharmaceutical composition as disclosed herein comprises one additional therapeutically active agent.
[413] In one embodiment, the present disclosure provides compounds comprising the structure of formula (II):
Figure imgf000073_0004
[414] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[415] M1 and M2 are each independently selected from a bond, -NR4-, or -NR4C(0) , -C(0)NR4-; [416] R1 and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyL wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
[417] wherein at least one of M1 and M2 is a bond or -NR4-;
[418] wherein when M1 is -NR4-, then R1 is cycloalkylalkyl, heterocyclylalkyl, arylalkyl, or heteroarylalkyl, wherein cycloalkyl, and, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
[419] wherein when M2 is -NR4-, then R2 is cycloalkylalkyl, heterocyclylalkyl, arylalkyl, or heteroarylalkyl, wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
[420] R4 is selected from an alkyl, alkenyl, cycloalkyl, and, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarydalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R :
[421] R4 is each independently H, alkyl, wherein each alkyl is optionally substituted with one or more R5;
[422] R5 is each independently I, Br, Cl, F, -CH2F, -P IF.·. -CF3, -OCFs, -CN, - alkyl-CN, -CONHa, -CONHR6, -CQNR6R6, -COOH, -M l ·. -NHR6, -NO2, -NR6R6, -Ns, - OH, OR6, -COOR6, -OSOsR6, oxo, R6, -SH, -SO2R6, -SOsH, -SOsR6, or -SR6;
[423] R6 is each independently alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl; or alternatively two R6 on the same N atom can together form a 3-6 membered N-heteroeyciyl; and
[424] R7 is each independently I, Br, Cl, F, -CH?.F, -CHF2, -CFs, -OCFs, -CN, - alkyl-CN, -CONH2, -CONHR6, -CONR6R6, -COOH, -M ! ·. -NHR6, -NO2, -NR6R6, -N3, - OH, OR6, -COOR6, -OSOsR6, oxo, R6, -SH, -SO2.R6, -SOsH, -SO3R6, -SR6, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, and, and heteroaryl is optionally substituted with one or more R’;
[425] wherein the compound is not /V-benzyl-7V-(5-(benzylamino)-l-phenyl-li/- l,2,4-†riazol-3-yl)acetamide, Ar-(5-((2-clilorobeiizyd)amino)-i -phenyl- Ii7- 1,2, 4-tnazol-3- yl)-2-fluorobenzamide and /V3,AP-bis(4-methylbenz}d)-l -phenyl- IH- 1 ,2, 4-triazole-3, 5- diamine. [426] In one embodiment of the compound of formula (II), at least one of -Mti R1 and -M2 R2 is -NR4-(CI-CJ alk lene)-cyc]oalkyl, -NR4-(CI-C3 alkylene)~heterocyclyl, -NR4-<Ci-C3 alkylene)-aryl, or -NR4-(CI-C3 alkylene)-heteroaryl; wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl is each optionally substituted with one or more R5.
[427] In one embodiment of the compound of formula (II), at least one of -M1_R] and -M2 R2 is -NR4-(CI-C3 alkylene)-phenyl, or -NR4-(CI~C alkyl ene)-pyridyl, wherein phenyl and pyridyl is each optionally substituted with one or more R5. In other embodiments, at least one of -IVti R1 and -M2 R2 is -NR4-CH2-phenyl, -NR4-CH2CH2-phenyl, -NR4-CH2-pyridyl, -NR4-
Figure imgf000075_0001
and pyridyl is each optionally substituted with one or more R5 In some embodiments, -M3 R! and -M2 R2 are each selected from -NR4-CH2-phenyl, -NR4-CH2CH2-phenyl, -NR4-CH2-
Figure imgf000075_0002
Figure imgf000076_0001
In one embodiment of the compound of formula (11), -IVF R1 is -NR4C(0)R!. In one embodi ent of the compound of formula (II), -M2 R2 is -NR4C(0)R2.
[429] In one embodiment of the compound of formula (II), R1 and R2 are each
independently selected from phenyl or pyndyl, each optionally substituted with one or more
[430] In one embodiment of the compound of formula (II), one of M1 and M2 is a bond.
[431] In one embodiment of the compound of formula (II), R1 and R2 are each
independently selected from phenyl or 5-6 membered heteroaryl, each optionally substituted with one or more R5. In other embodiments, R1 and R2 are each independently selected from phenyl, azetidinyl, pyrro!idinyi, piperidiny!, imidazo!y!, isoxazolyl, oxazolyl, thiazoiyl, pyndyl, pyndazinyl, pyrazmyl, pynmidinyl, pyridinoneor, or pyridine N-oxide, each optionally substituted with one or more R3.
[432] In one embodiment of the compound of formula (II), M1 is a bond and R1 is pyridyl, optionally substituted with one or more Rf
[433] In one embodiment of the compound of formula (II), M2 is a bond and R2 is pyridyl, optionally substituted with one or more R5.
[434] In one embodiment of the compound of formula (II), M1 is a bond and M2 is -NR4- or -NR4C(0)-.
[435] In one embodiment of the compound of formula (II), M2 is a bond and SVI! is -NR4- or -NR '( {())-.
[436] In one embodiment of the compound of formula (II), R3 is phenyl, optionally substituted with one or more R7; and R7 is each independently I, Br, Cl, F, -CH?.F, -CHF2, - CF3, -OCFJ, -CN, -NS, -OH, methyl, ethyl, propyl, -CºCH; -CN, -NH2, -NO2, -Ns, -OH, - OCF3, -OMe, -NM62, or -NEt2. [437] In one embodiment of the compound of formula (II), R5 and R7 are each
independently selected from I, Br, Cl, F, -CH2F, -CHF2, -CF3, -OCF3, -N3, -CN, -OH, methyl, ethyl, propyl, -CºCH; -CN, -NH2, -NO2, ~N3, -OH, -OCF3, -OMe, ~NMe2, or -NEt2.
[438] In one embodiment of tire compound of formula (II), R4 is each independently H or C1-C3 alkyl
[439] In one embodiment , the compound of formul a (P) has the structure of formula (II A) :
Figure imgf000077_0001
[440] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[441] R1 and R2 are each independently selected from an cycioalky!, aryl, biphenyl, heterocyclyl, or heteroaryl, each optionally substituted with one or more R5;
[442] R3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryi, cycloalkylalkyl, arylalkyi, arylalkenyl, aiylalkynyl, heterocydylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R7;
[443] R4 is each independently H, alkyl, wherein each alkyl is optionally substituted with one or more R3;
[444] R5 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CFs, -OCF3, -CN, - alkyl -CN. -CONH2, -CONHR6, -CONR6R6, -COOH, -M l '. M IR' . -NO2, -NR6R6, -Ns, - OH, OR6, -COOR6, -OSOsR6, oxo, R6, -SH, -SO2R6, -SOsH, -SOsR6, or -SR6;
[445] R6 is each independently alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl; or alternatively two R6 on the same N atom can together form a 3-6 membered N -heterocyclyl;
[446] R7 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CFs, -OCF3, -CN, - alkyl-CN, -COME, -CONHR6, -CONR6R6, -COOH, -M l ·. -M I ' . -NO-.. ~NR6R6, -N3, - OH, OR6, -COOR6, -OSO3R6, oxo, R6, -SH, -SO2R6, -SO3H, -SO3R6, -SR6, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R5.
[447] In one embodiment of the compound of formula (IIA), R1 is aryl, optionally substituted with one or more R5. In another embodiment, R1 is phenyl, optionally substituted with one or more R5. In some embodiments, 5 is 5-6 membered heteroaryl, optionally substituted with one or more R5. In other embodiments, R1 is pyridyl, optionally substituted with one or more R5.
[448] In one embodiment of the compound of formula (IIA), R2 is phenyl optionally
substituted with one or more R5. In some embodiments, R2 is
Figure imgf000078_0001
[449] In one embodiment of the compound of formula (IIA), R3 is cycloalky!, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more R7. In some embodiments, R3 is phenyl optionally substituted with one or more R7.
[450] In one embodiment of the compound of formula (IIA), R5 is I, Br, Cl, F, -CH2F, - C! !l x -CF3, -C1-C6 alkyl, alkynyl, -CN, -(C1-C3 alkylene)-CN, -NH?„ -NO2, -N3, -OH, - OCF3, -OMe, -NMe?., -NEte, or -C(0)0(Ci-C6 alkyl).
[451] In one embodiment of the compound of formula (IIA), R5 and R7 are each
independent!}' selected from I, Br, Cl, F, -CH2F, -CHF2, -CF3, -OCF3, -N3, -CN, -OH, methyl, ethyl, propyl, -CºCH; -CN, -NH2, -NO2, -N3, -OH, -OCF3, -OMe, -NMe?., or -NEtz.
[452] In one embodiment, the compound of formula (II) and (II A) excludes die compounds of Table C.
[453] In one embodiment of the compound of formula (II) and (IIA), the compound is selected from Table 3A below, or a pharmaceutically acceptable salt or solvate thereof.
Figure imgf000078_0002
Figure imgf000079_0001
Figure imgf000080_0001
Figure imgf000081_0002
[454] In one embodiment, the present disclosure provides compounds comprising the structure of formula (III):
Figure imgf000081_0001
455] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[456] L1, L2 and L3 are each independently selected from a bond, aikylene, or alkenylene;
[457] M1 and M are each independently selected from -NR4-, ~NR4C(Q)~, - NfC^R1)-, -C(Q)NR4-, -NR4C(0)NR4-, -C(O)-, -C(=NR4)-, -C(=NOR4)-, -OC(O)-, - C(0)()-, -0C(0)0-, -0C(0)NR4-, -NR4C(0)0-, -S(0)m-, -S(0)mNR4-, or -NR4S(0)m-, provided that M1 and M2 are not both -NR4-;
[458] R1 and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkyialkyl, arylalkyl, ary!aikenyl, arylalkynyl, heterocyclylalkyL heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
[459] R3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heteroeycly!alky!, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R7;
[460] R4 is each independently H, alkyl, wherein each alkyl is optionally substituted with one or more R5;
[461] R5 is each independently I, Br, Cl, F, -CH?.F, -CHF?, -CFs, -OCFs, -CN, - alkyl-CN, -CONH2, -CON HR ". ~CONR6R6, -COR6, -COO! I. -M l ·. -NHR6, -NO ·. - NR6R6, -NR6COR6, -(alkylene)NR6COR6, -Ns, -OH, OR6, -COOR6, -OSQ3R6, oxo, R6, - SH, -SO2R6, -SO:! I. -SO ;R". or -SR6;
[462] R6 is each independently alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl; or alternatively two R6 on the same N atom can together form a 3-6 membered N-heterocy cly! ;
[463] R7 is each independently I, Br, Cl, F, -CH2F, -CHF?, -CF , -OCF3, -CN, - alkyl-CN, -CONH2, -CONHR6, ~CONR6R6, -COOH, -NH2, -NHR6, -NO2, -NR6R6, -N3, - OH, OR6, -COOR6, -OSQ3R6, oxo, R6, -SH, -SO2R6, -SO3H, -SO3R6, -SR6, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more Ry
[464] m is 0, 1, or 2; and
[465] wherein the compound is not AyV'-(i~pheny!~lH-i,2,4~triaz.oie-3,5~ diyl)dibenzamide, 7V-(3-benzamido- 1 -phenyl- \H- 1 ,2,4-tnazol-5-yl)furan-2-carboxamide, iV-(5-cinnamamido-l-phenyl-l -l,2,4-triazol-3-yl)benzamide, 7V-(l-phenyl-5- (phenylamino)-l /7~1 ,2,4-triazol-3-yl)benzamide, 4-fluoro-/V-(5-(4-rne†hoxybenzamido)-l- pheiiyl-li/-l,2,4-tnazol-3-yl)benzamide, AyV'-(l -phenyl- IH-l, 2, 4-tn azole-3, 5-diyl)bis(4- methylbenzamide), JV-(5-((2-chlorobenzyl)amino)-l-phenyl-liif-l,2,4-triazol-3-yl)-2- fluorobenzamide, iV-(3~benzamido-1 -phenyl-1 //-l ,2,4-triazol-5-yl)-4-fluorohenzamide,/V-(3-benzamido-l-phenyl~li -l,2,4~triazol~5-yl)-4-nitrobenzamide, V-(3-benzamido-l- phenyi- lii-1 ,2,4-triazol-5-yl)-3-nitrobenzamide, and 4-((3-benzamido- 1 -phenyl- \H~
1 ,2,4-triazol-5-yl)carbamoy l)benzoic acid. [466] In one embodiment , the compound of formula (III) has the structure of formula (III A):
Figure imgf000083_0001
[467] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[468] M1 and M2 are each independently selected from -NR4-, -NR4C(0)- or - C(0)NR4-, provided that M1 and M2 are not both -NR4-;
[469] R1 and R2 are each independently phenyl, optionally substituted with one or more R5:
[470] wherein at least one of R1 or R2 is substituted with -(Ci-Ce
alkylene)NHCO(Ci-Cio alkyl) or -(Ci-Ce alkylene)N(Ci-C3 alkyl)CO(Ci-Cio alkyl);
Figure imgf000083_0002
F, -CHF?„ -CF: -Ci-Ce alkyl, alkynyl, -CN, -(C1-C3 alkylene)-CN, -NH2, -NO2, -N3, -OH, -OCFj, -OMe, -NMer, -NEt2, C(0)0(Ci-C6 alkyl), -CO(Ci-Cio alkyl), -NHCO(Ci-Cio alkyl), -N(Ci-C? alkyl)CO(Ci- C10 alkyl), -(Ci-Ce alky lene)NHCO(C 1 -C 10 alkyl), or -(Ci-Ce alkylene)N(Ci-C3 alkyl)CO(C]-Cio alkyl);
[474] R7a, R71', R7e, and R7e is each independently H, I, Br, Cl, F, -CH2F, -CHF2, - CF3, -OCF3, -N3, -CN, -OH, methyl, ethyl, propyl, C1-C3 haloalkyl, C1-C3 alkoxy, or Ci- Cs haloalkoxy; and
[475] R7c is H, I, Br, Cl, F, -CH2F, -CHF2, -CFs, -OCF3, -Ns, -CN, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, 4-6 membered heterocyclyl, or 5-6 membered heteroaiyl, wherein the heterocyclyl and heteroaryl is optionally substituted with one or more R5.
[476] In one embodiment , the compound of formula (III) has the structure of formula (MB):
Figure imgf000084_0001
[477] or a pharmaceutically acceptable salt or solvate thereof, wherein:
[478] M1 and M2 are each independently selected from -NR4-, -NR4C(0)- or - C(0)NR4-, provided that M1 and M2 are not both -NR4-;
[479] R1 and R2 are each independently phenyl, optionally substituted with one or more R":
[48Q] R3 is phenyl, substituted with one or more R7;
[481] R4 is each independently H or C3-C3 alkyl;
[482] R5 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CF3, -Ci-Ce alkyl, alkynyl, -CN, -(C1-C3 alkylene)-CN, -NH2, -NO2, -Ns, -OH, -OCFs, -OMe, -NMe2, -NEte, -C(0)0(Ci-C6 alkyl), -CO(Ci-Cio alkyl), -NHCO(Ci-Cio alkyl), -N(Ci-Cs alkyl)CO(Ci- C10 alkyl), -(Ci-Ce alkylene)NHCO(Ci-Cio alkyl), or -(Ci-Ce alkylene)N(Ci-C3 alkyl)CO(Ci-Cio alkyl); and
[483] wherein at least one R7 is heterocyciyl substituted with -CO(Ci-Cio alkyl), which is optionally further substituted with one or more R5.
[484] In some embodiment of the compounds of formula (III) and/or (PIA), at least one of R1 or R2 is substituted with -(C1-C3 alkylene)NHCO(Ci-C8 alkyl) or -(C1-C3 alkyl ene)N(Ci-Cs alkyi)CO(Ci-C8 alkyl). In some emebodiments, at least one of R5 or R2 is substituted with - CH2NHCO(CI-C8 alkyl) or -CH2N(Ci-C3 alkyl)CO(Ci-C8 alkyl).
[485] in some embodiment of the compounds of formula (III) and/or (III A), Rf is phenyl substituted with -(C1-C3 alkylene)NHCO(C]-Cs alkyl) or -(C1-C3 alkylene)N(Ci-C3 alkyl)CO(Ci-Cs alkyl). In some embodiments, R! is phenyl substituted with -CIRNHCO/Ci- Cs alkyl) or -CH2N(CI-C3 alkyl)CO(Ci-Ce alkyl). In some embodiments, R1 is phenyl substituted with CH2NHC 0(C4-C 8 alkyl) or -CH2N(CI-C3 alkyl)CO(C4-C8 alkyl).
[486] In some embodiment of the compounds of formula (III) and/or (III A), R2 is phenyl substituted with -(C1-C3 alkyleneiNHCOiCi-Cs alkyl) or -(C1-C3 alkylene)N(Ci-C3 alkyl)CO(Ci-Cg alkyl). In some embodiments, R2 is phenyl substituted with -CH2NHCO(CI- Cs alkyl) or -CH2N(Ci-C3 alkyl)CO(Ci-Cs alkyl). In some embodiments, R2 is phenyl substituted with CI FN! !('()(( i-('s alkyl) or -('I I2Nf < = -t' : alkyl)CO(C4-C8 alkyl). [487] In some embodiment of the compounds of formula (III) and/or (IIIA), R7a, R7b, R7c, R7e, and R7e is each independently H, I, Br, Cl, F, -CH2F, -CHF2, -CF3, -OCF3, -N3, -CN, -OH, methyl, ethyl, propyl, -CºCH; -CN, -NH2, -NO2, -Ns, -OH, -OCFs, -OMe, -NMe2, or -NEte. In some embodiments, R7a, R7b, R7e, and R7e is each independently H.
[488] In some embodiment of the compounds of formula (III) and/or (IIIB), R3 is phenyl, substituted with 6-membered heterocyclyl and wherein the 6-membered heterocyclyl is substituted with -COCCi-Cho alkyl). In one embodiment, R3 is phenyl substituted with a R3 is phenyl, substituted with 6-membered heterocyclyl comprising one or two heteroatoms selected from O, N, and S, and wherein the 6-membered heterocyclyl is substituted with -CO(Ci-Cio
[489] In some embodiment of the compounds of formula (III) and/or (MB), R3 is phenyl substituted with a piperidine or a piperazine, wherein the piperidine or the piperazine is substituted with -CO(Ci-Cio alkyl). In one embodiment, R3 is phenyl substituted with a piperidine or a piperazine, wherein the piperidine or the piperazine is substituted with -CO(C4- Cio alkyl).
[490] In some embodiment of the compounds of formula (III) and/or (IIIB), R’! and R are each independently phenyl, optionally substituted with one or more substitutent selected fro I, Br, Cl, F, -CHzF, -CHF2, -CF3, -OCFB, -N3, -CN, -OH, methyl, ethyl, propyl, -Cº€H; -CN, -NH2, -NO?., -Ns, -OH, -OCFs, -OMe, -NMe?., or -NEts.
[491] In one embodiment, the compound of formul a (III), excludes compounds of Table A. In one embodiment, the compound of formula (III), excludes compounds of Table B.
[492] In some embodiments, various embodiments disclosed herein for formula (I), (G), (IA), (IB), (IB1), (IC), (ID), (IE), and/or (IF) can be applied to the compounds of formula (III), (IIIA), and/or (IIIB).
[493] In one embodiment of the compounds of formula (III), (IIIA), and/or (IIIB), the compound is selected from Table 3B below, or a pharmaceutically acceptable salt or solvate thereof.
Figure imgf000086_0001
[494] In one embodiment, the compound of the invention excludes compounds in Tables A- D. In some embodiments, the compound of formula (I), (III), (G), (IA), (IB), (IB'), (IC), (ID), (IE), and (IF) excludes compounds in Table A. In some embodiments, the compound of formula (I), (III) (G), (IA), (IB), (IB'), (IC), (ID), (IE), and (IF) excludes compounds in Table
B. In other embodiments, the compound of formula (II) and (IIA) excludes compound of Table
C. In other embodiments, the compound of formula (II) and (IIA) excludes compound of Table
D.
Figure imgf000086_0002
Figure imgf000087_0001
Figure imgf000088_0001
86
Figure imgf000089_0001
f
Figure imgf000090_0001
Figure imgf000090_0002
Figure imgf000091_0001
Figure imgf000092_0001
90
Figure imgf000093_0001
Figure imgf000093_0002
91
Figure imgf000094_0001
Figure imgf000094_0002
Figure imgf000095_0001
Figure imgf000095_0002
93
Figure imgf000096_0001
[495] In another embodiment, the compounds described above may have particular functional characteristics. In one embodiment, the compound may have an oral bioavailability of about 10% to about 70% in a patient. In another embodiment, the compound may have an oral bioavailability of about 10% to about 50%. In another embodiment, the compound may have an oral bioavailability of about 10% to about 30%. In another embodiment, the compound may have an oral bioavailability greater than about 20%. In another embodiment, the compound may have an oral bioavailability in a patient with any of the ranges above when administered in the assay as in Example 6.
[496] In another embodiment, when administered orally, the compound may have a Tmax of about 0.2 hrs to about 2 hrs in a patient. In another embodiment, the compound may have a Tmax of about 0.3 hrs to about 1 hr m a patient. In another embodiment, the compound may have a Tmax of about 0.4 hrs to about 0.6 hr in a patient. In another embodiment, the compound may have a Tmax in a patient with any of the ranges above when admini stered in the assay as in Example 6.
[497] In another embodiment, when administered orally, the compound may have a Cmax of about 100 ng/'mL to about 1 ,000 ng/'niL in a patient. In another embodiment, when admini stered orally, the compound may have a Cmax of about 150 ng/mL to about 500 ng/'mL in a patient. In another embodiment, when administered orally, the compound may have a Cmax of about 200 ng/mL to about 400 ng/mL in a patient. In another embodiment, the compound may have a Cmax in a patient with any of the ranges above when administered in the assay as in Example 6
[498] In another embodiment, the compound may have a half-life in human liver microsomes greater than about 100 minutes. In another embodiment, the compound may have a half-life in human liver microsomes greater than about 300 minutes. In another embodiment, the compound may have a half-life in human liver microsomes greater than about 500 minutes. [499] In another embodiment, the compound may have half-life in human liver microsomes of about 100 minutes to about 1 ,000 minutes. In another embodiment, the compound may have half-life in human liver microsomes of about 200 minutes to about 800 minutes. In another embodiment, the compound may have half-life in human liver microsomes of about 500 minutes to about 700 minutes.
[500] In another embodiment, the compound may have a half-life in rat liver microsomes greater than about 100 minutes. In another embodiment, the compound may have a half-life in rat liver microsomes greater than about 300 minutes. In another embodiment, the compound may have a half-life in rat liver microsomes greater than about 500 minutes.
[501] In another embodiment, the compound may have half-life in rat liver microsomes of about 100 minutes to about 1,000 minutes. In another embodiment, the compound may have half-life in rat liver microsomes of about 200 minutes to about 800 minutes. In another embodiment, the compound may have half-life in rat liver microsomes of about 500 minutes to about 700 minutes.
[502] In a specific embodiment, the compound with any of the functional characteristics as described above may be a compound of formula (I), (G), (IA), (IB), (IB'), (IC), (ID), (IE), (IF), (III), (Hi A), (PIB), (II) and/or (IΊA), or a pharmaceutically acceptable salt or solvate thereof. In a specific embodiment, the compound with the functional characteristics as described above may from Table I , Table 2, Table 3A and-' or Table 3B.
Methods
[503] Ubiquitination is crucial for a plethora of physiological processes, including cell survival and differentiation and innate and adaptive immunity. Proteins are built-up to cater for the structural and biochemical requirements of the cell and they are also broken-down in a highly-regulated process serving more purposes than just destruction and space management. Proteins have different half-lives, determined by the nature of the amino acids present at their N-termini. Some will be long-lived, while other will rapidly be degraded. Proteolysis not only- enables the cell to dispose of misfolded or damaged proteins, but also to fine-tune the concentration of essential proteins within the cell, such as the proteins involved in the cell cycle. Tliis rapid, highly specific degradation can be achieved through the addition of one to several ubiquitin molecules to a target protein. The process is called ubiquitination.
[504] In recent years, considerable progress has been made in the understanding of the molecular action of ubiquitin in signaling pathways and how alterations in the ubiquitin system lead to the development of distinct human diseases it has been shown that ubiquitination plays a role in the onset and progression of cancer, metabolic syndromes, neurodegenerative diseases, autoimmunity, inflammatory disorders, infection and muscle dystrophies (Popovic et al. Nature Medicine 20, 1242-1253 (2014))
[505] Ubiquitin-protein (E3) ligases are a large family of enzymes that select various proteins for uhiquitination. These ubiquitin ligases, called“Ub ligases” are known to have a role in various diseases and conditions, including but not limited to, cancer, inflammation and infectious diseases
[506] One specific Ub ligase is Parkin iigase. Parkin ligase is a component of a multiprotein “E3” ubiquitin ligase complex, which in turn is part of the ubiquitin-proteasome system that mediates the targeting of proteins for degradation. Although the specific function of Parkin ligase is not known, mutations in Parkin ligase are linked to various diseases, such as Parkinson’s disease, cancer and mycobacterial infection. Parkin ligase is thus an attractive target for therapeutic intervention.
[507] Further, there are various known methods for regulating ligases known m the art. Many ligases, particularly ligases involved m the Uhiquitin-Proteasome Pathway System (UPS), are known to have Zinc Finger (ZnF) domains that stabilize critical protein binding regions in that ligase.
[508] ZnF domains coordinate zinc ions and this coordination stabilizes functional activity of the protein. The functional activity provided by proteins with ZnF domains can include the regulation of important cellular signaling pathways, such as recognizing ubiquitms, regulation of DNA, such as transcription and repair, and acting as cellular redox sensors. The binding of zinc to ZnF domains, or simply just regulating how zinc interacts with the ZnF domains, are essential to ligases involved in the UPS.
[509] Parkin ligase is known to have one or more ZnF domains. The present disclosure focuses on two different strategies for modulating ZnF domains in Parkin ligase. One strategy of the present disclosure includes using chelatin compounds that bind to the ZnF domains and thus disallowing the binding of zinc, or causing the dissociation of zinc, such as Zn, or Zn2+, from the ZnF domain. Another strategy' of the present disclosure includes using compounds that bind or react with a cysteine amino acid residue in the ZnF domain. One or more cysteine residues (and sometimes with the assistance of histidine residues) are essential in ZnF domains for binding to and/or coordinating to the zinc ion. The zinc ion (usually Zn2 ) can coordinate with multiple cysteine or histidine residues. The more cysteine residues there are in the domain, the more flexible is the ZnF domain Ligases, such as Parkin ligase are thought to have multiple cysteine residues coordinated with zinc in their ZnF domains. This flexibility in the ZnF domains of Parkin ligase is thought to allow the domain to he reversible, and is thus is one possible mechanism for regulating Parkin ligase. For example, efforts directed to this approach are disclosed in U.S. Patent Application No. 14,961,285; U.S. Provisional Application No. 62/237,400; U.S. Provisional Application No. 62/222,008, and U.S. Provisional Application No. 62/087,972, all of which are hereby incorporated by reference in their entirety.
[510] The present disclosure relates to the use of one or more agents or one or more compounds of formula (I), (G), (IA), (IB), (IB'), (1C), (ID), (IE), and (IF), (111), (IPA), and (IIIB), or (II) and (HA), or a pharmaceutically acceptable salt or solvate thereof, which have electrophilic, chelation or both electrophilic and chelation properties that can interact with the zinc ion and/or the cysteine residue(s) in a Parkin ligase. In one embodiment, compounds of the present disclosure modulate Parkin ligaseA activity. Specifically, without bound to any theory, it is believed that not allowing a zinc ion to coordinate in at least one of Parkin ligase’s ZnF domains induces its activity. The present disclosure is thus directed to a method for activating or modulating Parkin ligase by the chelation of Zn followed by its removal from the ZnF domain, or through electrophilic attack at the cysteine amino acid(s) that holds the Zn in place.
[511] Accordingly, in one embodiment of the present disclosure, a method of modulating or activating a Parkin ligase comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds of formula (I), (T'), (IA), (IB), (IB1), (IC), (ID), (IE), and (IF), (III), ( II I A) and (IIIB), or (II) and (PA), or a pharmaceutically acceptable salt or solvate thereof, is disclosed. In another embodiment, a method of modulating or activating a Parkin ligase comprising administering to a subject m need thereof a therapeutically effective amount of one or more compounds of formula (I), (G), (TA), (IB), (IB'), (IC), (ID), (IE), and (IF), (III), (PIA), and (IIIB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof, that disrupt at least one Parkin ligase zinc finger is disclosed. In another embodiment, a method of activating a Parkin ligase comprising administering to a subject two or more compounds that disrupt at least one Parkin ligase zinc finger is disclosed, wherein at least one of the compound is selected from a compound of formula (I), (G), (IA), (IB), (IB1), (IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof.
[512] The present disclosure relates to the use of one or more agents or one or more compounds of formula (I), (G), (IA), (IB), (IB1), (IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (IT) and (IIA), or a pharmaceutically acceptable salt or solvate thereof to promote parkin E3 ligase enzyme activity. [513] In a specific embodiment, the compounds of the present disclosure can be an electrophile or a chelator. In another embodiment, the compounds of the present disclosure can function as both an electrophile and as a chelator. For example, the compounds of the present disclosure can include multiple functional groups wherein at least one functional group has chelating properties and at least one other functional group has electrophilic properties.
[514] In another specific embodiment, the compound useful for methods in modulating or activating Parkin iigase as disclosed herein is selected from Tables 1-3, or a pharmaceutically acceptable salt or sol vate thereof.
[515] In another embodiment, the compound of the present disclosure is useful in a method to increase the Parkin iigase reaction with the Activity-based Ubiquitin vinyl su!fone probe. See e.g., Example 2.
[516] In another embodiment, the one or more compounds of the present disclosure can coordinate with a Zn ion, and/or bind or react with one or more cysteine residues. In a specific embodiment the Zn ion may be either a Znl or a Zn2+ ion. In another embodiment, the compound can coordinate to a Zn ion is a monodentate, bidentate, or tridentate ligand.
[517] In another embodiment, the compound of the present disclosure can bind and/or react with a thiol group in more than one cysteine residues. In another embodiment, the compound can bind and/or react with a thiol group m two cysteine residues. In another embodiment, the compound can hind and/or react with a thiol group in three cysteine residues. In another embodiment, the compound can bind and/or react with a thiol group m four cysteine residues. In another specific embodiment, the compound can bind or react with one or more cysteine residues in one or more domains selected from the group consisting amino acids 141 -225, amino acids 238-293, amino acids 313-377, and amino acids 418-449 of human Parkin Iigase. See http://www.uniprot.org/uniprot/O60260.
[518] The methods of the present disclosure also include activating auto-ubiquitinization of a Parkin Iigase by administering to a subject in need thereof a therapeutically effective amount of one or more compounds of formula (I), (F), (I A), (IB), (IB1), (IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof.
[519] In a specific embodiment, the one or more compounds of the present disclosure can disrupt at least one Parkin Iigase zinc finger. For example, Phospho Ubiquitin (pUB), an endogenous cellular regulator of Parkin, can be added to Parkin Iigase which can activate Parkin Iigase and its auto-ubiquitinization. In one embodiment, one or more compounds can be administered to a subject in need thereof that acts synergistically with Phospho Ubiquitin (pUB) in activating the Parkin Iigase. See, e.g., Example 3. In one embodiment, the one or more compounds that acts synergistically with pUB in activating the Parian ligase is a compound of formula (I), (F), (IA), (IB), (IB’), (IC), (ID), (IE), and (IF), (III), (PIA), and (IPB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, one or more compounds of the present disclosure can be administered with pUB to synergistically increase the activation of Parkin ligase and/or its auto-ubiquitinization.
[520] In another specific embodiment, the activation of the Parkin ligase treats or reduces the incidence of one or more diseases or ailments selected from the group consisting of Alzheimer's Dementia, Parkinson’s disease, Huntington Disease, Amyotrophic Lateral Sclerosis (ALS), Freidreich’s ataxia. Spinocerebellar Ataxia, Multiple Systems Atrophy, PSP, Tauopathy, Diffuse Lewy Body Disease, Lew Body dementia, any disorder characterized by abnormal accumulation of cx-synuclein, disorders of the aging process, stroke, bacterial infection, viral infection, Mitochondrial related disease, mental retardation, deafness, blindness, diabetes, obesity, cardiovascular disease, multiple sclerosis, Sjogrens syndrome, lupus, glaucoma, including pseudoexfoliation glaucoma, Leber's Hereditary Optic Neuropathy, and rheumatoid arthritis.
[521] In one embodiment, a method of treating Parkinson’s disease is provided, comprising administering to a subject need thereof a therapeutically effective amount of one or more compounds of formula (I), (G), (IA), (IB), (IB'), (IC), (ID), (IE), and (IF), (III), (III A), and (PIB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof
[522] Without bound to any theory, loss of dopamine neurons are believe to lead to Parkinson’s disease, which can be caused by damaged mitochondria. Damaged mitochondria leads to dopamine neuron loss across etiologies in Parkinson’s Disease patients. In a normal dopamine neurons, Parkin is activated in response to damaged mitochondria leading to their removal via mitophagy (e.g., mitochondrial autophagy).
[523] Park2 mutations are responsible for 50% of autosomal recessive early onset of Parkinson’s, thus, without bound to any theory, Parkin enzyme is believed to play a key role in maintenance of dopamine neuron health. Accordingly, restoring Parkin function can delay or prevent dopamine neuron loss.
[524] In some embodiments, the compound of formula (I), (G), (IA), (IB), (IB'), (IC), (ID),
(IE), and (IF), (III), (IIIA), and (IIIB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof delays or prevents dopamine neuron loss in a subject in need thereof, comprising administering a therapeutically effective amount of the compound to the subject. In some embodiments, the compound of formula (I), (G), (IA), (IB), (ΊB'), (IC), (ID), (IE), and
(IF), (III), (IIIA), and (IIIB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof restores dopamine neuronal balance in a subject in need thereof, comprising administering a therapeutically effective amount of the compound to the subject.
[525] In some embodiments, the compound of formula (I), i f). (IA), (IB), (IB1), (IC), (ID), (IE), and (IF), (III), (IIIA), and (MB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof slows the progression of Parkinson’s Disease in a subject in need thereof, comprising administering a therapeutically effective amount of the compound to the subject. In some embodiments, the slowing of the progression is in genetic and sporadic Parkinson’s Disease.
[526] In some embodiments, the compound of formula (I), (T'), (IA), (IB), (IB1), (IC), (ID), (IE), and (IF), (III), (IIIA), and (MB), or (II) and (HA), or a pharmaceutically acceptable salt or solvate thereof promotes removal of damaged mitochondria in a subject in need thereof, comprising administering a therapeutically effective amount of the compound to the subject.
[527] In some embodiments, the compound of formula (I), (G), (IA), (IB), (IB1), (IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (11) and (HA), or a pharmaceutically acceptable salt or solvate thereof enhances mitophagy a subject in need thereof.
[528] In a specific embodiment, the bacterial infection is Mycobacterium infection. In another specific embodiment the viral infection is HIV, Hepatitis B infection or Hepatitis C infection. Another embodiment of the present invention includes methods of treating and/or reducing the incidence of cancer, specifically comprising administering to a subject in need thereof a therapeutically effective amount of one or more compounds that disrupt at least one Parkin ligase zinc finger and induces Parkin ligase activity. In a specific embodiment, the activated Parkin ligase suppresses the growth of one or more tumors and/or prevents metastasis of one or more tumors.
[529] In another embodiment the cancer may be selected from one or more of the group consisting of Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, AIDS-Related Cancers, Kaposi Sarcoma, Lymphoma, Anal Cancer, Appendix Cancer, Astrocytomas, Childhood Atypical Teratoid/Rhabdoid Tumor, Basal Cell Carcinoma, Skin Cancer (Nonmelanoma), Childhood Bile Duct Cancer, Extraliepatic Bladder Cancer, Bone Cancer, Ewing Sarcoma Family of Tumors, Osteosarcoma and Malignant Fibrous Histiocytoma, Brain Stem Glioma, Brain Tumors, Embryonal Tumors, Germ Cell Tumors, Craniopharyngioma, Ependymoma, Bronchial Tumors, Burkitt Lymphoma (Non-Hodgkin Lymphoma), Carcinoid Tumor, Gastrointestinal Carcinoma of Unknown Primary, Cardiac (Heart) Tumors, Lymphoma, Primary, Cervical Cancer, Childhood Cancers, Chordoma, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Chronic Myeloproliferative Neoplasms Colon Cancer, Colorectal Cancer, Cutaneous T-Cell Lymphoma, Ductal Carcinoma In Situ, Endometrial Cancer, Ependymoma, Esophageal Cancer, Esthesioneuroblastoma, Ewing Sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer, Intraocular Melanoma, Retinoblastoma, Fibrous Histiocytoma of Bone, Malignant, and Osteosarcoma, Gallbladder Cancer, Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumors, Extragonadal Cancer, Ovarian Cancer, Testicular Cancer, Gestational Trophoblastic Disease, Glioma, Brain Stem Cancer, Hairy Ceil Leukemia, Head and Neck Cancer, Heart Cancer, Hepatocellular (Liver) Cancer, Histiocytosis, Langerhans Cell Cancer, Hodgkin Lymphoma, Hypopharyngeal Cancer, Intraocular Melanoma, Islet Cell Tumors, Pancreatic Neuroendocrine Tumors, Kaposi Sarcoma, Kidney Cancer, Renal Cell Cancer, Wilms Tumor and Other Childhood Kidney Tumors, Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia, Chronic Lymphocytic Cancer, Chronic Myelogenous Cancer, Hairy Cell Cancer, Lip and Oral Cavity Cancer, Liver Cancer (Primary), Lobular Carcinoma In Situ (LCIS), Lung Cancer, Non-Small Cell Cancer, Small Cell Cancer, Lymphoma, Cutaneous T-Cell (Mycosis Fungoides and Sezary Syndrome), Hodgkin Cancer, Non-Hodgkin Cancer,
Macrog!obu!inemia, Waldenstrom, Male Breast Cancer, Malignant Fibrous Histiocytoma of Bone and Osteosarcoma, Melanoma, Intraocular (Eye) Cancer, Merkel Cell Carcinoma, Mesothelioma, Malignant, Metastatic Squamous Neck Cancer with Occult Primary', Midline Tract Carcinoma Involving NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndromes, My elody splash c/My el oproliferative Neoplasms, Myelogenous Leukemia, Chronic, Myeloid Leukemia, Acute, Myeloma Multiple, Chronic Myeloproliferative Neoplasms, Nasal Cavity' and Paranasal Sinus Cancer, Nasopharyngeal Cancer,
Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Lip and Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Epithelial Cancer, Low Malignant Potential Tumor, Pancreatic Cancer, Pancreatic Neuroendocrine Tumors (Islet Cell Tumors), Papillomatosis, Paraganglioma, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, Pituitary Tumor, Plasma Cell Neoplasm/Multiple Myeloma, Pleuropulmonary Blastoma, Primary Central Nervous System Lymphoma, Rectal Cancer, Renal Cell (Kidney) Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary' Gland Cancer, Sarcoma, Ewing Cancer, Kaposi Cancer, Osteosarcoma (Bone Cancer), Soft Tissue Cancer, Uterine Cancer, Sezary· Syndrome, Skin Cancer, Childhood Melanoma, Merkel Cell Carcinoma, Nonmelanoma, Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Ceil Carcinoma, Skin Cancer (Nonmelanoma), Childhood Squamous Neck Cancer with Occult Primary, Metastatic Cancer, Stomach (Gastric) Cancer, T-Cell Lymphoma, Cutaneous Cancer, Testicular Cancer, Throat Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Unknown Primary', Carcinoma of Childhood, Unusual Cancers of Childhood, Urethral Cancer, Uterine Cancer, Endometrial Cancer, Uterine Sarcoma, Vaginal Cancer, Vulvar Cancer, Waldenstrom Macroglobulinemia, Wilms Tumor, and Women's Cancers.
[530] In a specific embodiment, the cancer is glioblastoma, small cell lung carcinoma, breast cancer and/or prostate cancer. In another embodiment, the administration of the Parkin !igase suppresses one or more tumors in the subject.
[531] In another specific embodiment, the compound eliminates damaged mitochondria, increases cell viability during cellular stress, decreases tumor transformation and/or mitigates alpha-synuclein in cells.
[532] In another embodiment, the methods of the present disclosure include treating and/or reducing the incidence of Parkinson’s disease, specifically by administering to a subject in need thereof a therapeutically effective amount of one or more compounds that disrupt at least one Parkin hgase zinc finger and induces Parkin ligase activity, wherein the compound can coordinate with a Zn ion and/or react with a thiol group in a cysteine(s). In one embodiment, the compound that disrupts at least one Parkin ligase zinc finger and incudes Parkin ligase activity' in the above mentioned method is selected from compound of formula (I), (G), (1A),
(IB), (IB ), (IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof. In another embodiment, the one or more compounds eliminate damaged mitochondria, increases cell viability during cellular stress and/or mitigates alpha-synuclein in cells.“Somatic Mutations of the Parkinson’s disease- associated gene PARK2 in glioblastoma and other human malignancies” {Nature Genetics Jan 2010 42(1)77-82). In one embodiment, the compound that eliminate damaged mitochondria, increase cell viability during cellular stress and/or mitigates alpha-synuclein in cells in the above mentioned method is a selected from compound of formula (I), (G), (IA), (IB), (IB1),
(IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof.
[533] In another embodiment, the Parkin ligase activation alters ubiquitination. Specifically, the alteration of ubiquitination is caused by the ability of Parkin to modify a substrate protein by covalent attachment of Ubiquitin, a substrate protein being Parkin itself, or another protein such as Mitofusion 1 or 2, FBW7, or other publicly reported substrates of Parkin ligase.
[534] Furth er embodiments of the present disclosure relate to meth ods of treating, preventing, or ameliorating one or more symptoms associated with neurological diseases or disorders including but not limited to Alzheimer’s Dementia, Parkinson’s disease, Huntington Disease, Amyotrophic Lateral Sclerosis (ALS), Freidreich’s ataxia, Spinocerebellar Ataxia, Multiple Systems Atrophy, PSP, Tauopathy, Diffuse Lewy Body Disease, Lewy Body dementia, any disorder characterized by abnormal accumulation of a-synuclem, disorders of the aging process, and stroke.
[535] Other embodiments of the present discl osure relate to methods of treating, preventing, or ameliorating one or more symptoms associated with hut not limited to mental retardation, deafness, blindness, diabetes, obesity, cardiovascular disease, and autoimmune diseases such as multiple sclerosis, Sjogrens syndrome, lupus, glaucoma, including pseudoexfoliation glaucoma, Leber's Hereditary Optic Neuropathy, and rheumatoid arthritis.
[536] Further embodiments of the present disclosure of the present invention relate to methods of treating, preventing, or ameliorating one or more symptoms associated with but not limited to Mitochondrial Related Diseases or Capsules as follows:
» Alpers Disease
* Barth Syndrome / LIC (Lethal Infantile Cardiomyopathy)
* Beta-oxidation Defects
* Camitme-Aeyl-Carmtine Deficiency
* Carnitine Deficiency
* Creatine Deficiency Syndromes
* Co-Enzyme Q10 Deficiency
* Complex 1 Deficiency
» Complex II Deficiency
* Complex III Deficiency
* Complex IV Deficiency / COX Deficiency
* Complex V Deficiency
* CPEO
* CPT I Deficiency
» CPT II Deficiency
* KSS
* Lactic Acidosis * LBSL - Leukodystrohpy
* LCAD
* LCHAD
» Leigh Disease or Syndrome
* Luft Disease
* MAD / Glutaric Aciduria Type II
* MCAD
* MELAS
* MERRF
* MIRAS
» Mitochondrial Cytopathy
* Mitochondrial DNA Depletion
* Mitochondrial Encephalopathy
* Mitochondrial Myopathy
* MNGIE
* NARP
* Pearson Syndrome
* Pyruvate Carboxylase Deficiency
» Pyruvate Dehydrogenase Deficiency
* POLG Mutations
* Respiratory Chain
* SCAD
* SCHAD
* VLCAD.
[537] In one embodiment, the methods of the present disclosure include treating and/or reducing the incidence of cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), (F), (I A), (IB), (IB1), (IC), (ID),
(IE), and (IF), (III), (IHA), and (IIIB), or (II) and (PA), or a pharmaceutically acceptable salt or solvate thereof The compound of the present disclosure can disrupts at least one Parkin ligase zinc finger and induces Parkin ligase activity, wherein the compound can coordinate with a zinc ion and/or bind or react with a cysteine. In a specific embodiment, the Parkin ligase suppresses the growth of one or more tumors and/or prevents metastasis of one or more tumors. In another embodiment, the compound of formula (I), (G), (IA), (IB), (IB1), (IC), (ID), (IE), and
(IF), (III), (HI A), and (IIIB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof eliminates damaged mitochondria, increases cell viability during cellular stress, decreases tumor transformation and/or mitigates alpha-synuclein in cells. In another embodiment, the cancer is glioblastoma, small cell lung carcinoma, breast cancer or prostate cancer. In another embodiment, the cancer is lymphoma. In another embodiment, the cancer is mantle cell lymphoma. In another embodiment, the cancer is colon cancer, lung cancer, and/or ovarian cancer.
[538] In a specific embodiment, the methods of the present disclosure include treating and/or reducing the incidence of Parkinson’s disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), (Is), (IA), (IB), (IB'), (IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof that disrupts at least one Parkin ligase zinc finger and induces Parkin ligase activity, wherein the compound can coordinate with a zinc ion and/or bind or react with a cysteine. In a specific embodiment, the compound of the present disclosure eliminates damaged mitochondria, increases cell viability during cellular stress and/or mitigates alpha-synuclein in cells.
[539] In one embodiment, the methods of the present disclosure excludes administration of compounds disclosed in "fable A or "fable C.
Pharmaceutical Compositions and Formulations
[540] The present disclosure also includes pharmaceutical compositions for modulating or activating a Parkin ligase in a subject. In one embodiment, a pharmaceutical composition comprises one or more compounds of formula (I), (G), (IA), (IB), (IB'), (IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, one or more compounds of formula (I), (G), (IA), (IB), (IB1), (1C), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof, in a pharmaceutical composition as described herein disrupts at least one Parkin ligase zinc finger. In another embodiment, one or more compounds of formula (I), (F), (IA), (IB), (IB’), (IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (II) and (IIA), or a pharmaceutically acceptable salt or sol vate thereof, m a pharmaceutical composition as described herein coordinates with a Zn ion, and/or react with at least one thiol group in a cysteine.
[541] In one embodiment of the present disclosure, a pharmaceutical composition comprises a therapeutically effective amounts of one or more compounds of formula (I), (G), (IA), (IB), (IB'), (IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (II) and (II A), or a pharmaceutically acceptable salt or solvate thereof.
[542] In a specific embodiment, a pharmaceutical composition, as described herein, comprises one or more compounds selected from Table 1, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, a pharmaceutical composition as described herein comprise one or more compounds selected from Table 2, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, a pharmaceutical composition as described herein comprise one or more compounds selected from Table 3A, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, a pharmaceutical composition as described herein comprise one or more compounds selected from Table 3B, or a pharmaceutically acceptable salt or solvate thereof.
[543] In one embodiment, a pharmaceutical composition described herein does not contain a compound disclosed in Table A or Table C.
[544] In one embodiment, a pharmaceutical composition, as described herein, comprising one or more compounds of formula (I), (G), (IA), (IB), (IB'), (IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (II) and (PA), or a pharmaceutically acceptable salt or solvate thereof, further comprises one or more additional therapeutically active agents. In one embodiment, one or more additional therapeutically active agents are selected from therapeutics useful for treating cancer, neurological disease, a disorder characterized by abnormal accumulation of a- synuclein, a disorder of an aging process, cardiovascular disease, bacterial infection, viral infection, mitochondrial related disease, mental retardation, deafness, blindness, diabetes, obesity, autoimmune disease, glaucoma, Leber's Hereditary Optic Neuropathy, and rheumatoid arthritis.
[545] In a further embodiment of the present disclosure, a pharmaceutical composition comprising one or more compounds of formula (I), (G), (IA), (IB), (IB'), (IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient or adjuvant is provided. The pharmaceutically acceptable excipients and adjuvants are added to the composition or formulation for a variety of purposes. In another embodiment, a pharmaceutical composition comprising one or more compounds of formula (I), (G), (IA), (IB), (IB' l, (IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (II) and (HA), or a pharmaceutically acceptable salt or solvate thereof, further comprises a pharmaceutically acceptable carrier. In one embodiment, a pharmaceutically acceptable carrier includes a pharmaceutically acceptable excipient, binder, and/or diluent. In one embodiment, suitable pharmaceutically acceptable excipients include, but are not limited to, water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone.
[546] In certain embodiments, the pharmaceutical compositions of the present disclosure may additionally contain other adjunct components conventionally found in pharmaceutical compositions, at their art-established usage levels. Thus, for example, the pharmaceutical compositions may contain additional, compatible, pharmaceuticaily-active materials such as, for example, antipruritics, astringents, local anesthetics or anti-inflammatory agents, or may contain additional materials useful in physically formulating various dosage forms of the compositions of the present invention, such as dyes, flavoring agents, preservatives, antioxidants, opacifiers, thickening agents and stabilizers. However, such materials, when added, should not unduly interfere with the biological activities of the components of the compositions of the present invention. The formulations can be sterilized and, if desired, mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously interact with the oligonucleotide(s) of the formulation.
[547] For the purposes of this disclosure, the compounds of the present disclosure can be formulated for administration by a variety of means including orally, parenterally, by inhalation spray, topically, or rectalJy in formulations containing pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used here includes subcutaneous, intravenous, intramuscular, and intraarterial injections with a variety' of infusion techniques. Intraarterial and intravenous injection as used herein includes administration through catheters.
[548] The compounds disclosed herein can be formulated in accordance with the routine procedures adapted for desired administration route. Accordingly, the compounds disclosed herein can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formu!atory agents such as suspending, stabilizing and/or dispersing agents. Tire compounds disclosed herein can also be formulated as a preparation for implantation or injection. Thus, for example, the compounds can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives (e.g., as a sparingly soluble salt). Alternatively, the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen- free water, before use. Suitable formulations for each of these methods of administration can be found, for example, in Remington: The Science and Practice of Pharmacy , A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, PA. [549] In certain embodiments, a pharmaceutical composition of the present disclosure is prepared using known techniques, including, but not limited to mixing, dissolving, granulating, dragee-makmg, levigating, emulsifying, encapsulating, entrapping or tableting processes
[550] In one embodiment, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), (G), (IA), (IB), (IB'), (IC), (ID), (IE), and (IF), (III), (IIIA), and (IΉB), or (II) and (PA), or a pharmaceutically acceptable salt or solvate thereof, as disclosed herein, combined with a pharmaceutically acceptable carrier. In one embodiment, suitable pharmaceutically acceptable carriers include, but are not limited to, inert solid fillers or diluents and sterile aqueous or organic solutions. Pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, from about 0.01 to about 0.1 M and preferably Q.05M phosphate buffer or 0.814 saline. Such pharmaceutically acceptable carriers can be aqueous or non-aqueous solutions, suspensions and emulsions. Examples of non-aqueous solvents suitable for use in the present application include, but are not limited to, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
[551] Aqueous carriers suitable for use in the present application include, but are not limited to, water, ethanol, alcoholic/aqueous solutions, glycerol, emulsions or suspensions, including saline and buffered media. Oral carriers can be elixirs, syrups, capsules, tablets and the like.
[552] Liquid earners suitable for use m the present application can be used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compounds. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic sol v ent, a mixture of both or pharmaceutically acceptable oils or fats. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
[553] Liquid carriers suitable for use in the present application include, but are not limited to, water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyi cellulose solution), alcohols (including monohydrie alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration, the carrier can also include an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are useful in sterile liquid form comprising compounds for parenteral administration. The liquid carrier for pressurized compounds disclosed herein can be halogenated hydrocarbon or other pharmaceutically acceptable propellent. [554] Solid carriers suitable for use in the present application include, but are not limited to, inert substances such as lactose, starch, glucose, methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like. A solid carrier can further include one or more substances acting as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material. In powders, the carrier can be a finely divided solid which is in admixture with the finely divided active compound. In tablets, the active compound is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active compound. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, poly vinylpyrrolidine, low melting waxes and ion exchange resins. A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing m a suitable machine the active ingredient m a free flowing form such as a powder or granules, optionally mixed with a binder (e.g., povidone, gelatin, hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (e.g., sodium starch glycolate, cross-linked povidone, cross-linked sodium carboxymethyl cellulose) surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropyl methyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
|555] Parenteral carriers suitable for use in the present application include, but are not limited to, sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils. Intravenous carriers include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose and the like. Preservatives and other additives can also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.
[556] Carriers suitable for use in the present application can be mixed as needed with dismtegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known in the art. The carriers can also be sterilized using methods that do not deleteriously react with the compounds, as is generally known in the art. [557] Diluents may be added to the formulations of the present invention. Diluents increase the hulk of a solid pharmaceutical composition and/or combination, and may make a pharmaceutical dosage form containing the composition and/or combination easier for the patient and care giver to handle. Diluents for solid compositions and-' or combinations include, for example, microcrystalline cellulose (e.g., AVICEL), microf e cellulose, lactose, starch, pregelatinized starch, calcium carbonate, calcium sulfate, sugar, dextrates, dextrin, dextrose, dibasic calcium phosphate dihydrate, tnbasic calcium phosphate, kaolin, magnesium carbonate, magnesium oxide, maltodextrin, mannitol, poly methacrylates (e.g., EUDRAGTT(r)), potassium chloride, powdered cellulose, sodium chloride, sorbitol, and talc.
[558] Additional embodiments relate to the pharmaceutical formulations wherein the formulation is selected from the group consisting of a solid, powder, liquid and a gel. In certain embodiments, a pharmaceutical composition of the present invention is a solid (e.g., a powder, tablet, a capsule, granulates, and/or aggregates). In certain of such embodiments, a solid pharmaceutical composition comprising one or more ingredients known in the art, including, but not limited to, starches, sugars, diluents, granulating agents, lubricants, binders, and disintegrating agents.
[559] Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients whose functions include helping to bind the active ingredient and other excipients together after compression. Binders for solid pharmaceutical compositions and/or combinations include acacia, alginic acid, carbomer (e.g., carbopol), carboxymethyicellulose sodium, dextrin, ethyl cellulose, gelatin, guar gum, gum tragacanth, hydrogenated vegetable oil, hydroxy ethyl cellulose, hydroxypropyl cellulose (e.g., KLUCEL), hydroxypropyl methyl cellulose (e.g., METHOCEL), liquid glucose, magnesium aluminum silicate, maltodextrin, methylcellulose, polymethacrylates, povidone (e.g., KOLLIDON, PLASDONE), pregelatinized starch, sodium alginate, and starch.
[560] The dissolution rate of a compacted solid pharmaceutical composition m the patient’s stomach may be increased by the addition of a disintegrant to the composition and/or combination. Disintegrants include alginic acid, carboxymethyicellulose calcium, carboxymethyicellulose sodium (e.g., AC-DI-SOL and PRIMELLOSE), colloidal silicon dioxide, croscarmellose sodium, crospovidone (e.g., KOLLIDON and POLYPLASDONE), guar gum, magnesium aluminum silicate, methyl cellulose, microcrystalline cellulose, polacnlin potassium powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycoiate (e.g., EXPLOTAB), potato starch, and starch. [561] Glidants can be added to impro ve the fiowahility of a non-compacted solid composition and/or combination and to improve the accuracy of dosing. Excipients that may function as glidants include colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
[562] When a dosage form such as a tablet is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition and/or combination to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate.
[563] Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition and/or combination of the present invention include rnaltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl ma!tol, and tartaric acid.
[564] Solid and liquid compositions may also be dyed using any pharmaceutically acceptable colorant to improve their appearance and/or facilitate patient identification of the product and unit dosage level.
[565] In certain embodiments, a pharmaceutical composition of the present invention is a liquid (e.g., a suspension, elixir and/or solution). In certain of such embodiments, a liquid pharmaceutical composition is prepared using ingredients known in the art, including, but not limited to, water, glycols, oils, alcohols, flavoring agents, preservatives, and coloring agents.
[566] Liquid pharmaceutical compositions can be prepared using compounds of formula (1), (!'), (IA), (IB), (IB1), (IC), (ID), (IE), and (IF), (III), (IIIA), and (MB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof, and any other solid excipients where the components are dissolved or suspended in a liquid carrier such as water, vegetable oil, alcohol, polyethylene glycol, propylene glycol, or glycerin.
[567] For example, formulations for parenteral administration can contain as common excipients sterile water or saline, po!yalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like. In particular, biocompatible, biodegradable lactide polymer, lactide/glycolide copolymer, or polyoxyethylene- poly oxy propylene copolymers can be useful excipients to control the release of active compounds. Other potentially useful parenteral delivery systems include ethylene-vinyl acetate copolymer particles, osmotic pumps, implantable infusion systems, and liposomes. Formulations for inhalation administration contain as excipients, for example, lactose, or can be aqueous solutions containing, for example, polyoxyethylene-9-auryl ether, glycocholate and deoxycholate, or oily solutions for administration in the form of nasal drops, or as a gel to be applied intranasally. Formulations for parenteral administration can also include glycocholate for buccal administration, methoxysa!icylate for rectal administration, or citric acid for vaginal administration.
[568] Liquid pharmaceutical compositions can contain emulsifying agents to disperse uniformly throughout the composition and/or combination an active ingredient or other excipient that is not soluble m the liquid carrier. Emulsifying agents that may be useful m liquid compositions and/or combinations of the present invention include, for example, gelatin, egg yolk, casein, cholesterol, acacia, tragacanth, chondrus, pectin, methyl cellulose, earbomer, cetosteaiyl alcohol, and cetyl alcohol.
[569] Liquid pharmaceutical compositions can also contain a viscosity enhancing agent to improve the mouth-feel of the product and/or coat the lining of the gastrointestinal tract. Such agents include acacia, alginic acid bentonite, earbomer, carboxymethylcellulose calcium or sodium, cetostearyl alcohol, methyl cellulose, ethylcellulose, gelatin guar gum, hydroxyethyl cellulose, hydroxypropyi cellulose, hydroxypropyl methyl cellulose, maltodextrin, polyvinyl alcohol, povidone, propylene carbonate, propylene glycol alginate, sodium alginate, sodium starch glycolate, starch tragacanth, and xanthan gum.
[570] Sweetening agents such as aspartame, lactose, sorbitol, saccharin, sodium saccharin, sucrose, aspartame, fructose, mannitol, and invert sugar may be added to improve the taste.
[571] Preservatives and chelating agents such as alcohol, sodium benzoate, butylated hydroxyl toluene, butylated hydroxyanisole, and ethylenediamine tetraacetic acid may be added at levels safe for ingestion to improve storage stability.
[572] A liquid composition can also contain a buffer such as guconic acid, lactic acid, citric acid or acetic acid, sodium guconate, sodium lactate, sodium citrate, or sodium acetate. Selection of excipients and the amounts used may be readily determined by the formulation scientist based upon experience and consideration of standard procedures and reference works in the field.
[573] In one embodiment, a pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, etc.). In certain of such embodiments, a pharmaceutical composition comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. In certain embodiments, other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives). In certain embodiments, injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like. Certain pharmaceutical compositions for injection are presented in unit dosage form, e.g., in ampoules or m multi-dose containers. Certain pharmaceutical compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, such suspensions may also contain suitable stabilizers or agents that increase the solubility of the pharmaceutical agents to allow for the preparation of highly concentrated solutions.
[574] The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentera!ly acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophiiized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in tire preparation of injectables. Formulations for intravenous administration can comprise solutions in sterile isotonic aqueous buffer. Where necessary', the formulations can also include a solubilizing agent and a local anesthetic to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophiiized powder or water free concentrate in a hermetically sealed container such as an ampule or sachet indicating the quantity' of active agent. Where the compound is to be administered by infusion, it can be dispensed in a formulation with an infusion bottle containing sterile pharmaceutical grade water, saline or dextrose/water. Where the compound is administered by injection, an ampule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
[575] Suitable formulations further include aqueous and non- aqueous sterile injection solutions that can contain antioxidants, buffers, bacteriostats, bactericidal antibiotics and solutes that render the formulation isotonic with the bodily fluids of the intended recipient; and aqueous and non-aqueous sterile suspensions, which can include suspending agents and thickening agents.
[576] In certain embodiments, a pharmaceutical composition of the present invention is formulated as a depot preparation. Certain such depot preparations are typically longer acting than non-depot preparations. In certain embodiments, such preparations are administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. In certain embodiments, depot preparations are prepared using suitable polymeric or hydrophobic materials (for example an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
[577] In certain embodiments, a pharmaceutical composition of the present invention comprises a delivery system. Examples of deliver' systems include, but are not limited to, liposomes and emulsions. Certain deliver systems are useful for preparing certain pharmaceutical compositions including those comprising hydrophobic compounds. In certain embodiments, certain organic solvents such as dimethylsulfoxide are used.
[578] In certain embodiments, a pharmaceutical composition of the present invention comprises a co-solvent system. Certain of such co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. In certain embodiments, such co-solvent systems are used for hydrophobic compounds. A non limiting example of such a co-solvent system is the VPD co-solvent system, which is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80 and 65% w/v polyethylene glycol 300. The proportions of such co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics. Furthermore, the identity' of co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
[579] In certain embodiments, a pharmaceutical composition of the present invention comprises a sustained-release system A non-limiting example of such a sustained-release system is a semi-permeable matrix of solid hydrophobic polymers. In certain embodiments, sustained-release systems may, depending on their chemical nature, release pharmaceutical agents over a period of hours, days, weeks or months. [580] Appropriate pharmaceutical compositions of the present disclosure can he determined according to any clinically-acceptable route of administration of the composition to the subject. The manner in which the composition is administered is dependent, in part, upon the cause and/or location. One skilled in the art will recognize the advantages of certain routes of administration. The method includes administering an effective amount of the agent or compound (or composition comprising the agent or compound) to achieve a desired biological response, e.g., an amount effective to alleviate, ameliorate, or prevent, in whole or in part, a symptom of a condition to be treated, e.g., oncology and neurology disorders. In various aspects, the route of administration is systemic, e.g., oral or by injection. The agents or compounds, or pharmaceutically acceptable salts or derivatives thereof, are administered orally, nasally, transdermal!y, pulmonary, inhalationally, buccally, sublingually, intraperintoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, intraportal !y, and parenteral!y. Alternatively or in addition, the route of administration is local, e.g., topical, intra-tumor and peri-tumor. In some embodiments, the compound is administered orally.
[581] In certain embodiments, a pharmaceutical composition of the present disclosure is prepared for oral administration. In certain of such embodiments, a pharmaceutical composition is formulated by combining one or more agents and pharmaceutically acceptable carriers. Certain of such carriers enable pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject. Suitable excipients include, but are not limited to, fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). In certain embodiments, such a mixture is optionally ground and auxiliaries are optionally added. In certain embodiments, pharmaceutical compositions are formed to obtain tablets or dragee cores. In certain embodiments, disintegrating agents (e.g., cross-linked polyvinyl pyrrolidone, agar, or algimc acid or a salt thereof, such as sodium alginate) are added.
[582] In certain embodiments, dragee cores are provided with coatings. In certain such embodiments, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to tablets or dragee coatings. [583] In certain embodiments, pharmaceutical compositions for oral administration are push- fit capsules made of gelatin. Certain of such push-fit capsules comprise one or more pharmaceutical agents of the present invention in admixture with one or more filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In certain embodiments, pharmaceutical compositions for oral administration are soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. In certain soft capsules, one or more pharmaceutical agents of the present invention are be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added.
[584] In certain embodiments, pharmaceutical compositions are prepared for buccal administration. Certain of s uch pharmaceutical compositions are tablets or lozenges formulated in conventional manner.
[585] In certain embodiments, a pharmaceutical composition is prepared for transmucosal administration. In certain of such embodiments penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
[586] In certain embodiments, a pharmaceutical composition is prepared for administration by inhalation. Certain of such pharmaceutical compositions for inhalation are prepared the form of an aerosol spray in a pressurized pack or a nebulizer. Certain of such pharmaceutical compositions comprise a propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In certain embodiments using a pressurized aerosol, the dosage unit may be determined with a valve that delivers a metered amount. In certain embodiments, capsules and cartridges for use in an inhaler or insufflator may be formulated. Certain of such formulations comprise a powder mixture of a pharmaceutical agent of the invention and a suitable powder base such as lactose or starch.
[587] In other embodiments the compound of the present disclosure are administered by the intravenous route. In further embodiments, the parenteral administration may be provided in a bolus or by infusion.
[588] In certain embodiments, a pharmaceutical composition is prepared for rectal administration, such as a suppository or retention enema. Certain of such pharmaceutical compositions comprise known ingredients, such as cocoa butter and/or other glycerides.
[589] In certain embodiments, a pharmaceutical composition is prepared for topical administration. Certain of such pharmaceutical compositions comprise bland moisturizing bases, such as ointments or creams. Exemplary' suitable ointment bases include, but are not limited to, petrolatum, petrolatum plus volatile silicones, and lanolin and water in oil emulsions. Exemplary suitable cream bases include, but are not limited to, cold cream and hydrophilic ointment
[590] in certain embodiments, the therapeutically effective amount is sufficient to prevent, alleviate or ameliorate symptoms of a disease or to prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art
[591] In certain embodiments, one or more compounds of formula (I), (G), (1A), (IB), (IB'), (IC), (ID), (IE), and (IF), (III), (ΪΪIA), and (HIB), or (II) and (DA), or a pharmaceutically acceptable salt or solvate thereof are formulated as a prodrug. In certain embodiments, upon in vivo administration, a prodrug is chemically converted to the biologically, pharmaceutically or therapeutically more active form. In certain embodiments, prodrugs are useful because they are easier to administer than the corresponding active form. For example, in certain instances, a prodrug may be more bioavailable (e.g., through oral administration) than is the corresponding active form. In certain instances, a prodrug may have improved solubility' compared to the corresponding active form. In certain embodiments, prodrugs are less water soluble than the corresponding active form. In certain instances, such prodrugs possess superior transmittal across cell membranes, where water solubility is detrimental to mobility'. In certain embodiments, a prodrug is an ester. In certain such embodiments, the ester is metabolically hydrolyzed to carboxylic acid upon administration. In certain instances the carboxylic acid containing compound is the corresponding active form. In certain embodiments, a prodrug comprises a short peptide (polyaminoaeid) bound to an acid group. In certain of such embodiments, the peptide is cleaved upon administration to form the corresponding active form
[592] In certain embodiments, a prodrug is produced by modifying a pharmaceutically active compound such that tire active compound will be regenerated upon in vivo administration. The prodrug can be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity', to improve the flavor of a drug or to alter other characteristics or properties of a drag. By virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, those of skill in this art, once a pharmaceutically active compound is known, can design prodrugs of the compound (see, e.g., Nogrady (1985) Medicinal Chemistry' A Biochemical Approach, Oxford University' Press, New York, pages 388-392).
[593] In various aspects, the amount of the compound of formula (I), (G), (IA), (IB), (IB1), (IC), (ID), (IE), and (IF), (III), (IIIA), and (IIIB), or (II) and (IIA), or a pharmaceutically acceptable salt or solvate thereof, or compounds disclosed in Tables 1, 2, 3.4 and/or 3B, or a pharmaceutically acceptable salt or solvate thereof, can be administered at about 0.001 mg/kg to about 100 mg/kg body weight (e.g., about 0.0! mg/kg to about 10 mg/kg or about 0.1 mg/kg to about 5 mg/kg).
[594] The concentration of a disclosed compound in a pharmaceutically acceptable mixture will vary depending on several factors, including the dosage of the compound to be administered, the pharmacokinetic characteristics of the compound(s) employed, and the route of administration. The agent may be administered in a single dose or in repeat doses. The dosage regimen utilizing the compounds of the present invention is selected m accordance with a variety7 of factors including type, species, age, weight, sex and medical condition of the patient; the severity of the condition to be treated; the route of administration; the renal and hepatic function of the patient; and the particular compound or salt thereof employed. Treatments may be administered daily or more frequently depending upon a number of factors, including the overall health of a patient, and the formulation and route of administration of the selected compound(s). An ordinarily skilled physician or veterinarian can readily determine and prescribe the effective amount of the drug required to prevent, counter or arrest the progress of the condition.
[595] The compounds or pharmaceutical compositions of the present disclosure may be manufactured and/or administered in single or multiple unit dose forms.
[596] Having now generally described the invention, the same will be more readily understood through reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.
Figure imgf000120_0001
Assay principle:
[597] The assay based on the irreversible reaction of an Activity-Based Probe (ABP) with the active site cysteine in the enzyme. ABP consists of a ubiquitin moiety with an epitope tag (e.g. HA tag) at the N-terminus, and a reactive group at the C-terminus. The activity of Parkin-RBR (w/o the RO inhibitory domain) is significantly higher than the activity of Parkin-RORBR or the activity of full-length Parkin. The covalent attachment of ABP to Parkin can be monitored by Time Resolved Fluorescence Resonance Energy Transfer (TR-FRET)
~ Parkin-RORBR, full-length Parkin low TR-FRET signal (negative control)
-Parkin RBR high TR-FRET signal (positive control) [598] Compounds increasing the activity of Parkin-RORBR or the activity of full-length - Parkin can be identified by an increase in TR-FRET signal.
Strategy: use of N-terminal His-SUMO tagged constructs of Parkin-RORBR, full-length Parkin and Parkin-RBR. (from Evotec Slides; Based on Riley et al. 2013. Nat Commun. 4: 1982 & on information provided by E3x Bio; grant Application)
Constructs:
[599] - Full-length Parian (1-465), RORBR (141 -465) and RBR (238-465) expression with N-terminal Hise-SUMO-tag (can potentially be removed during purification using SENP1 protease) in E coli as described by Riley et al.
-N-terminal Hise-tag enabling TR-FRET-assay use of the purified protein that still have the N-terminal Hise-SUMO-tags on.
- Small scale tests are conducted for all constructs to evaluate which construct, full-length Parkin or RORBR, give better yield to facilitate an HTS-assay.
Phase 1: Protein Production
[600] - Initiate gene synthesis through third party for full-length Parkin with N-terminal His6~ SUMO, Hiss-SUMO-RQRBR and Hise-SUMO-RBR, codon-optimized for expression in E. coli and subcloning into a suitable expression vector
- Small scale test expression evaluated by Western Blotting to estimate the yield of soluble protein
- Transform the RBR construct as well as either the full-length Parkin construct or the RORBR construct into BL21 (DE3) and express as outlined in Riley et al., in the scale of 6- 24L (depending on outcome of small scale test expression)
- Purification of -10 mg of the RBR construct as well as either the full-length Parkin construct or the RORBR construct as described by Riley et al., i.e. IMAC, MonoQ and size exclusion.
Phase 2: Assay Development
[601] Goals;
- Set-up robust primary screening assays in 1,536-well assay plate format
~ Establish assays in 384-well format with a reasonable dynamic range (e.g. using Parkin +/- the R0 inhibitory domain) - Optimize assay (e.g. in terms of concentrations of assay components, buffer, additives, order of addition of reagents, and incubation temperature)
- Run time course experiments to define optimal incubation times
- Demonstrate assay robustness (goal: Z’>0.5)
- Demonstrate readout stability
- Test DMSQ tolerance
- Demonstrate specificity of the assay signal obtained using the Parian RBR domain (w/'o the R0 inhibitory domain) by titration of Ub (competing with ABP)
- Transfer assay from 384- to final 1 ,536-well screening plate format; adapt the assay to the EVOscreen™ Mark III HTS platform
- If necessary, fine-tune the assay conditions in order to optimize assay robustness in this high density plate format (goal: Z’>0.5) and to demonstrate assay suitability for high- throughput screening (HTS)
- Confirm stability of assay reagents under screening conditions over time
- Demonstrate plate-to-piate and day-to-day assay robustness
- Estimate and procure the amounts of all assay reagents required for screening and hit profiling.
Phase 3: Screening
[602] Marker Library' Screen (MLS):
- Pre-screening of a diverse marker library of approximately 2.5k representative lead-like compounds against the primary screening assay at two concentrations in triplicate
- Statistical analysis of the MLS and hit definition using the 3 -sigma- method (plate-based, based on the scatter of compound-free DMSO wells)
- Selection of the optimal compound concentration for primary screening
Primary Screen (PS):
- Screening of approximately 75,000 lead-like compounds against the primar ' screening assay at one uniform compound concentration (n=l); re-screening of compound plates that do not meet an agreed re-screen criterion (e.g Z’>0.5)
- Hit definition for the primary' screen using the 3-sigma-method (plate-based, based on the scater of compound-free DMSO wells)
- Statistical analysis of the primary screen Primary Hit Compounds (Parkin activators)
Hit Confirmation (HC):
- Selection of a set of up to approximately 750 primary hits for Hit Confirmation - Cherry picking of the selected compounds and reformatting for testing
- Retesting of the selected cpds against the primary screening assay at the compound screening concentration (n=3)
- Statistical analysis of the Hit Confirmation campaign Identification of confirmed small molecule Parkin activators.
Phase 4: HitProfilmg (HP):
- Selection of a set of up to approximately 250 confirmed hit compounds for Hit Profiling
- Cherry picking of the selected compounds and reformatting for concentration-response testing
- Concentration-response testing as 11 -point compound dilution series against the primary screening assay (n=2)
- Automated data fi tting of the concentration response curves and calculation of the resulting ICso values
- LC/MS inspection of the hit compounds to confirm compound identity' and purity
- Structure-activity relationship analysis (SAR) of the active hit compounds
- Confirmed & profiled small molecule Parkin activators.
Example 2; Activity-Based Probe Assay using an Ubiquitin vinyl sulfone probe
[603] An Ubiquitin vinyl sulfone probe can be used that irreversibly binds to the active site cysteine of Parkin ligase. Covalent attachment of the probe to the Parkin can be monitored by TR-FRET. Candidate activator compounds can be identified by increasing the activity of Parkin ligase due to an increase in TR-FRET signal. Screening for activating compounds can be distinguished from the controls as follows:
100% activation signal = Heat activated Parkin + 100 nM control activator in DMSO.
0% activation signal ::: Heat activated Parkin + DMSO only.
Parkin activators can be identified by an increase of the 0% activation signal TR-FRET signal.
[604] Assay Conditions:
Assay Plate: White 384 well plate (Coming 3572)
Enzyme: Parkin-His tagged 203 mM (10.5 mg/ml)
Probe: Ubiquitin vinyl-sulfone (HA-Ub-VS Boston Biochem U-212)
DMSO (Sigma cat # D4540 -100ML)
Reaction Buffer: 50 mM HEPES (pH 8.5), 150 mM NaCl, 0.01% Tween 20, 0.1% BSA Detection Buffer: 50 mM HEPES (pH 8 5), 150 mM NaCl, 0.01 % Tween 20, 0.1 % BSA,
800mM KF
Detection Reagent A: 2 6 nM Anti-6HTS-Eu crypiate and 40 nM Anii-HA-XL665 in detection buffer
Eu cryptate: Anti-6HIS-Eu cryptate (CisBio 61HISKLA)
XL665: Anti-HA-XL665 (CisBio 610HAXLA)
Enzyme Reaction (15min pre incubation Parkin with activator only)
Parkin: 40 nM
HA-Ub-VS Probe: 70 nM
Activator/DMSO: 2X Activator/2% DMSO
Reaction time: 60 minutes
Temperature: 22 °C
Total volume: 10 mΐ reaction
Figure imgf000124_0001
Take 10 pi of Enzyme Reacti on above and add 10 pi detection Reagent A under the following conditions:
Reaction time: 60 minutes
Temperature: 22 °C
Total volume: 20 pi
[605] Assay procedure (Using HP D-3QQ compound dispenser and Bravo for the operation):
1) Heal activate Parkin in reaction buffer (500 mΐ /1 5 ml tube: Eppendorf Thermomixer 5 minutes, 400 rpm at 58 °C and put on ice until needed).
2) Load assay plate wells with 4.8 mΐ 84.5 nM Parkin in reaction buffer by use of Bravo.
3) Deliver 0.2 mΐ 200X activator candidates in DMSO by use of HP D-300 compound dispenser. Highest 200X concentration = 20 pm and then twofold dilutions.
4) Spin 1000 rpm, 2 minutes, at room temp.
5) Incubate plate for 15 minutes at room temp.
6) Add 5 pi 140 nM HA-Ub-VS Probe in reaction buffer by use of Bravo.
7) Spin 1000 rpm, 2 minutes, at room temp.
8) Incubate plate for 60 minutes at room temp.
9) Add 10 pi 2.6 nM Anti-6HIS-Eu cryptate and 40 nM Anti-HA-XL665 in detection buffer.
10) Spin 1000 rpm, 2 minutes, at room temp.
11 ) Incubate plate for 60 minutes at room temp.
12) Read plates on Perkin Elmer Envision instrument with the following parameters:
LANCE dual laser protocol loaded into the Envision® software
Top Mirror: LANCE/DELFLA Duel/Bias (Bar code 446)
Emission Filter: APC 665 EM (Bar code 205)
2nd Emission Filter: Europium 615 EM (Bar code 203) Read 655 nm (channel 1) and 615nm (channel 2) wavelengths on Envision®
[606] Data Analysis: The Data can be read in CSV files. There are two tables in those CSV files, which are the values of 655nm (channel i) and 615nm (channel 2) wavelengths respectively. The data is converted to an HTRF Ratio ::: (Channel 1 / Channel 2) *10,000
[607] The average of all the OuM controls (DMSO only) = BKGD (Background - 0% activation). Subtract BKGD from each HTRF Ratio value = HTRF-BKGD. The average of all the lOOuM lOOnM control activator in DMSO controls = Max (100% activation). The following equation is then used to calculate % Activation for each well/candidate as follows: % Activation = (HTRF -BKGD/Max) * 100.
[608] The % Activation of compound titration can then he used to find activation EC50 or highest % activation if less than 75% activation is seen for the candidate compound.
[609] Graphpad Prisim was used with Transform X values: X = Log(X) and nonlinear regression (dose-response-stimulation): Log(agonist) vs Response - variable slope (four parameters) with constrains set to Bottom = 0 and Top = 100.
[610] The Activity -B sed Probe Assay was performed with various compounds m Tables 1, 2, 3 A and 3B. As shown in Table 4.
Figure imgf000125_0001
612] Table 4. Probe Assay EC50
Figure imgf000125_0002
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Example 3: Parkin pUB Auto-ubiquitinylation Assay
[613] A Parkin pUB Auto-ubiquitinylation Assay is used to evaluate a compound’s potency to activate Parkin’s ability to Auto-ubiquitinylate itself.
[614] The principle of this assay is that the E3 Ligase Parkin catalyzes the transfer of Ubiquitin to target proteins, but also has the ability to auto-ubiquitinylate itself. The phospho- TJbiquition (pUb) added to the assay alters the Parkin to a state where small molecule activators can enable the Parkin to auto-ubiquitinylate though the El - E2 cascade reaction. The use of a Eu cryptate Ubiquition and anti 6His-d2 that binds to the His tagged Parkin will give a signal when the Eu cryptate Ubiquition is auto-ubiquitinylate onto the Parkin which can be monitored by TR-FRET. [615] Similar to the Activity-based probe assay in Example 2, screening for activating compounds can be distinguished from the controls as follows:
100% activation signal = pUb activated Parkin + 40 nM control activator m DMSO.
0% activation signal ::: pUb activated Parkin + DMSO only.
Parkin activators can be identified by an increase of the 0% activation signal TR-FRET signal.
Assay Plate: White 384 well plate (Coming 3572)
Enzyme 1 : El (Ubiquitin-activating enzyme/UBEl Boston Biochem E-305)
Enzyme 2: E2 (UBcH7/Ube2L3 Boston Biochem E2-640)
Enzyme 3: Parkin-His tagged 203 mM (10.5 mg/ml)
pUb: Phospho-Ubiquitin (S65) (Boston Biochem U-l 02)
Eu Cryptate Reagent: Ubiquitin Eu (CisBio 61UBIKLA)
DMSO: DMSO (Sigma-34869-2.5L)
Reaction Buffer: 50 niM HEPES, 50 mM NaCl, 1 mM MgC , 0.005% Tween 20, 0 1%
PF-127 (Fisher Scientific 50-310-494), pH 8.5
Detection Buffer: 50 mM HEPES, 50 mM NaC!, 800 mM KF, 5 mM EDTA, 0.005%
Tween 20, 0.1% PF-127, pH 8.5
Detection Reagent Z: 13.4 nM Anti-6His-d2 in detection buffer
d2 Reagent: Anti-6His-d2 (CisBio 61HISDLA)
Assay Conditions:
Enzyme Reaction (15min pre-incubation with Parkin, pUb and activator only)
Parkin: 196 nM
pUb: 196 nM
DMSO: 1% DMSO
El: 5 nM
E2: 50 nM
Ubiquitin Eu: 8.8 nM
Reaction time: 120 minutes
Temperature: 22 °C
Total volume: 10 mΐ reaction
[618] Detection Reaction
[619] Take 10 mΐ of Enzyme Reaction above and add 10 mΐ detection Reagent Z under the following conditions:
Reaction time: 60 minutes
Temperature: 22 °C
Total volume: 20 mΐ
Assay Procedure:
1) Assay plate wells are loaded with 4 9 mΐ 400.0 nM Parkin, 400 nM pUb in reaction buffer by use of Eppendorf 12-channel pipette. 2) Deliver 0.1 mΐ 100X activator candidates in DMSO by use of Echo 555 compound dispenser. Highest iOOX concentration ::: 100 pm and then twofold dilutions. Add each compound and control in duplicate wells.
3) Spin 1000 rp , 2 minutes, at room temp.
4) Incubate plate for 15 minutes at room temp.
5) Add 5m1 10 nM El, 100 nM E2, 17.6 nM Ubiquitin Eu and 2 mM ATP in Reaction Buffer by use of Eppendorf 12-channel pipette.
6) Spin 1000 rpm, 2 minutes, at room temp.
7) Incubate plate for 120 minutes at room temp.
8) Add 10 mΐ 13.4 nM anti his d2 in detection buffer by use of Eppendorf 12-channel pipette.
9) Spin 1000 rpm, 2 minutes, at room temp.
10) Incubate plate for 120 minutes at room temp.
11) Read plates on Perkin Elmer Envision instrument with the following parameters:
LANCE dual laser protocol loaded into the Envision® software
Top Mirror; LANCE/DELFIA Duel/Bias (Bar code 446)
Emission Filter: AFC 665 EM (Bar code 205)
2nd Emission Filter: Europium 615 EM (Bar code 203)
Read 655 nm (channel 1) and 615nm (channel 2) wavelengths on Envision®
[620] Data Analysis: Tire Data can be read m CSV files. There are two tables in those CSV files, which are the values of 655nm (channel 1 ) and 615nm (channel 2) wavelengths respectively. The data is converted to an HTRF Ratio = (Channel 1 / Channel 2) *10,000
[621] The average of all the OuM controls (DMSO only) = BKGD (Background - 0% activation). Subtract BKGD from each HTRF Ratio value = HTRF-BKGD. The average of all the lOOuM control activator in DMSO controls = Max (100% activation). The following equation is then used to calculate % Activation for each well/candidate as follows: % Activation = (HTRF-BKGD/Max)*l00.
[622] The % Activation of compound titration can then be used to find activation EC50 or highest % activation if less than 75% acti vation is seen for the candidate compound.
[623] XLFIT5 model 205 was applied for the data analysis. EC50 fit model (4 Parameter Logistic Model/Sigmoidal dose-Response Model); fit ::: (A+((B-A)/(l+((C/x)AD)))); res = (y- fit). The parameters are:
A: Bottom Top
C: Relative EC50
D: Hill Slope
Constrains set to Bottom = 0 and Top = 100.
[624] This Parkin plJB auto-ubiquitinylation Assay is performed with various compounds in Tables 1, 2, 3 A and/or 3B.
Figure imgf000131_0001
Assay
[625] Compounds were also tested for metabolic stability in both rat liver rnicrosornes (RLM) and the compounds are tested for human liver rnicrosornes (HLM) and their half-life is calculated (See Tables 5A and 5B). The assay was performed as follows. The total volume for each incubation was 250 pL. A 100 mM DMSO solution of compound (diluted from 10 mM stock solution) was spiked into 50 mM KH2PQ4 (pH 7.4) buffer containing liver microsome at a concentration of 1.0 mg/mL. The reaction was initiated by the addition of 50 pL of 1 mM NADPH. The final concentration of each compound was 1 mM (1% DMSO). The positive controls, phenaceiin for CYP1A2, diclofenac for CYP2C9, omeprazole for CYP2C19, dextromethorphan for CYP2D6 and midazolam for CYP3A4 were added to a separate tube with the final substrate concentrations of 1 mM (1% DMSO) for evaluating the enzyme activities in the liver rnicrosornes. At 0, 15, 30 and 60 min, an aliquot of 15 m L reaction mixtures were removed and 200 pL of methanol (with internal standard of 25 ng/mL propranolol) was added to quench the reaction. The resulting mixture was centrifuged and supernatant was used for LC-MS/MS analysis.
[626] The signals for each compound, or the metabolites for the probe substrates and the internal standard were integrated and the peak area ratios to internal standard were generated. Percent parent remaining at a specified timepoint was calculated based on the peak area ratios at time 0 (as 100%) for in vitro metabolic stability studies in liver microsome and hepatocyte. The observed rate constant (k0bs) for the metabolism of substrates was calculated by plotting the natural log of percentage substrate remaining versus time of incubation with the slope being kobs. The half-life ( 1/2) was calculated according to the following equation:
T1/2 = 0.693/kobs
[627] Table 5A. Rat Liver Microsome Half-Life
Figure imgf000132_0001
[628] Table SB. Human Liver Microsome Half-Life
Figure imgf000132_0002
Example 5: In Vivo Cancer Xenograft Assay
[629] Compound 42 was evaluated for in vivo therapeutic efficacy the treatment of subcutaneous HCT-116 (colon cancer) xenograft model in nude mice.
[630] Each mouse was inoculated subcutaneously at the flank region with either HCT-l 16 cells (1.0 x 106) in 0.1 ml of IxPBS mixed with Main gel (1 : 1) for tumor development and xenotransplantation.
[631] Twenty (20) animals with approx 120-150 mm tumors are selected for HCT-l 16 follow' up experiment and randomly placed into Groups 1 , 2, 3, and 4, wherein Group 1 is for mice administered with a vehicle negative control; Group 2 is mice treated with Compound F at 25 nig/kg daily for up to 26 days; Group 3 is mice treated with 1 mg/kg of Compounds 42 daily for up to 26 days; and Group 4 is mice treated with 5 mg/kg of Compound 42 daily for up to 26 days. The vehicle with or without drug is administered to the mouse by intrapentoneal injection. The formulation with respective drug is as follow-s:
10% - DMA: N,N-Dimethyl acetamide
15% - Solutol HS 15: Macrogol 15 Hydroxy Stearate, Polyethylene glycol-15- hydroxystrerate; and 75% - 20% aqueous HR-b-CD: Hydroxypropyl-beta-cyclodextrin
Figure imgf000133_0001
Compound F
[632] Before grouping and treatment, all animals were weighed and the tumor volumes were confirmed (approx. 120- 150 mirri) using electronic caliper. Since the tumor volume can affect the effectiveness of any given treatment, mice were assigned into groups using randomized block design as following: First, the experimental animals were divided into homogeneous blocks based on their tumor volume. Secondly, within each block, randomization of experimental animals to different groups were conducted. By using randomized block design to assign experimental animals, we ensured that each animal had the same probability of being assigned to any given treatment groups and therefore systematic error was minimized.
[633] After tumor cells were inoculated, the animals were checked daily for morbidity and mortality. At the time of routine monitoring, the animals were checked for any adverse effects of tumor growth and treatments on normal behavior such as mobility, visual estimation of food and water consumption, body weight gain/loss, eye/hair matting and any other abnormal effects. Death and observed clinical signs were recorded. Tumor volumes were measured every three days in two dimensions using an electronic caliper, and the volume data were expressed in mm3 using the formula: V = 0.5 a x b2 wh ere a and b are th e long and short diameters of the tumor, respectively. Tumor volume average is then recorded for each day for groups 1-4 until day 26.
[634] Figure 1 sho 's the xenograft study result for Compound 42. Compound 42 at 5 mg/kg reduced tumor size by greater than 50%.
Example 6: Cancer Cell Proliferation Assay
[635] Measurement of the inhibitive effect of compounds on cancer cell proliferation was performed. Various cell lines were tested, including HCT-116 (colon); A549 (lung); TOV-21G (ovarian); Calu-6 (lung); and LS-174T (colon); and cell lines H1703 (Lung) and SKOV3 (ovarian); JEKO-1 (lymophoma); TOV-112D (ovarian) are tested. The assays were performed under the following conditions: Cells are harvested at a concentration of 4 X 104 cells/ml in media. Volumes of 100 mΐ/well of these cell suspensions were added to a 96 well plate using a multichannel pipette. Plates were gently agitated to ensure an even dispersion of cells over a given plate. Cells were then incubated at 37°C, 5% CO overnight. Following this, 100 mΐ of compound at var ing concentrations w¾s added to wells in triplicate. Control wells are those with 100 mΐ media containing 0 33% DMSO added to cell suspension (this is the equivalent volume of DMSO found in the highest concentration of drug). Plates were then gently agitated, as above, and incubated at 37 °C, 5% CO2 for 72hrs (control wells have reached 80-90% confTuency). Assessment of cell proliferation in the presence of the compo und was determined by the acid phosphatase assay.
[636] Following the incubation period of 72 hrs, media was removed from the plates. Each well on the plate was washed twice with 100 mΐ PBS. This was then removed and 100 mΐ of freshly prepared phosphatase substrate (!OmM p-nitrophenol phosphate in 0. 1M sodium acetate, 0.1% triton X-100, pH 5.5) was added to each well The plates were then incubated in the dark at 37 °C for 2 hours. Colour development was monitored during this time. The enzymatic reaction wasstopped by the addition of 50 mΐ of IN NaOH. The plate wes read in a dual beam plate reader at 405 nm w ith a reference wavelength of 620 ran. The absorbance reading of the latter is subtracted from the former, and the effect of the drug on cell proliferation was then measured as a percentage against the control cells (DMSO), which is taken as 0% inhibition. Table 6A below shows ICso values on cancer cell proliferation including HCT-l 16 (colon); A549 (lung); TOV-21G (ovarian); Calu-6 (lung); and LS-174T (colon). Table 6B below shows IC50 values on cancer cell proliferation including JEKO-l (iymophoma) and TOV-1 12D (ovarian). Fig. 2 shows the % inhibition of cancer cell line proliferation with Compound 42. Table 6C shows ICso values corresponding to Compound 42’s cell proliferation data shown in Fig. 2. Table 6D shows ICso values for Compound 42 tested in another set of cell proliferation assay with various cancer cell lines. Table 6E shows ICso values for Compound F and Compound 42 in a cell proliferation assay with various cancer cell lines.
[637] Table 6A. ICso Values of V arious Compounds on Cancer Cell Line Proliferation
Figure imgf000135_0001
Figure imgf000136_0001
NA = not available
638] Table 6B. EC50 Values of Various Compounds on Cancer Cell Line Proliferation
Figure imgf000137_0001
[639] Table 6C. IC50 Values for Compound 42 on Various Cancer Cells
Figure imgf000137_0002
[640] Table 6D. EC50 V alues for Compound 42 on Various Cancer Cells
Ceil lift® £€$9 {nM}
C m(HCT-iiS! a?
lung <A$49) 72
Mantle Ceil p® vl) 154
Oven a ft (A27SO) sa
Ovarian (£¾- 7 42
O aftan (OAW281 P4
O ar an OA 43| 166
Ovarian SKOV3) 326
Overs a fS &26) 3S4
Ovarian (TOVll/D) 98
Figure imgf000138_0001
641] Table 6E. 1C50 Values for Compound F and Compound 42 on Various Cancer Ceils
Figure imgf000138_0003
Figure imgf000138_0002
[642] The pharmacokinetics and oral bioavailabihty of various compounds was evaluated following IV or PO administration to fasted male Sprague-Dawley mice (N :::: 3/route/dose). Each compound was administered to fasted male Sprague-Dawley mice as a single dose of 1 mg/kg (IV) or 5 mg/kg (PO). For IV dosing, each compound was formulated in 10% DMA-' 15% Solutol/ 75% HRb-CD (20%) as a 1 mg/mL solution for IV (3 mg/kg), for IP (5 mg/kg) and for PO (10 mg/kg) administrations. [643] Blood samples (0.250 mL) were collected into EDTA tubes then processed to generate plasma samples. Blood samples were collected at pre-dose, 0.083, 0 25, 0.5, 1, 2, 4, 8 and 24 hours post-dose administration. Plasma concentrations of each compound were determined using LC-MS/MS with a lower limit of quantitation of 1.0 ng/mL. Tire pharmacokinetic parameters wure determined by non-compartmental methods using WinNonlin
[644] The pharmacokinetic parameters of each compound were determined by non-compartmental analysis (Model 201 for IV administration and Model 200 for PO administration) using WinNonlin Version 6.4 (Pharsight, Mountain View, CA). The area under the curve from the time of dosing to the last measurable concentration, AUC(o-t), was calculated by the linear trapezoidal rule. The area under the concentration-time curve extrapolated to infinity, AUC(o-*), was calculated as follows: AUC(o-*) = AUC(o-t> + CWk
[645] Where Ciast is the last measurable concentration and k is the first order rate constant associated with the terminal elimination phase, estimated by linear regression of log concentration versus time. The half-life (T1/2) of the terminal elimination phase was estimated based on the following equation: T1/2 ::: 0.693/k
[646] K was determined based on at least three timepoints with R2 >0.9. Additional parameters were calculated as follows: CL = Dose/ AUGo- )
[647] Where CL is the clearance of the compound of the disclosure in L/hr/kg, Dose is the administered dose in rng/kg. Mean residence time (MRT) was calculated as follows:MRT = AUMC(o-oo> / AUC(o-ro)
[648] Where area under the first moment curve extrapolated to infinity (AUMC(o- )) wus calculated as follows: AUMQo- ) = AUMClast + tlast*Clast/k+ Clast/ k 2
[649] The steady state volume of distribution (Vss) was calculated as follows: Vss ::: CL x MRT.
[650] The oral bioavailability based on AUQo-t) wus calculated as follows: F(%) = AUCPO/AUCIV X Dosew/Dosepo x 100. For IV administration, the initial concentration, Co is reported and is an extrapolated value. For PO administration, the maximum concentration, Cmax is report and is an observed value.
[651] Compound 42 had reasonable IV clearance and Vss of 1.3 L/kg with T3/2 of 16 hours (Table 7). Compound 42 had lower systemic exposures following IP injection and oral administration with oral bioavailability of 21% after oral dosing ("fable 7).
[652] The mean plasma concentration of Compound 42 in mice after IV, IP, and PO administration is shown in Figure 3. [653] Table 7. Mouse intravenous (IV), intraperitoneai (IP) and oral (PO) bioavail ability for Compound 42
Figure imgf000140_0001
Example 8, Mitophagy Cellular Assay
[654] Mitophagy cellular assay was performed. Fig. 4 shows mitophagy was promoted by Compound 42 treated with CCCP (carbonyl cyanide m-chlorophenyl hydrazine). Without bound to any theory', functional Parkin initiates mitophagy in two steps: 1) Parkin with PINK ! identifies and isolates damaged mitochondria and 2) elimination of the damanged mitochondria Fig. 4 show's that Compound 42 increases removal of damaged mictochondria.
[655] The mitophagy cellular assay was performed as follows:
[656] Cel! Culture (YFP-Parkin Ceils)
[6S7[ S-HeLa stably expressing a YFP-Parkin fusion protein were utilised m high content screenin assays to assess Parkin-dependent endpoints. 4000 cells w¾re seeded in each well of a 96 well plate (Perkin Elmer ViewPlate-96 F TC, cat. N. 6005182) and left to grow for 24- hours. Cells w¾re then incubated with vehicle (DMSG) or increasing concentrations of compound (1 , 2 5, 5, 10 mM) for 1 hour prior to adding 6 mM carbonyl cyanide m-chlorophenyl hydrazone (CCCP), each condition run in replicate of three. After 20 hours, the cells were processed for immunofluorescence.
[658] Immunofluorescence
[659] Samples were fixed in 4% PFA for 25 minutes RT and permeabilized with PBS 0.1% Triton-X100 for 3 minutes on ice, blocked with PBS 3% BSA, 0.3% Triton-XlOO for 2 hours RT. followed by overnight incubation with primary antibody at 4 °C (0.5 pg/ml rabbit Tomm20 antibody FL-145; Santa Cruz Biotechnology) diluted in PBS 0.1% BSA, 0.3% Triton-Xl OO. The secondary goat anti-rabbit antibody conjugated with DyLight 649 (Jackson ImmunoResearch) was applied for 1 hour at room temperature at a concentration of 2.8pg/ml in conjunction with 1 pg/ml Hoechst33342. Cells were imaged using an Olympus ScanR automated microscope equipped with motorised stage and 20x APO planar objective. 18 images were acquired for each well using the following combination of excitation-'emission filters: Hoechst33342 was excited through a 350/50 nm band pass filter and fluorescence intensity7 was collected through a 460/30 band pass filter. YFP w'as excited through a 500/20 nm band pass filter and fluorescence intensity was collected through a 540/35 band pass filter. DyLight 649 was excited through a 640/30 nm band pass filter and fluorescence intensity was collected through 700/75 band pass filter. Images were processed and analysed as described in the Image Analysis section.
[660] Image analysis
[661] Images w'ere processed and analyzed using Columbus HCS Analysis software (V ersion 2.5.0., PerkinElmer) as follow's: Tomm20 fluorescence intensity 'as corrected using the parabola algorithm. Hoechst 33342 fluorescence was used to identify and count cells. Cells w¾re segmented according to Tomm20 fluorescence intensity. Spot detection was optimized to recognize number and total cellular area of Tomm20 stained clusters (mitochondria). Tomm20 staining intensity, spot numbers and spot area w¾re used to train a linear classifier algorithm that discriminated between Tomm20 positive (high intensity, spot numbers and spot area) and Tomm20 negative cells (low' intensity, spot numbers and spot area). Bar graphs v ere generated reporting the number of Tomm20 negative cells expressed as percentage of total cells imaged for each w'ell. Results w'ere shown as mean ± SD of 3 experiment performed in triplicate.
[662] Statistical analysis
[663] Normalized data from the bar graphs were imported m Prism 7.0a (Graphpad™). The equation Y=Bottom + (Top-Bottom)/(l+10A((LogEC50-X)*HillSlope)) (log agonist vs. response - variable slope (4 parameters)) was applied to fit a non-linear curve to the dose response data and calculate ECso values.
[664] Immunoblotting and detection of Parkin substrates
[665] Hela YFP Parkin cells were cultured as described above, and 3 x 105 cells were plated in each w'ell of a 6 well plate. 24 hours later, pre-incubated for one hour with 1% DMSO, 2.5, 5, or 10 mM compound (compound 42) in 1% DMSO and then treated with 6 mM CCCP with 2.5, 5, or 10 mM compound. As controls, cells were treated with DMSO and 6 mM CCCP alone. 4 hrs post treatment cells were washed three times with IX PBS (3x5 min) and lysed with SDS lysis buffer (30 rnM Tris/2%SDS/10% Glycerol). Cell lysates were sonicated for 15 secs, and protein quantification of cell lysates was determined by Thermo Scientific BCA assay.
[666] Sample lysates were normalized for protein concentration and separated on 4% - 12% pre-cast BOLT™ 15 well SDS-PAGE gels (Invitrogen) for 38 mins at 200V, and transferred to PVDF using iBLOT2 system (Life Technologies).
[667] Processing of PVDF membranes for immune detection of Parkin substrates used specific antibodies to MFN2 (abl 24773, Abeam. D2D10, Cell Signaling), VDAC (Anti- VDAC/Porin abl4734, Abeam), MitoNEET (16006-1 -AP, Proteintech) and Parkin (P6248 PRK8, Sigma-Aldrich) followed by incubation in secondary antibody (Jackson ImmunoResearch HRP) and visualization of reaction by chemiluminesence (Fujifilm LAS-
Figure imgf000142_0001
[668] Compound 42 was screened against 44 protein targets at 10 mM. The % inhibition shown in Table 8 indicates Compound 42’s abilit' to displace radioligands. If the % inhibition is less than 50%, the test compounds is consider to have no effect. Thus, as shown m Table 8, Compound 42 demonstrated to have no effects against the 44 protein targets.
[669] Table 8. % Inhibition of protein targets by Compound 42
Assay % Inhih
Figure imgf000143_0001
Figure imgf000143_0002
[670] Compound 42 was also screened in a kinase panel assay. As shown in Table 9, Compound 42 does not inhibit CDK 4/6 or other kinases.
[671] Table 9. % Inhibition of kinase targets by Compound 42
Figure imgf000143_0003
[672] Lastly, Compound 42 w¾s screened in a CYP inhibition assay. Compound 42 have no significant CYP inhibition activity for the 5 major CYP enzymes tested as shown in Table 10.
[673] Table 10. % inhibition of Various CYP by Compound 42
Figure imgf000144_0002
*no inhibition
[674] Representative Synthesis
[675] Below examples demonstrate general methods in which one skilled in the art could use to synthesize the compounds of the disclosures. One skilled in the art would readily understand that below examples provide guidance for the synthesis and one skilled in the art would understand that by changing starting materials or intermediates, various asymmetric triazole compounds of the present disclosure can he obtained.
Example 10: Synthesis of A7~[5~henzamido-l-(4~iodophenyI)-l,2,4-triazoI-3-yI]benzamide
(Compound E)
Figure imgf000144_0001
[676] Step a: Synthesis of (4-iodophenyl)hydrazine
[677] To a suspension of 4-iodoaniline (10.00 g, 45.66 mmol, 1.00 eq) in HCi (12 M, 30 mL) at 0 °C was added dropwise a solution of NaNCh (3 15 g, 45.66 mmol, 1.00 eq) in H20 ( 13 mL), and the resulting mixture was stirred at 25 °C for 1 h. Then a solution of SnCk (30.91 g, 136.98 mmol, 3.00 eq) in HCI (12 M, 20 mL) was added dropwise at 0 °C. The reaction mixture w¾s stirred at 25 °C for 1 h TLC (DCM/MeOH = 10: 1) indicated the starting material was consumed completely and a new spot formed. The reaction mixture was filtered and the filter cake was dried under reduced pressure to afford (4-iodophenyl)hydrazine (9.50 g, HC1 salt, crude) as a purplish red solid. 'Ή NMR (400 MHz, DMSO-aV) d ppm: 10 39 (br, 3H), 8.50 (br, GH), 7.59 (d, ,/= 8 8 Hz, 2H), 6.86 (d, J= 8.8 Hz, 2H).
[678] Step b: Synthesis of l-(4-iodophenyl)-l,2,4-triazole-3, 5-diamine
To a solution of (4-iodopheny])hydraz.ine hydrochloride (6.50 g, 24.03 mmol, 1.00 eq) in H2O (15 rnL) was added 1-cyanoguanidine (2.02 g, 24 03 mmol, 1.00 eq ) and 1 Id (12 M, 5 ml.). The reaction mixture was stirred at 100 °C for 3 h. TLC (DCM/MeQH = 8/1) indicated the starting material was consumed completely and new spots formed. The reaction was basified to pH=8 with aq. NaOH solution (40%, w/v). After removal of the solvent under vacuum, hexane (100 rnL) was added and the resulting mixture was stirred at 25 °C for 15 min. The mixture was filtered and the filter cake was washed with DCM (150 mL). The solids were collected and dried in vacuo to afford l-(4-iodophenyl)-l, 2, 4-triazole-3, 5-diamine (1.00 g, crude) as a brown solid. LC-MS (ESI): m/z 301.8 (M+H)+.
[679] Step e: Synthesis of 7V-[5-benzamido-l-(4-iodophenyl)-l,2,4-triazol-3- yl] benzamide
[680] To a mixture of l-(4-iodopheny])-l,2,4-triazole-3, 5-diamine (500 mg, 1.66 mmol, 1.00 eq) in pyridine (20 mL) was added benzoyl chloride (934 mg, 6.64 mmol, 771.69 /iL, 4.00 eq), then the mixture was stirred at 100 °C for 5 h. LC-MS indicated the desired product was detected. Ethyl acetate (60 mL) was added and the resulting mixture was washed with HC1 (1 M, 40 rnL x 3). The organic layer was dried over anhydrous NaiSCh, concentrated to afford the crude product, which was purified by prep-HPLC (column: Phenomenex Synergi Cl 8 150x25x10 wm; mobile phase: [water (0.05% HC1)-ACNJ; B%: 50%-70%, 10.5min) to affordY-[5-benzamido-l-(4-iodophenyl)-l,2,4-triazol-3-yl]benzamide (21.80 mg, 42.80 ymol, 3% yield, 99+% purity) as a white solid. ¾ NMR (400 MHz, DMSO-tfc) d ppm: 11.27 (br, 1H), 11.01 (br, 1H), 8.10-8.00 (m, 2H), 8.00-7.80 (m, 4H), 7.67-7.60 (m, 2H), 7.56-7.36 (m, 6H); ,3C NMR (75 MHz, DMSO-aV) d ppm: 166.8, 165.8, 155.5, 146.1, 138.7, 137.2, 134 0, 133.3, 132.6, 129.2, 129.0, 128.4, 125.1, 94.6 LC-MS (ESI): m/z 510.0 (M+Hy .
Example 11: Synthesis of 2-metbyk/V-[5-[(2-methylbenzoyl)amino]-l-phenyl-l,2,4- triazol-3-yl] benzamide (Compound F)
Figure imgf000146_0001
[681] Step a: Synthesis of 1 -phenyl- 1, 2, 4-triazole-3, 5-diamine
[682] To a solution of 1-cyanoguanidine (10.00 g, 118.93 mmol, 1.00 eq) and phenylhydrazine (12.86 g, 118.93 mmol, 11.69 mL, 1.00 eq) in H20 (40 mL) was added hydrochloric acid (12 M in water, 8 mL). Then the reaction mixture was stirred at 100 °C for 14 h. The reaction mixture was basified pH to 8 with 40% sodium hydroxide aqueous solution. After removal of the solvent, the residue was slurried with hexane (150 mL) and followed by DCM (200 mL). The mixture was filtered and the filter calve w¾s collected to give 1 -phenyl- 1, 2, 4-triazole-3,3-diamine (36.00 g, 197 27 mmol, 83% yield) as a yellow solid. 3H NMR (400 MHz, DM SO ·./·· ) d 7.48-7.40 (m, 4H), 7.23-7.19 (m, i l l ). 6.70 (brs, 2H), 6.23 (brs, 2H).
[683] Step b: Synthesis of 2-methyl-7V-[5-[(2-methylbenzoyl)amino]-l-phenyl-l,2,4-triazol- 3-y]]benzamide
[684] To a solution of 1 -phenyl- 1, 2, 4-triazole~3, 5-diamine (800 mg, 4.57 mmol, 1.00 eq) in pyridine (10 mL) w-as added 2-methylbenzoyl chloride (2.12 g, 13.70 mmol, 1.78 mL, 3.00 eq). The reaction mixture was heated to 110 °C and stirred for 12 h. LC-MS indicated the starting material was consumed completely and desired compound was detected. The reaction mixture was quenched by saturated aqueous NHrCl (80 mL), and then extracted with ethyl acetate (100 mL x 3). The organic layers were combined, washed with sat. NH4Cl (50 mL), and sat.brine (50 mL), then dried over anhydrous Na2SC)4, filtered and concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (3-50% ethyl acetate/petroleum ether) to afford the crude product. It was further purified by prep-HPLC (column: Phenomenex Synergi CIS 15Qx25x l0/im; mobile phase: | water (0.05% HC1)-ACN|; B%: 37%-57%, 10.5 min) to afford 2-methyl-/V-[5-[(2-meihylbenzoyl) amino]-l -phenyl-1 ,2,4- triazol-3-y!]benzamide (22.0 mg, 52.40 //mol, 98% purity) as a white solid. Ή NMR (400 MHz, CDsOD) d 7.61-7.54 (m, 2H), 7.52-7.50 (m, 4H), 7.42-7.39 (m, 3H), 7.31-7.25 (m, 4H), 2.48 (s, 31 !}. 2.29 i s. 3H); i3C NMR (100 MHz, CD3OD) d 169.9, 169 6, 154.1, 145.4, 136.7, 136.2, 130.8, 130.7, 129.2, 127.2, 127.1, 125.5, 125.5, 125.4, 18.4. LC-MS (ESI): m/z 412.1 (M+H) .
Figure imgf000146_0002
tri azo 1-5-y 1 ) benzanii de (Compound R3) am! 2-methyl-N-(3-(3-methylpyridin-2-yl)-l- phenyl- 1 H- 1 ,2,4-triazo!-5-yI)benz.iimide (Compound S3)
Figure imgf000147_0001
[685] Step A: Synthesis of 3,5-dibromo-l-phenyl-lH-l,2,4-tnazole
[686] Two hatches of phenylboronic acid (13 5 g, 111 mmol, 1.0 eq), 3,5-dibromo~lH-i,2,4~ triazo!e (25 g, 110 mmol, 1.0 eq), Cu(QAc)2 (30 g, 165 mmol, 1.5 eq), pyridine (26.5 g, 335 mmol, 27 mL, 3.0 eq) and 4A MS (5 g, 22.0 mmol) in toluene (250 mJL) was degassed and purged with O2 for three times, and then the mixture was stirred at 80 °C for 16 h under O? atmosphere (15 psi). After completion of the reaction, the two batches of reaction mixture were mixed and filtered, then concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (ISCO®; 200 g SepaFlash1® Silica Flash Column, eluent of 0-10% ethyl acetate/petroleum ether gradient @ 80 mL/min) to give 36 g crude product with 67% purity. 2 g was used for next step directly. The remaining 34 g was diluted with DCM (200 mL) and washed with saturated aqueous NaHC03 (100 mL c 1), brine (100 mL), dried over anhydrous Na2S04, filtered and concentrated under reduced pressure to give 3, 5-dibromo-l -phenyl-1 ,2,4-triazole (29.2 g, 37% yield, 85% purity) as a light yellow solid. i.C-YlS (ESI): m/z (M+H) 303.9.
[687] Step B: Synthesis of 3-bromo-M -(4-methoxy benzyl)- 1 -phenyl 1 H- 1 ,2,4-triazol-5 - amme [688] Two batches of 3 ,5-dibromo-l -phenyl- 1,2,4-triazole (2 g, 5.61 mmol, 1.0 eq), (4- meihoxypheny]) methanamine (795 rng, 5.80 mmol, 0.75 mL, 1.0 eq) and K2C03 (1.16 g, 8.42 mmol, 1.5 eq) in NMP (3 mL) was stirred at 150 °C for 1 h under microwave. TLC (petroleum ether/ethyl acetate:=:2: l) showed one main spot with desired product was detected for the two batches. The two batches of reaction mixture were combined, diluted with DCM (80 mL), washed with water (50 mL x 3), saturated NaCl (50 mL), dried over Na2S04, filtered and concentrated under reduced pressure. The residue w¾s purified by flash silica gel chromatography (TLC: petroleum ether/ ethyl acetate=5:l; ISCO®; 20 g SepaFlash® Silica Flash Column, eluent of 0-20% ethyl acetate/petroleum ether gradient @ 80 mL/min) to give 5-bromo-N-[(4-methoxyphenyl)methyl]-2-phenyl-l,2,4-triazol-3-amine (2.4 g, 58% yield, 97% purity) as light yellow oil. LC-MS (ESI): m/z (M+H) 359.1/361.1.
[689] Step €: Synthesis of N-(4-methoxybenzyl)-3-(5-methylpyridin-2-yl)-l-phenyJ-lH- 1,2,4 -tri azol -5 -amine
[690] A mixture of 5-bromo-N-[(4-methoxyphenyl)methyl]-2-phenyl-l,2,4-triazol-3-amine
(500 mg, 1.35 mmol, 1.0 eq), tributyl-(5-methyl-2-pyridyl)stannane (500 mg, 1.31 mmol, 0.97 eq) and [2-(2-aminophenyl)phenyl]- chloro-palladium;dicyclohexyl-[2-(2,6- dimethoxyphenyl)phenyl]phosphane (100 mg, 139 pmol, 0.1 eq) in THF (20 mL) was degassed and purged with N2 for three times, and then the mixture was stirred at 90 °C for 16 h under N2. Most of start material remained. Then the reaction mixture was filtered and [2-(2- aminophenyl) phenyl ]-chloro-palladium;dicy clohexyl-[2-(2, 6- dimethoxyphenyl)phenyl]phosphane (100 mg, 139 pmol, 0.1 eq) was added to the mixture. The reaction mixture was stirred at 90 °C for 72 h. After being cooled to room temperature, the reaction mixture was quenched by addition of saturated aqueous KF (20 mL) and stirred at 15 °C for 1 h. Then the mixture w¾s filtered and extracted with DCM (40 mL c 3). The combined organic layers were dried over NanSCL, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SiO?., petroleum ether/ethyl acetate=10/i to 2: 1; DCM: MeOH = 10: 1) to give N-[(4-methoxyphenyl)methyl]-5-(5-methyl- 2-pyridyl)-2-phenyl-l,2,4-triazol-3-amine (320 mg, 43% yield, 67% purity) as a yellow oil. LC-MS (ESI): m/z (M+H) 372.3.
[691] Step D: Synthesis of 3-(5-methylpyridin-2-yl)-l-phenyl-lH-l,2,4-triazol-5-amine
[692] A mixture of N~[(4-methoxyphenyl)methyl]-5-(5-methyl-2-pyridyl)-2-phenyl-l,2,4~ triazol-3 -amine (320 mg, 577 pmol, 1 eq) in TFA (7.70 g, 67.5 mmol, 5 mL) was stirred at 50 °C for 2 h. After the reaction was completely, the reaction mixture wus concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Luna Cl 8 150x25 5pm; mobile phase: [water (0.225% FA)-ACN]; B%: 15%-36%, 10 min) to give a crude product. The crude product was diluted with DCM (20 mL)/H20 (20 ml.) and adjusted the pH to 10-12 w ish M l H LO. Then extracted with DCM (20 mL c 3), the combined organic layers were dried over NazSOr, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC (SiCte, DCM:MeOH=T0: 1) to give 5-(5-methyl-2-pyridyl)-2-phenyl- L2,4~triazoi~3~amine (70 mg, 48% yield) as a white solid. LC-MS (ESI): m/z (M+H) 252 0; 1H NMR (400 MHz, DMSO-d6) 8.46 (s, 1H), 7.88-7.86 (d, 1H), 7.69-7.67 (dd, 1H), 7.64-7.62 (d, 2H), 7.57-7.53 (t, 2H), 7.42-7.39 (t, 1H), 6.56 (s, 2H), 2.34 (s, 3H).
[693] Step E: Synthesis of 2-Tnethyl-N-(3-(5-methylpyridin-2-yl)-l-phenyl-lH-l,2,4-triaz.ol- 5-yl)benzamide (Compound R3)
[694] To a solution of 5-(5-methyl-2-pyridyl)-2-phenyl-l,2,4-triazol-3-amine (70 mg, 279 mihoΐ, 1.0 eq) and pyridine (68.6 g, 867 mihoΐ, 3.1 eq) in MeCN (9 mL) was added the solution of 2-methyl- benzoyl chloride (60 mg, 388 pmol, 50.4 uL, 1.4 eq) MeCN (1 mL) drop-wise at 80 °C. The mixture was stirred at 80 °C for 2 h. Only a few desired product was formed, then a solution of 2-methylbenzoyi chloride (90 mg, 582.17 pmol, 2.1 eq) in MeCN (1 mL) was added dropwise at 80 °C. The mixture was stirred at 80 °C for 16 h. After being cooled to room temperature, the reaction mixture was adjusted pH to 11 -12 by saturated aqueous LiOH and stirred at 15 °C for 16 h. The reaction mixture was extracted with DCM (30 mL). The organic layer was washed with saturated aqueous NaHC03 (30 mL), brine (30 mL); dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by prep- HPLC (column: Phenomenex Synergi Cl 8 150x25x 10 pm; mobile phase: [water (0.05%HC1)- ACNj;B%: 32%-52%, 7.8min) to give 2-methyl-N-[5-(5-methyl-2-pyridyl)-2-phenyl-l,2,4- triazol-3-yl]henzamide (45 g, 80% yield, HC1 salt) as a white solid.
[695] LC-MS (ESI): m/z (M+H) 370.2; 1H NMR (400 MHz, DMSO-d6) 11.32 (s, 1H), 8.75- 8.74 (m, 1H), 8.22-8.20 (d, 1H), 8.12-8.09 (dd, 1H), 7.84-7.82 (m, 2H), 7.64-7.60 (m, 2H), 7.53-7.51 (m, 2H), 7.45-7.40 (id, 1H), 7.33-7.28 (m, 2H), 2.46 (s, 3H), 2.20 (s, 3H). 13C NMR (75 MHz, DMSO~d0) 168 6, 156.9, 147.8, 146.79, 143.19, 141.8, 136.6, 136.3, 136 0, 134.0, 131.0, 130.8, 129.5, 129.2, 127.5, 125.8, 123.8, 122.3, 19.3, 17.9.
[696] Step F: Synthesis of N-(4-methoxybenzyl)-3-(3-methylpyridin-2-yl)-l-phenyl-lH- 1 ,2,4-triazol-5-amine
[697] A mixture of 5-bromo-N-[(4-methoxyphenyl)methyl]-2-phenyl-l,2,4-triazol-3-amine (600 mg, 1.62 mmol, 1.0 eq), tributyi-(3-methyl-2-pyndyi)stannane (500 mg, 1.31 mmol, 0.8 eq) and [2-(2-ammophenyi)phenyl] -chloro-palladium;dicyclohexyl-[2-(2,6- dimethoxyphenyl)phenyl]phosphane (100 mg, 139 pmol, 0.86 eq) in THF (20 mL) was degassed and purged with N2 for three times, and then the mixture was stirred at 90 °C for 60 h under N2. But most of start materia] remained, the mixture was filtered and [2~(2~ aminophenyl)phenyl]-chloro-pal!adium;dicyc!ohexyl-[2-(2,6- dimethoxyphenyl)phenyl]phosphane (100 mg, 139 pmol, 0.86 eq) was added. The reaction mixture was stirred at 90 °C for additional 32 h in a tube. After being cooled to room temperature, the reaction mixture was quenched by addition of saturated aqueous KF (20 mL) and stirred at 15 °C for 30 nnn. Then the mixture was diluted with DCM (20 mL) and extracted with DCM (30 mL c 3). The combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (TLC: EtOAc; S1O2, petroleum ether/ethyl acetate=5/l to 2: 1; DCM: MeOH = 10: 1) to give a crude product. The crude product was repurified by prep-TLC (SiG?., EtOAc) to give N-| (4- meihoxyphenyl)methyTj~5~(3~methyl~2~pyridyl)~2~phenyl~1 ,2,4-triazol-3-amine (1 10 mg, 1 1 % yield, 61% purity) as yellow oil.LC-MS (ESI): m/z (M+H) 372.0.
[698] Step G: Synthesis of 3-(3-methylpyridin-2-yl)-l-phenyl-lH-l,2,4-triazol-5-amine
[699] A mixture of N-[(4-metboxyphenyl)methyl]-5-(3-methyl-2-pyridyl)-2-phenyl-l,2,4- triazol-3-amine (1 10 mg, 181 pmol, 1.0 eq) in TFA (4.62 g, 40.5 mmol, 3 mL) was stirred at 50 °C for 2 h. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. The residue was diluted with DCM (15 mL) and water (10 mL), and adjust pH to 9-10 by K2CO3 (solid). Then the resulting was extracted with DCM (15 mL x 2), the combined organic layers were concentrated under reduced pressure. The residue was purified by prep-TLC (TLC: DCM:MeOH=10: l; S1O2, DCM:MeOH = 10: 1) to give 5-(3-methyl-2- pyridyl)-2-phenyl-l,2,4-triazol-3-amine (55 mg, crude) as a white solid. LC-MS (ESI): m/z (M+H) 252.0.
[700] Step H: Synthesis of 2-methyl-N-(3-(3-methylpyridin-2-yl)-l-phenyl-lH-l,2,4~ triazol-5-yl)benzamide (Compound S3)
[701] To a solution of 5-(3-methyl-2-pyridyl)-2-phenyl-l ,2,4-triazol-3-amine (55 mg, 219 pmol, 1.0 eq), pyridine (98 mg, 1.24 mmol, 5.7 eq) and DMAP (26 mg, 213 pmol, 0.97 eq) in toluene (9 mL) was added the solution of 2-methylbenzoyl chloride (100 mg, 647 mol, 3.0 eq) in toluene (1 mL) dropwise at 80 °C. Then the mixture was stirred at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in CH3CN (10 mL) and adjusted the pH to 11-12 by saturated aqueous LiOH and stirred at 15 °C for 16 h. The reaction mixture was extracted with DCM (30 mL). The organic layer was washed with satuirated NaHC03 (30 mL), brine (30 mLxl), dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by prep-HPLC (column: Phenomenex Synergi 08 150x25x10 pm; mobile phase: [water (0.05%HCl)-ACNj; B%: 30%- 45%,7.8min) lo give 2-methyl-N-[5- (3-methyl-2-pyridyl)-2-pheny]-l,2,4-triazol-3- yljbenzamide (16.1 mg, 17.54% yield, HC! salt) as a white solid. LC-MS (ESI): m/z (M+H) 370.2; 11 1 NMR (400 MHz, DMSO-d6) 11.30 is. 11 1 ). 8.69-8.68 (d. 11 1). 8.26-8.24 (d, 1 1 1 ). 7 77-7.71 (m, 3H), 7.64-7.61 (m, 2H), 7.57-7.49 (m, 2H), 7.45-7.41 (td, 1H), 7.34-7.29 ( , 21 1 ). 2 74 (s, 31 1 ). 2 22 (s, 31 1 ).
Figure imgf000151_0001
Compound Y1
[702] Step A; To a mixture of pyridine-2-carbonitrile (10.0 g, 96.1 mmol) in ;-PrOH (57.7 g, 960 mmol, 9.99 eq), NaOMe (155 mg, 2.87 mmol, 0.03 eq) was added at 0 °C. Then the mixture was stirred at 20 °C for 4 hr. The mixture was concentrated under vacuum to give a residue n- Hexane (50 mL) and AcOH (0.15 mL) -was added to the residue. Then the solution was filtered and the filtrate was concentrated under vacuum to give isopropyl pyridine-2-carboximidate (crude, 2) as brown oil, which was used for the next step without further purification.
[703] Step B: A solution of NH2CN (7.5 g, 178 mmol, 1.95 eq), sodium dihydrogen phosphate (42.0 g, 350 mmol, 3.83 eq) and Na2HP04*12H20 (32.0 g, 89.4 mmol, 0 98 eq) in HiO (100 mL) was added isopropyl pyridine-2-carboximidate (15.0 g crude, 1.0 eq, 2). Then the mixture was stirred at 20 °C for 16 h. DCM (300 mL) was added to the reaction mixture. The organic layer was concentrated under vacuum. The residue was purified by flash chromatography (ISCO®; 220 g Sepa Flash® Silica Flash Column, eluent of 0-25% Ethyl acetate/Petroleum ether gradient at 100 mL/min; TLC (petroleum ether/ethyl acetate = 5/1, Rr = 0.24) to give isopropyl A-cyanopicolinimidate (10.0 g, 57% yield, 3) as a white solid. LC- MS (ESI): m/z (M+H) 190.1; ¾ NMR (400 MHz, DMSO-t/,) 8.81-8.79 ini. ! ! ! ). 8.1 1 -8.07 (dt, 1H), 7 95-7.93 (m, 1H), 7.74-7.71 (m, 1H), 5 34-5.28 (hepl, 1H), 1.41-1.39 (d, 6H).
[704] Step C: A mixture of isopropyl L'-cyanopicolinimidate (1.0 g, 5.29 mmol, 3) and phenylhydrazine (627 mg, 5.80 mmol, 1.1 eq) in MeOH (15 mL) was stirred at 80 °C for 16 h. After being cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography (TLC: petroleum ether/ ethyl acetate=0/L Rr =0.1) (SiO?., petroleum ether/ethyl acetate=l/0, 5/1, 2/1, 0: 1) to afford 2-phenyl- 5-(2-pyridyi)-l,2,4-triazol-3-amine (900 mg, 70% yield, 4) as a brown solid. LC-MS (ESI): m/z (M+H) 238.1.
[705] Step D: To a mixture of 2-phenyI~5~(2~pyridy!)-l,2,4-triazol-3-amine (200 mg, 843 «mol, 1.0 eq, 4) and NaOH (180 mg, 4.50 mmol, 5.34 eq) in THF (2 mL) and H20 (2 mL), benzoyl chloride (242 mg, 1.72 mmol, 2 04 eq) was added. Then the mixture was stirred at 20 °C for 20 h. The reaction mixture was adjusted to pH = 7 by HCI (2 M in water, 2 mL). The mixture u as concentrated under vacuum. The residue was purified by reversed phase column (HCI condition) to give 7V-[2-phenyl-5-(2-pyridyl)-l,2,4-triazol-3-yl]benzamide (70.1 mg, 21 % yield, Compound Yl) as a white solid LC-MS (ESI): m/z (M+H) 342, 1; 3H NMR (400 MHz, DMSO-O¾+D20) 8.83-8.82 (d, 1H), 8.44-8.41 (m, 2H), 7.97-7.95 (d, 2H), 7.89-7.86 (m, 1H), 7.74-7.72 (m, 2H), 7.64-7.60 (m, 1H), 7.55-7.50 (m, 4H), 7.48-7.44 (dd, 1H). !3C NMR (100 MHz, DMSO-dy) 167.1 , 156.7, 148.8, 146.8, 145.5, 142,9, 137.0, 133 3, 132.5, 130.0, 129.6, 129.1 , 128.6, 126.6, 123.8, 123.5.
Example 14: Synthesis of iV,/V-(l-(4-(trifluoromethox )phenyl)- 177-1, 2, 4-triazole-3, 5- diyl)bis(2-methylbenzamide) (Compound 42)
Figure imgf000152_0001
[706] Compound 42 can be synthesized according to Examples 8 and 9. (4- (Trifluoromeihoxy)phenyl)hydrazine can be prepared starting from 4- (trifiuoromethoxy)aniline instead of 4-iodoaniline according to Example 10, step a. Compound 42 can then be prepared in two steps according to Example 11 starting with (4- (Trifluoromethoxy)pheny])hydrazine instead of pheny lhydrazine.
[707] 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.
[708] While the invention has been described in connection with proposed specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth and as follow-s in the scope of the appended claims.

Claims

WHAT IS CLAIMED IS:
1. A compound of formula (I):
Figure imgf000154_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein:
L1, L’ and Id are each independently selected from a bond, alkylene, or alkenylene;
M1 and M2 are each independently selected from -NR4-, -NR4C(G)~, -N(C(0)R1)~, - C(0)NR4-, -NR4C(0)NR4-, -C(Q)-, -C(=NR4)-, -C(=NQR4)-, -OC(O)-, -C(Q)0-, -0C(0)0-, -0C(0)NR4-, -NR4C(0)0-, -S(0)m-, -S(0 .NR4~, or -NR4S(0)m-, provided that M! and M2 are not both -NR4-;
R1 and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, a ryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cydoalkylalkyi, aryialkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyd, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
R3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocyc!oaikyl, heteroaryl, cycioa!ky!aikyl, aryla!kyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cydoalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R7;
R4 is each independently H, alkyl, wherein each alkyl is optionally substituted with one or more R5;
R5 is each independently I, Br, Cl, F, -CFI2F, -CHF2, -CF3, -OCFs, -CN, -alkyl-CN, - COM ! ·. -CON! IRC -CONR6R6, -COO! !. -NI K -NHR6, -NO-. -NR6R6, -N3, -OH, OR6, - CQQR6, -OSO3R6, oxo, R6, -SH, -SQ2.R6, -SO ti l. -SO3R6, or -SR6:
R6 is each independently alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl; or alternatively two Rb on the same N atom can together form a 3-6 membered N- heterocyclyl;
R7 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CF3, -OCF3, -CN, -alkyl-CN, - CONH2, -CONHR6, -CONR6R6, -COOH, -NFI2, -NHR6, -NO2, -NR6R6, -Ns, -OH, OR6, - COQR6, -OSQ3R6, oxo, R6, -SH, -SO2R6, -SO3H, -SO3R6, -SR6, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocydyl, aryl, and heteroaryl is optionally substituted with one or more R5;
m is 0, 1, or 2; and
wherein the compound is not AyV’-(l-phenyl-l//-l,2,4-triazole-3,5-diyl)dibenzamide, 7V-(3- benzamido- 1 -phenyl- i//~l,2,4-triazol-5-yl)furan-2-carboxamide, /V-(5-cinnamamido-l- phenyl-l//-l,2,4-triazol-3-yl)benzamide, /'/-(! -phemi-5-(phenylamino)~ 1H-12, 4-triazo!-3~ yljbenzamide, 4-fluoro-/V-(5-(4-methoxybenzamido)-l -phenyl- li -l, 2, 4-triazol-3- y IJbenzami de, NN'-( 1 -phenyl- Hi- 1 ,2,4-tri azole-3, 5 -diy l)bi s(4-methy ibenzamide), N-{5 -((2- chlorobenzyl)amino)~i~phenyl~ i/7~l,2,4~iriazol-3-yi)-2~f3uorobenzamide, Y-(3-benzamido-l- phenyl-li -l,2,4-triazol-5-yl)-4-fluorobenzamide, Afr-(3-benzamido-l-phenyl-l/ -l,2,4~ triazol-5-yl)-4-nitrobenzamide, /V-(3-benzamido-l-phenyl-l//-l,2,4-triazol-5-yl)-3- nitrobenzamide, and 4-((3 -benzamido- 1 -pheny 1 - III- 1 ,2,4-triazol-5 -y 1 lcarbamoy l)benzoic acid.
2. The compound of claim 1, wherein L1, L2 and L3 are each independently a bond.
3. The compound of claim 1 or 2, wherein M! and M2 are each independently selected from -NR4-, -NR4C(0)-, -C(0)NR4~, -N(C(0)R1)-, or -NR4S(0)n!-.
4. The compound of any one of claims 1-3, wherein M1 and M2 are each independently selected from -NR4-, -NR4C(())- or -C(0)NR4-.
5. The compound of claim 3 or 4, wherein R4 at each occurrence is independently H or alkyl.
6. The compound of any one of claims 1-5, wherein L3 is a bond and R3 is an aryl or a heteroaryl, optionally substituted with one or more R7.
7. The compound of claim 6, wherein R3 is a phenyl or phenyl fused bicycle, optionally substituted with one or more R7.
8. The compound of claim 6, wherein R ' is heteroaryl selected from imidazolyl or pyrazolyl, optionally substituted w th one or more R7.
9. The compound of any one of claims 6-8, wherein R7 is each independently I, Br, Cl,
F, -CFI2F, -CHF, -CF, -OCFs, -CN, ~NH2, -NMe?, -NO?, -Ns, -OFF OR6, R6, ~SH, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, a yl, and heteroaryl is optionally substituted with one or more RF
10 The compound of claim 7, wherein R3 is a phenyl substituted with a 4-6 membered heterocyclyl, which is optionally substituted with one or more R7.
1 1. The compound of claim 8, wherein R1 and R2 are each independently selected from phenyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, phenyl-(Ci-Cs alkyl)-, phenyi-(C?.-C3 alkenyl)-, 5-6 membered heteroaryl -(Ci-C 3 alkyl)-, or heteroaryl~(C2~C3 alkenyl)-, wherein each cycloalkyl, aryl, heteroaryl portion is optionally substituted with one or more R5.
12. The compound of claim 11, wherein the 6-10 membered aryl or 5-10 membered heteroaryl is a bi cyclic ring.
13. The compound of any one of claims 1-12, wherein R5 is selected from I, Br, Cl, F, Ci- Ce alkyl, alkynyl, -CN, -(Ci-Cs alkylene)-CN, -NH?„ -NO?., -Ns, -OH, -OCFs, -OMe, -NMe?, or -NEt?.
14. The compound of any one of claims 1-6, wherein at least one of R!, R2, and R3 is phenyl and substituted with at least one of methyl, ethyl, -CºCH, I, Br, Cl, F, -CF3, -CN, - CH2CN, -CH2CH2CN, -M l·. -NOL -Ns, -OH, -OP· :. -OMe or -NMe2.
15. The compound of claim 1 -6, wherein at least two of R], R2, and R3 is phenyl and substituted with at least one of methyl, ethyl, -CºCH, I, Br, Cl, F, -CF3, -CN, -CH2CN, - CH2CH2CN, -M i’. -NO2, -Ns, -OH, -OCF3, -OMe or -NMe?..
16. The compound of claims 14 or 15, wherein at least one of R1, R2, and R3 is pyridyl, optionally substituted with one or more of methyl, ethyl, -CºCH, I, Br, Cl, F, -CF3, -CN, - Ci i’CM -CH2.CH2.CN, -M l··. -NO?., -Ns, -OH, -OCF3, -OMe or -NMe?.
17. The compound of claim 1 , wherein the compound has the structure of formul a (F)
Figure imgf000157_0001
or a pharmaceutically acceptable salt or sol vate thereof, wherein:
L3, M1, M2, R1, R2, and R3 are as defined in claim 1.
18. The compound of claim 17, wherein M1 and M2 are each independently selected from -NR4-, -NR ! '({))-. -C(0)NR4-, -N CfOjll1)-, or -NR4S(0)m-.
19. The compound of claim 17, wherein R] and R2 are each independently selected from phenyl, 6-10 membered aryl, 5-10 membered heteroaryl, 4-10 membered heterocyclyl, phenyl-(Ci-C3 alkyl)-, phenyi-(C?.-C3 alkenyl)-, 5-6 membered heteroaryl-(Ci-C3 alkyl)-, or heteroaryl-(C2-C3 alkenyl)-, wherein each cycloalkyl, aryl, heteroaryl portion is optionally substituted with one or more R5; and
R3 is an aryl or a heteroaryl, optionally substituted with one or more R7.
20. The compound of claim 1, wherein the compound has the structure of formula (IA)
Figure imgf000157_0002
or a pharmaceutically acceptable salt or solvate thereof, wherein:
M1 and M2 are each independently selected from -NR4C(0)- or -C(0)NR4-;
R1 and R2 are each independently
Figure imgf000157_0003
R3 is selected from
Figure imgf000157_0004
R4 is each independently H or C1-C3 alkyl; and R7a, R7b, R7e, and R7e is each independently H, I, Br, Cl, F, -CH2F, -CHF2, -CFs, -
OCF3, -N3, -CN, -OH, raethyl, ethyl, propyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C1-C3 haioalkoxy;
R7c is H, I, Br, Cl, F, -CFI2F, -CHF2, -CFs, -OCFs, -N3, -CN, -OH, Ci-Cs alkyl, Ci-Cs haloalkyl, C1-C3 alkoxy, C1-C3 haioalkoxy, 4-6 membered heterocyclyl, or 5-6 membered heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one or more R5;
R5 is I, Br, Cl, F, -CH2F, -CHF2, -CFs, -Ci-Ce alkyl, alkynyl, -CN, -(C1-C3 alkylene)- CN, -M l·. -NO2, -Ns, -OH, -OCFs, -OMe, -NMez, -NEla, or -C(0)0(Ci-Ce alkyl);
wherein at least one of R7a, R7b, R7c, R7e, and R7eis not H.
21. The compound of claim 20, wherein R3 is selected from
Figure imgf000158_0001
22. The compound of claim 21, wherein four of R7a, R7b, R7c, R7e, and R7e is H.
23. The compound of claim 21, wherein three of R7a, R7b, R7c, R7e, and R7eis H.
24. The compound of any one of claims 20-23, wherein R7a, R7b, R7c, R7e, and R7e is each independently H, I, Br, Cl, F, -CH2F, -CHF2, -CFs, -OCF3, -N3, -CN, -OH, methyl, ethyl, propyl, -C t i l: -CN, -NH2, -NO2, -Ns, -OH, -OCF3, -OMe, -NMe?, or -M il ·.
25. The compound of claim 20, wherein
Figure imgf000158_0002
26 The compound of claim 25, wherein R7c is I, Br, -CFI2F, -CHF2, -CFs, methyl, ethyl, propyl, -CºCH; -CN, -NH2, -NO2, -Ns, -OH, -OCFs, -OMe, -NMe2, or -Mil·.
27. The compound of claim 25, wherein R7c is I, Br, -CH2F, -CFIF2, -CFs, -OCF3, or - OMe.
28. The compound of claim 25, wherein R/c is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or pyrazolyl, each optionally substituted with one or more R5.
29. The compound of claim 1 , wherein the compound has the structure of formula (IB);
Figure imgf000159_0001
or a pharmaceutically acceptable salt or sol vate thereof, wherein:
M'! and M2 are each independently selected from -NR4-, -NR4C(0)- or -C(0)NR4-;
R1 and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, and, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arytalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cyc!oalky!, atyl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
wherein one of -M! R! and -M2 R2 is -NR4-(cycloalkylalkyT), -NR4-(heterocydylalkyl), -NR4-(arylalkyl), or -NR4-(heteroaiyl alkyl), wherein cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
RJ is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, aryl alkyl, arylalkenyl, arylalkynyl,
heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, atyl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R7;
R4 is each independently H or C1-C3 alkyl;
R5 is I, Br, Cl, F, -CH2F, -CHF2, -CFs, -Ci-Ce alkyl, alk nyl, -CN, -(C1-C3 alkylene) CN, -M l ··. -NO2, -N3, -OH, -OCF3, -OMe, -NMez, -NEt?„ or -C(0)0(Ci-Ce alkyl); and
R7 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CF3, -OCF3, -CN, -alkyl -CN, - COM I ·. -CONHR6, -CONR6R6, -COOH, -M l·. -NHR6, -NO:·. -NR6R6, -N3, -OH, OR6, -
CQQR6, -OSQ3R6, oxo, R6, -SH, -SO2R6, -SO ! 1. -SO3R6, -SR6, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R5.
30. The compound of claim 29, wherein one of -M1_R! and -M2 R2 is -NR4-(Ci-C:< alkylenej-cycloalkyl, -NR4-(CI-C3 alkylene)-heterocyclyl, -NR4-(CI-C3 alkylene)-aryl, or - NR4-(CI-C3 alkylene)-heteroaryl; wherein cycloalkyl, aryl, heteroaryd, and heterocyclyl is each optionally substituted with one or more R5.
31. The compound of claim 29, wherein one of -M! Rf and -M2 R is -NR4-(CI-CJ alkylene)-phenyl, or -NR4-(CI-C3 alkylene)-pyridyl, wherein phenyl and pyridyl is each optionally substituted with one or more R5.
32. The compound of claim 31, wherein one of -M^R1 and -M2~R2 is -NR4-CH2~phenyl, -
Figure imgf000160_0001
Figure imgf000160_0002
wherein phenyl and pyridyl is each optionally substituted with one or more R5.
33. The compound of any one of claims 29-32, wherein R! and R2 are each independently selected from phenyl or pyridyl, each optionally substituted with one or more R5.
34. The compound of any one of claims 29-31, wherein one of -IVTll1 and -M2 R2 is - NR4-(CI-C3 alkylene)-phenyl, or -NR4-(Ci-Cs aikylene)-pyndyl, and the other one of -IVR R1 and -M2 R2 is -NR4C(0)-phenyl, -NR4C(0)-pyridyl, -C(0)NR4-phenyl, or -C(0)NR4-pyridyl; wherein each phenyl and pyridyl is optionally substituted with one or more R5.
35. The compound of claim 34, wherein one of -M^R1 and -M2~R2 is -NR4-(CI-C3 alkylene)-phenyl, or -NR4-(CJ -C3 alk lene)-pyridyl, wherein each phenyl and pyridyl is optionally substituted with one or more R\ and the other one of -M^R1 and -M R2 is
Figure imgf000161_0001
36. The compound of claim 35, wherein one of -M1_R! and -M2 R2 is -NR4-(Ci-C:< alkylenej-phenyl, or -NR4-(CI-C3 alkylene)-pyridyl, wherein each phenyl and pyridyl is optionally substituted with one or more R5, and the other one of -M^R1 and -M2 R2 is
Figure imgf000161_0002
37 The compound of any one of claims 29-36, wherein R3 is phenyl, optionally substituted with one or more R7; and
R7 is each independently I, Br, Cl, F, -CH?.F, -CHF?, -CFs, -OCFs, -CN, -N3, -OH, methyl, ethyl, propyl, -CºCH; -CN, -NH2, -NO?, -N3, -OH, -OCF3, -OMe, -NMe2, or -NEC.
38. The compound of any one of claims 29-37, wherein R5 is selected from 1, Br, Cl, F, - Cl I 1 . -CHF2, -CF3, -OCF3, -NS, -CN, -OH, methyl, ethyl, propyl, -CºCH; -CN, A I k -NO?,
-Ns, -OH, -OCF3, -OMe, -NMe?, or -NEta.
39. The compound of any one of claims 29-38, wherein the compound is not
Figure imgf000161_0003
40. The compound of claim 1, wherein the compound has the structure of formula
Figure imgf000161_0004
Figure imgf000162_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein:
R5 is cycioalkyialkyl, heterocyclylalkyl, arylalkyl, or heteroarylalkyi, wherein cycloalky], aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R3;
R2 is selected from cycloalkyl, aryl, biphenyl, heterocyclyl, or heteroaryl, wherein each optionally substituted with one or more R5;
R3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycioalkyialkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyi, heteroaryialkenyl, or heteroarylaikynyl, wherein each cycloalky], aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more
R4 is each independently H or C1-C3 alkyl;
R5 is I, Br, Cl, F, -CH2F, -CHF2, -CF3, -Ci-Ce alkyl, alkynyl, -CN, -(C1-C3 alkylene)- CN, -NH2, -NOv -Nr, -OH, -OCF3, -OMe, ~NMe2, -NEta, or -C(0)0(Ci-C6 alkyl); and
R7 is each independently 1, Br, Cl, F, -CH2F, -CHF2, -CF3, -OCF3, -CN, -alkyl-CN, - CONH2, -CONHR6, -CONR6R6, -COOH, -NH2, -NHR6, -NO2, -NR6R6, -N3, -OH, OR6, - COOR6, -OSO3R6, oxo, R6, -SH, -SO2R6, -SO3H, -SO3R6, -SR6, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, and, and heteroaryl is optionally- substituted with one or more R5.
41 The compound of claim 40, wherein R1 is -C1-C3 alkylene-cycloalkyl, -C1-C3 alkylene-heterocyclyl, -C1-C3 alkylene-aryl, or -C1-C3 alkydene-heteroaryd; wherein cycioalkyl, aryl, heteroaryl, and heterocyclyl is each optionally substituted with one or more
42. The compound of claim 41, wherein R1 is -C1-C3 alkylene-phenyl or -C -Cs alkylene- pyndyl, wherein phenyl and pyridyl is each optionally substituted with one or more R5.
43. The compound of claim 42, wherein R5 is -CHz-phenyl, -CH2CH2-phenyl, -CH?-
Figure imgf000163_0003
Figure imgf000163_0001
wherein phenyl and pyridyl is each optionally substituted with one or more R:
44. The compound of any one of claims 40-42, wherein R2 is aryl or 5-6 membered heteroaryl, each optionally substituted with one or more R’
45. The compound of claim 44, wherein R2 is phenyl optionally substituted with one or more R’
46. The compound of any one of claims 40-45 or 134, wherein R3 is phenyl, optionally substituted with one or more R7; and
R7 is each independently I, Br, Cl, F, -CFI2F, -CHF2, -CF3, -OCF3, -CN, ~N3, -OH, methyl, ethyl, propyl, -CºCH; -CN, -NH2, -NO2, -N3, -OH, -OCF3, -OMe, -NMe?, or -NEt?
47. The compound of any one of claims 40-46 or 134, wherein R5 is selected from I, Br, Cl, F, -CH2F, -CHF2, -CF3, -OCF3, -Ns, -CN, -OH, methyl, ethyl, propyl, -CºCH; -CN, -NH2, -NO?., -Ns, -OH, -OCF3, -OMe, -NMe?, or -NEt?.
48. The compound of claim 1 , wherein the compound has the structure of formula (TC):
Figure imgf000163_0002
or a pharmaceutically acceptable salt or solvate thereof, wherein:
M1 and M2 are each independently selected from -NR4-, -NR4C(0)- or -C(0)NR4-;
R1 and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyi, 5-6 membered heteroaryl, cydoalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or
heteroaryialkyny!, wherein each cycloalkyl, atyl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more Rs;
wherein at least one of -Mti R1 and -M2 R2 is -NR4-(4-6 membered heterocyclyl), -NR4- (5-6 membered heteroaryl), or -NR4-naphthalenyl, wherein 4-6 membered heterocyclyl, 5-6 membered heteroaryi, and naphthalan 1 is each optionally substituted with one or more Rs;
R3 is selected phenyl, optionally substituted with one or more R7;
R4 is each independently H or C1-C3 alkyl; and
R5 and R7 are each independently selected from !, Br, Cl, F, -CH2F, -CHF2, -CF3, -Ci- C6 alkyl, alkynyl, -CN, -(CI-CJ alkylene)-CN, -NH2, -NO2, -NT, -OH, -OCF3, -OMe, -NMe?., - NEtr, or ( {(>)()((' : -(' alkyl).
49. The compound of claim 48, wherein at least one of -IViti R1 and -M2 R2 is -NR4- azetidinyl, -NR4-pyrrolidinyl, -NR4-piperidmyl, -NR4-imidazolyl, -NR4-isoxazolyl, -NR4- oxazolyl, -NR4 -thiazolyl, -NR4-thiophenyl, -NR4-pyridyl, -NR4-pyridazinyl, -NR4-pyrazinyl, - NR4-pyrimidinyl, or ~NR4~pyridinone, wherein each of azetidinyl, pyrrolidinyl, piperidinyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, pyridyl, pyndazinyl, pyrazinyl, pyrimidinyl, or pyridinone is optionally substituted with one or more R5.
50. The compound of claim 48, wherein at least one of -MO Rf and -M2 R2 is -NR4-pyridyl, wherein pyridyl is optionally substituted with one or more R5.
51. The compound of any one of claims 48-50 wherein -IVf R1 and -M2 R2 are each -NR4- pyridyl, wherein pyridyl is optionally substituted with one or more R5.
52. The compound of claim 48-50, wherein one of -M^R1 and -M2 R2 is -NR4-azetidinyl, -NR4-pyrrolidinyl, ~NR4~piperidinyl, -NR4-imidazolyl, ~NR4~isoxazolyi, ~NR4~oxazolyi, - NR4-thiazolyl, -NR4-thiophenyi, -NR4 -pyridyl, -NR4-pyridazinyl, -NR4-pyrazinyl, -NR4- pyrimidinyl, or -NR4-pyridinone, wherein each of azetidinyl, pyirolidinyl, piperidinyl, imidazolyl, isoxazolyl, oxazo!yi, thiazolyl, pyridyl, pyridazinyl, pyrazinyl, pyrimidiny!, or pyridinone is optionally substituted with one or more R5, and the other one of -Mh R1 and
Figure imgf000165_0001
53. The compound of claim 52, wherein one of -MTR1 and -M2 R2 is-NR4-azetidinyl, - NR4-pyrrolidinyl, -NR4-piperidmyl, -NR4-imidazolyl, -NR4-isoxazolyl, -NR4-oxazolyl, -NR4- thiazoly!, -NR4-thiophenyl, -NR4-pyridyl, -NR4-pyridazinyl, -NR4~pyrazinyl, -NR4- pyrimidinyl, or -NR4 -pyridinone, wherein each of azetidinyl, pyrrolidinyl, piperidmyl, imidazolyl, isoxazolyl, oxazoiyl, thiazolyi, pyridyi, pyridazinyl, pyrazinyi, pyrimidmyl, or pyridinone is optionally substituted with one or more R1, and the other one of -M1_Rl and -
Figure imgf000165_0002
54. The compound of any one of claims 48-53, wherein R3 and R7 is each selected from I, Br, Cl, F, -CH2F, -CHF2, -CFS, -OCFS, ~N3, -CN, -OH, methyl, ethyl, propyl, -CºCH; -CN, - NH2, -NO ' -N3, -OH, -on· :. -OMe, ~NMe2, or -NEte.
55. The compound of any one of claims 48-54, wherein the compound is not
Figure imgf000165_0003
56. The compound of claim 1, wherein the compound has the structure of formula (ID):
Figure imgf000166_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein:
M1 and M2 are each independently selected from -NR4-, -NR4C(())- or -C(0)NR4-;
R] and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkyl alkyl, arylalky!, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
R3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl,
heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R7;
R4 is each independently H or C1-C3 alkyl; and
R5 and R7 are each independently selected from I, Br, Cl, F, -CFI2F, -CHF2, -CF3, -Ci- C6 alkyl, alkynyl, ~CN, -(C1-C3 alkylene)-CN, -NH2, -NO2, -N3, -OH, -OCF3, -OMe, -NMe2, - NEt2, or -C(0)0(Ci-C6 alkyl);
wherein at least one of R1 and R2 is a phenyl substituted with at least one of -CºCH or \\
57. The compound of claim 56, wherein M1 and M2 are each -NR4C(0)-.
58. The compound of claim 56 or 57, wherein, at least one of R1 and R2 is a phenyl substituted with at least one of -CºCH or -N3 and the other one of R1 and R2 is a phenyl or pyridyl, optionally substituted with one or more R5.
59. The compound of any one of claims 56-58, wherein R3 is phenyl optionally substituted with one or more R7.
60. The compound of any one of claims 56-59, wherein R5 and R7 is each selected from I,
Br, Cl, F, -CFI2F, -CHF2, -CFs, -OCFj, -Ns, -CN, -OH, methyl, ethyl, propyl, -CºCH, -CN,
NH2, -NO2, -Ns, -OH, -OCF3, -OMe, -NMe2, or -NET.
61. The compound of claim 1 , wherein the compound has the structure of formula (IE):
Figure imgf000167_0001
or a pharmaceutically acceptable salt or sol vate thereof, wherein:
M1 and M2 are each independently selected from -NR4-, -NR4C(0)~, -C(0)NR4-, or - S(0)mNR4-;
R5 and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, and, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, aryl alkyl, arylalkenyl, arylalkynyl, heterocydylalkyl, heteroaiylalkyl, heteroaiylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
R3 is selected from an aryl or heteroaryl, wherein aryl and heteroaryl is optionally substituted with one or more R7;
R4 is each independently H or C1-C3 alkyl; and
R' and R7 are each independently selected from I, Br, Cl, F, -CH2F, -CHF2, -CF3, -Ci- C& alkyl, alk nyl, -CN, -(C1-C3 alkylene)-CN, -NH2, -NO2, -N3, -OH, -OCF3, -OMe, -NMe2, - NEt?., or -C(0)0(Ci-C6 alkyl);
wherein when M1 and M2 are both -NR4C(0)-, at least one of R1 and R2 is selected
Figure imgf000167_0002
62. The compound of claim 61, wherein M1 and M2 are both -S(0)mNR4-.
63. The compound of claim 61, wherein M1 and M2 are both -C(0)NR4-.
64. The compound of any one of claims 61-63, wherein at least one of R1 and R2 is a phenyl or pyridyl, optionally substituted with one or more R5.
65 The compound of any one of claims 61-64, wherein R! and R2 is phenyl, optionally substituted with one or more R5.
66. The compound of any one of claims 61 -65, wherein at least one of R1 and R2 is
Figure imgf000168_0002
67. The compound of any one of claims 61-66, wherein at least one of R3 is a phenyl or pyridyl, optionally substituted with one or more R7.
68 The compound of any one of claims 61-67, wherein R3 and R7 is each selected from I, Br, Cl, F, -CH2F, -CTIF2, -CF3, -OCFs, -N3, -CN, -OH, methyl, ethyl, propyl, -CºCH, -CN, - NH2, -NOL -N3, -OH, -OP· :. -OMe, -NMe2, or -NEte.
69. The compound of any one of claims 61 -68, wherein the compound is not
Figure imgf000168_0001
70. The compound of claim 1 , wherein the compound has the structure of formula (IF)
Figure imgf000169_0001
or a pharmaceutically acceptable salt or solvate thereof, wherein:
M1 is selected from -NR4-, -NR4C(0)- or -C(0)NR4-;
R3 and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyeiyl heterocycloalkyl, 5-6 membered heteroaryl, cycloa!ky!aikyl, ary!aikyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroaryla!kenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyeiyl portion is optionally substituted with one or more R’;
R3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyeiyl heterocycloalkyl, heteroaryl, cycloa!kylalkyi, arylalkyl, arylalkenyl, arylalkynyl,
heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, axyl, heteroaryl, and heterocyeiyl portion is optionally substituted with one or more R7;
R4 is each independently H or C1-C3 alkyl; and
R5 and R7 are each independently selected from I, Br, Cl, F, -CFI2F, -CHF2, -CF3, -Ci- C6 alkyl, alkynyl, ~CN, -(C1-C3 alkylene)-CN, -NH2, -NO2, -N3, -OH, -OCF3, -OMe, -NMe2, - NEt2, or -C(0)0(Ci-C6 alkyl).
71. The compound of claim 70, wherein R3 and R2 are each independently selected from aryl or 5-6 membered heteroaryl, each optionally substituted with one or more R5.
72 The compound of claim 70, wherein R2 is phenyl optionally substituted with one or more R5.
3. The compound of claim 72, wherein R2 is
Figure imgf000169_0002
74 The compound of any one of claims 70-73, wherein R3 is cycloalkyl, aryl, heterocyeiyl, or heteroaryl, each optionally substituted with one or more R7.
75. The compound of any one of claims 70-74, wherein R3 is phenyl optionally substituted with one or more R7.
76 The compound of claim 1 having one of the following structures:
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
or a pharmaceutically acceptable salt thereof.
77 Ίΐie compound of claim 1, having one of the following structure:
Figure imgf000181_0003
79. A compound having one of the following structures:
Figure imgf000181_0002
or a pharmaceutically acceptable salt thereof.
80. The compound of claim 1, wherein compounds of Table A are excluded.
81. The compound of any one of claims 1-75 or 134, wherein compounds of Table A are excluded.
82. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of any one of claims 1-81 or 134.
83. The pharmaceutical composition of claim 82, wherein the compound has the following structure:
Figure imgf000182_0001
pharmaceutically acceptable salt thereof.
84. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and
Figure imgf000182_0002
pharmaceutically acceptable salt thereof.
85. The pharmaceutical composition of any one of claims 82-84, further comprising one additional therapeutically active agent.
86. A method of modulating a Parkin !igase, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-81 or 134.
87. A method of modulating a Parkin ligase, comprising administering to a subject in
need thereof an effective amount of a compound
Figure imgf000183_0001
pharmaceutically acceptable salt thereof.
88. A method of treating a disease or a condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 -81 or 134.
89. A method of treating a disease or a condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of
Figure imgf000183_0002
pharmaceutically acceptable salt thereof.
90. The method of claim 88 or 89, wherein the disease or the condition is cancer.
91. The method of claim 90, wherein the cancer is Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, AIDS-Related Cancers, Kaposi Sarcoma, Lymphoma, Anal Cancer, Appendix Cancer, Astrocytomas, Childhood Atypical Teratoid/Rhabdoid Tumor, Basal Cell Carcinoma, Skin Cancer (Nonmelanoma), Childhood Bile Duct Cancer, Extrahepatic Bladder Cancer, Bone Cancer, Ewing Sarcoma Family of Tumors, Osteosarcoma and Malignant Fibrous Histiocytoma, Brain Stem Glioma, Brain Tumors, Embryonal Tumors, Germ Cell Tumors, Craniopharyngioma, Ependymoma, Bronchial Tumors, Burkitt Lymphoma (Non-Hodgkin Lymphoma), Carcinoid Tumor, Gastrointestinal Carcinoma of Unknown Primary, Cardiac (Heart) Tumors, Lymphoma, Primary, Cervical Cancer, Childhood Cancers, Chordoma, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Chronic Myeloproliferative Neoplasms Colon Cancer, Colorectal Cancer, Cutaneous T-Ceil Lymphoma, Ductal Carcinoma In Situ, Endometrial Cancer, Ependymoma, Esophageal Cancer, Esthesi oneurobl astoma, Ewing Sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer, Intraocular Melanoma, Retinoblastoma, Fibrous Histiocytoma of Bone, Malignant, and Osteosarcoma, Gallbladder Cancer, Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumors, Extragonadal Cancer, Ovarian Cancer, Testicular Cancer, Gestational Trophoblastic Disease, Glioma, Brain Stem Cancer, Hairy Cell Leukemia, Head and Neck Cancer, Heart Cancer, Hepatocellular (Li ver) Cancer, Histiocytosis, Langerhans Cell Cancer, Hodgkin Lymphoma, Hypopharyngeal Cancer, Intraocular Melanoma, Islet Cell Tumors, Pancreatic Neuroendocrine Tumors, Kaposi Sarcoma, Kidney Cancer, Renal Cell Cancer, Wilms Tumor and Other Childhood Kidney Tumors, Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia, Chronic Lymphocytic Cancer, Chronic Myelogenous Cancer, Hairy' Cell Cancer, Lip and Oral Cavity Cancer, Liver Cancer (Primary'), Lobular Carcinoma In Situ (LCIS), Lung Cancer, Non-Small Cell Cancer, Small Cell Cancer, Lymphoma, Cutaneous T-Cell (Mycosis Fungoides and Sezary Syndrome), Hodgkin Cancer, Non-Hodgkin Cancer, Macroglobulinemia, Waldenstrom, Male Breast Cancer, Malignant Fibrous Histiocytoma of Bone and Osteosarcoma, Melanoma, Intraocular (Eye) Cancer, Merkel Cell Carcinoma, Mesothelioma, Malignant, Metastatic Squamous Neck Cancer with Occult Primary', Midline Tract Carcinoma Involving NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms, Myelogenous Leukemia, Chronic, Myeloid Leukemia, Acute, Myeloma Multiple, Chronic Myeloproliferative Neoplasms, Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity- Cancer, Lip and Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Epithelial Cancer, Low Malignant Potential Tumor, Pancreatic Cancer, Pancreatic Neuroendocrine Tumors (islet Cell Tumors), Papillomatosis, Paraganglioma, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, Pituitary Tumor, Plasma Cell Neoplasm/Multiple Myeloma, Pieuropulmonary Blastoma, Primary Central Nervous System Lymphoma, Rectal Cancer, Renal Cell (Kidney) Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary- Gland Cancer, Sarcoma, Ewing Cancer, Kaposi Cancer, Osteosarcoma (Bone Cancer), Soft Tissue Cancer, Uterine Cancer, Sezary Syndrome, Skin Cancer, Childhood Melanoma, Merkel Cell Carcinoma, Nonmelanoma, Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma, Skm Cancer (Nonmelanoma), Childhood Squamous Neck Cancer with Occult Primary, Metastatic Cancer, Stomach (Gastric) Cancer, T-Cell Lymphoma, Cutaneous Cancer, Testicular Cancer, Throat Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Unknown Primary, Carcinoma of Childhood, Unusual Cancers of Childhood, Urethral Cancer, Uterine Cancer, Endometrial Cancer, Uterine Sarcoma, Vaginal Cancer, V ulvar Cancer, Waldenstrom Macroglobulinemia, Wilms Tumor, or Women's Cancers.
92, The method of claim 90, wherein the cancer is colon cancer, lung cancer, or ovarian cancer.
93. The method of claim 86 or 88, wherein the compound has one of the following structures:
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
ı92
Figure imgf000195_0001
Figure imgf000196_0001
94 The method of claim 86 or 88, wherein the compound has the following structure:
Figure imgf000197_0003
96. A compound of formula
Figure imgf000197_0001
Figure imgf000197_0002
or a pharmaceutically acceptable salt or solvate thereof wherein:
M! and M2 are each independently selected from a bond, -NR4-, or -NR4C(0)-, - C(0)NR4-;
R1 and R2 are each independently selected from an alkyl, alkenyl, cycloalkyl, and, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyi, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, ar\d, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
wherein at least one of M1 and M2 is a bond or -NR4-;
wherein when M1 is -NR4-, then R1 is cycloalkylalkyi, heterocyclylalkyl, arylalkyl, or heteroarylalkyl, wherein cycloalkyl, and, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
wherein when M2 is -NR4-, then R2 is cycloalkylalkyi, heterocyclylalkyl, arylalkyl, or heteroarylalkyl, wherein cyc!oalkyi, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5; RJ is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, aryl alkyl, arylalkenyl, arylalkynyl, heterocyclylaikyl, heteroaxylalkyl, heteroatylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R7;
R4 is each independently H, alkyl, wherein each alkyl is optionally substituted with one or more R5:
R5 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CF3, -OCF3, -CN, -alkyl-CN, - COM ! ·. -CONHR6, -CONR6R6, -COO! !. -NH2, -NHR6, -NO2, -NR6R6, -N3, -OH, OR6, - COOR6, -OSO3R6, oxo, R6, -SH, -SO2R6, -SO l. -SO3R6, or -SR6;
R6 is each independently alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl; or alternatively two R6 on the same N atom can together form a 3-6 membered N~ heterocyclyl; and
R7 is each independently 1, Br, Cl, F, -CH2F, -CHF2, -CF3, -OCF3, -CN, -alkyl-CN, - CONH2, -CONHR6, -CONR6R6, -COOH, -NH2, -NHR6, -NO2, -NR6R6, -N3, -OH, OR6, - COOR6, -OSO3R6, oxo, R6, -SH, -SO2R6, -SOsH, -SO3R6, -SR6, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally- substituted with one or more R5;
wherein the compound is not /V-benzyl-AM3~(benzylamino)-l~phenyl~ ! //-!, 2,4- triazol-3-y!)acetamide, iV-(5-((2-chlorobenzyl)amino)-l-phenyl-li/-l,2,4-triazol-3-yl)-2- fluorobenzamide and Arv¥'-bis(4-methyTbenzyl)- 1 -phenyl- \H- 1 ,2,4-triazole-3,5-diamine.
97. The compound of claim 96, wherein at least one of -M^R1 and -M2 R2 is -NR4-(Ci-C3 alkylenej-cycloalkyl, -NR4-(CI-C3 alkyiene)~heteroeyclyi, -NR4-(CI-C3 alkylene)-aiyl, or - NR4-(C I-C3 alkylene)-heteroaryl; wherein cycloalkyl, aryl, heteroaryd, and heterocyclyl is each optionally substituted with one or more R5.
98. The compound of claim 97, wherein at least one of dVFll1 and -M2 R2 is -NR4-(CI-C3 alkyiene)-phenyl, or -NR4-(CI-C3 alkylene)-pyridyl, wherein phenyl and pyridyl is each optionally substituted with one or more R5.
99. The compound of claim 98, wherein at least one of -M^R1 and -M2 R2 is -NR4-CH2-
Figure imgf000199_0003
Figure imgf000199_0001
and pyridyl is each optionally substituted with one or more R5.
100. The compound of claim 99, wherein -MRR1 and -M R2 are each selected from -NR4- CH2~phenyl, -NR4-CH2CH2-phenyl, -NR4-CH2-pyridyl. -NR4-CH2CH2-pyridyl,
Figure imgf000199_0002
Figure imgf000200_0001
; wherein phenyl and pyridyl is each optionally substituted with one or more R5.
101. The compound of any one of claims 96-100, wherein Rf and R2 are each
independently selected from phenyl or pyridyl, each optionally substituted with one or more
R:
102. The compound of any one of claims 96-101, wherein one of M1 and M is a bond.
103. The compound of claim 102, wherein R] and R2 are each independently selected from phenyl or 5-6 membered heteroaryl, each optionally substituted with one or more R3.
104. The compound of claim 102, wherein R1 and R2 are each independently selected from phenyl, azetidinyl, pyrrolidinyl, piperidinyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl, pyridyl, pyridazinyi, pyraziny!, pyrimidiny!, pyridinoneor, or pyridine N-oxide, each optionally substituted with one or more R3.
105. The compound of claim 102, wherein M1 is a bond and R1 is pyridyl, optionally substituted with one or more R5.
106. The compound of claim 102, wherein M2 is a bond and R2 is pyridyl, optionally substituted with one or more R5.
107. Tire compound of claim 102, wherein, M1 is a bond and M2 is -NR4- or -NR4C(0)-.
108. The compound of claim 102, wherein, M2 is a bond and M1 is -NR4- or -NR4C(0)-.
109. The compound of any one of claims 96-108, wherein R3 is phenyl, optionally substituted with one or more R7; and
R7 is each independently 1, Br, Cl, F, -CH2F, -CHF2, -CFs, -OCF3, -CN, -Ns, -OH, methyl, ethyl, propyl, ··( < 1 1. -CN, -MR., -NO?., -N3, -OH, -OCFs, -OMe, -NMe?, or -NEta.
1 10. The compound of any one of claims 96-109, wherein R5 and R7 are each
independently selected from I, Br, Cl, F, -CH2F, -CHF2, -CF3, -OCF3, -N3, -CN, -OH, methyl, ethyl, propyl, -CºCH; -CN, -NH2, -NO’. -Ns, -OH, -OCF3, -OMe, -NMes, or -NEt?..
111. The compound of any one of claims 96-110, wherein R4 is each independently H or
C1-C3 alkyl.
1 12. The compound of claim 96, wherein the compound has the structure of formula (II A):
Figure imgf000201_0001
(HA),
or a pharmaceutically acceptable salt or solvate thereof, wherein:
R3 and R ' are each independently selected from an cycloalkyl, aryl, biphenyl, heterocyclyl, or heteroaryl, each optionally substituted with one or more Rs:
R3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalkylalkyl, arylalkyl, arylalkenyl, arylalkynyl,
heterocyclylalkyl, heteroarylalkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R7;
R4 is each independently H, alkyl, wherein each alkyl is optionally substituted with one or more R5;
R5 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CFs, -OCF3, -CN, -alkyl-CN, - CONH2, -CONHR6, -CONR6R6, -COOH, -M l·. -NHR6, -NO·. ~NR6R6, -N3, -OH, OR6, - COOR6, -OSO3R6, oxo, R6, -SH, -SQ2R6, -SOsH, -SO3R6, or -SR6;
R6 is each independently alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyi; or alternatively two Rb on the same N atom can together form a 3-6 membered N- heterocyclyl;
R7 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CF3, -OCF3, -CN, -alkyl-CN, - CONH2, -CONHR6, -CONR6R6, -COOH, -Ni l··. -NHR6, -NO2, -NR6R6, -Ns, -OH, OR6, - COOR6, -OSO3R6, oxo, R6, -SH, -SO2R6, -SOsH, -SO3R6, -SR6, cycloalkyl, heterocyclyl. aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R5.
113. The compound of claim 1 12, wiierein R1 is aryl, optionally substituted with one or more R5.
114. The compound of claim 113, wherein R1 is phenyl, optionally substituted with one or more R3.
115. The compound of claim 112, wherein R1 is 5-6 membered heteroaryl, optionally substituted with one or more R5.
116. The compound of claim 1 15, wherein R1 is pyridyl, optionally substituted with one or more R5.
1 17. The compound of any one of claims 1 12-1 16, wherein R2 is phenyl optionally substituted with one or more R5.
118. The compound of claim 1 17, wherein R2 is
Figure imgf000202_0001
119. The compound of any one of claims 112-118, wherein R3 is cycloalkyl, aryl, heterocyclyl, or heteroaryl, each optionally substituted with one or more R7.
120. The compound of claim 1 19, wherein R3 is phenyl optionally substituted with one or more R7.
121. The compound of any one of claims 112-120, wherein Rs is 1, Br, Cl, F, -CFbF, - CHF2, -CFS, -Ci-C6 alkyl, alkyny!, -CN, -(Ci-Cs a!kyIene)-CN, -NH2, -NO2, -Ns, -OH, - OCFs, -OMe, -NM62, ~NEt2, or -C(0)0(Ci~C6 alkyl).
122. The compound of any one of claims 112-120, wherein R5 and R7 are each
independently selected from I, Br, Cl, F, -CFBF, -CHF2, -CF3, -OCF3, -N3, -CN, -OH, methyl, ethyl, propyl, -CºCH; -CN, -NH2, -NO2, -N3, -OH, -OCF3, -OMe, ~NMe2, or -NEC.
123. The compound of claim 96, wherein compounds of Table C are excluded.
124. The compound of any one of claims 97-122, wherein compounds of Table C are excluded.
125. The compound of claim 96, wherein the compound has one of the following structures:
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
or a pharmaceutically acceptable salt thereof.
126. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound of any one of claims 96-125.
127. The pharmaceutical composition of claim 126, further comprising one additional therapeutically active agent.
128. A method of modulating a Parkin ligase, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 96-125.
129. A method of treating a disease or a condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 96-125.
130. The method of claim 129, wherein the disease or the condition is cancer.
131. The method of claim 130, wherein the cancer is Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, AIDS-Related Cancers, Kaposi Sarcoma, Lymphoma, Anal Cancer, Appendix Cancer, Astrocytomas, Childhood Atypical Teratoid/Rhabdoid Tumor, Basal Cell Carcinoma, Skin Cancer (Nonmelanoma), Childhood Bile Duct Cancer, Extrahepatie Bladder Cancer, Bone Cancer, Ewing Sarcoma Family of Tumors, Osteosarcoma and Malignant Fibrous Histiocytoma, Brain Stem Glioma, Brain Tumors, Embryonal Tumors, Germ Cell Tumors, Craniopharyngioma, Ependymoma, Bronchial Tumors, Burkitt Lymphoma (Non-Hodgkin Lymphoma), Carcinoid Tumor, Gastrointestinal Carcinoma of Unknown Primary', Cardiac (Heart) Tumors, Lymphoma, Primary, Cervical Cancer, Childhood Cancers, Chordoma, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Chronic Myeloproliferative Neoplasms Colon Cancer, Colorectal Cancer, Cutaneous T-Cell Lymphoma, Ductal Carcinoma In Situ, Endometrial Cancer, Ependymoma, Esophageal Cancer, Esthesioneuroblastoma, Ewing Sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer, Intraocular Melanoma, Retinoblastoma, Fibrous Histiocytoma of Bone, Malignant, and Osteosarcoma, Gallbladder Cancer, Gastric (Stomach) Cancer, Gastrointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumors, Extragonadal Cancer, Ovarian Cancer, Testicular Cancer, Gestational Trophoblastic Disease, Glioma, Brain Stem Cancer, Hairy Cell Leukemia, Head and Neck Cancer, Heart. Cancer, Hepatocellular (Liver) Cancer, Histiocytosis, Langerhans Cell Cancer, Hodgkin Lymphoma, Hypopharyngeal Cancer, intraocular Melanoma, Islet Cell Tumors, Pancreatic Neuroendocrine Tumors, Kaposi Sarcoma, Kidney Cancer, Renal Cell Cancer, Wilms Tumor and Other Childhood Kidney Tumors, Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia, Chronic Lymphocytic Cancer, Chronic Myelogenous Cancer, Hairy Cell Cancer, Lip and Oral Cavity Cancer, Liver Cancer (Primary'), Lobular Carcinoma In Situ (LCIS), Lung Cancer, Non-Small Cell Cancer, Small Cell Cancer, Lymphoma, Cutaneous T-Cell (Mycosis Fungoides and Sezary Syndrome), Hodgkin Cancer, Non-Hodgkin Cancer, Macroglobulin emia, Waldenstrom, Male Breast Cancer, Malignant Fibrous Histiocytoma of Bone and Osteosarcoma, Melanoma, Intraocular (Eye) Cancer, Merkel Cell Carcinoma, Mesothelioma, Malignant, Metastatic Squamous Neck Cancer with Occult Primary, Midline Tract Carcinoma Involving NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides, M eiodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms, Myelogenous Leukemia, Chronic, Myeloid Leukemia, Acute, Myeloma Multiple, Chronic Myeloproliferative Neoplasms, Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, euroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity' Cancer, Lip and Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous His tiocytoma of Bone, Epithelial Cancer, Low Malignant Potenti al Tumor, Pancreatic Cancer, Pancreatic Neuroendocrine Tumors (Islet Cell Tumors), Papillomatosis, Paraganglioma, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, Pituitary' Tumor, Plasma Cell Neoplasm/Multiple Myeloma, PI europul monary Blastema, Primary Central Nervous System Lymphoma, Rectal Cancer, Renal Cell (Kidney) Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary' Gland Cancer, Sarcoma, Ewing Cancer, Kaposi Cancer, Osteosarcoma (Bone Cancer), Soft Tissue Cancer, Uterine Cancer, Sezary' Syndrome, Skin Cancer, Childhood Melanoma, Merkel Cell Carcinoma, Nonmelanoma, Small Ceil Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma, Skin Cancer (Nonmelanoma), Childhood Squamous Neck Cancer with Occult Primary, Metastatic Cancer, Stomach (Gastric) Cancer, T-Cell Lymphoma, Cutaneous Cancer, Testicular Cancer, Throat Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Unknown Primary, Carcinoma of Childhood, Unusual Cancers of Childhood, Urethral Cancer, Uterine Cancer, Endometrial Cancer, Uterine Sarcoma, Vaginal Cancer, Vulvar Cancer, Waldenstrom Macroglobulinemia, Wilms Tumor, or Women's Cancers.
132. The method of claim 130, wherein the cancer is colon cancer, lung cancer, or ovarian cancer.
133. The method of claim 128 or 129, wherein the compound has one of the following structures:
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
or a pharmaceutically acceptable salt thereof.
134. The compound of claim 44, wherein R2 is
Figure imgf000211_0002
135. A compound of formula
Figure imgf000211_0003
Figure imgf000211_0004
or a pharmaceutically acceptable salt or solvate thereof wherein;
L1, L2 and L3 are each independently selected from a bond, alkylene, or a!keny!ene;
M1 and M2 are each independently selected from -NR4-, -NR4C(0)-, -N^C^R1)-, - C(0)NR4-, -NR4C(0)NR4-, -C(0)- -C(=NR4)-, -C(=NOR4)-, -OC(O)-, -C(0)0-, -0C(0)0-, -0C(0)NR4-, -NR4C(0)0~, -S(0)m-, -S(0)mNR4-, or -NR4S(0)m-, provided that M1 and M2 are not both -NR4-;
R5 and R2 are each independently selected from an alkyl alkenyl, cycloalkyl, aryl, biphenyl heterocyclyl heterocycloalkyl, heteroaryl, cycloalkyl alkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroaryl alkyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R5;
R3 is selected from an alkyl, alkenyl, cycloalkyl, aryl, biphenyl, heterocyclyl heterocycloalkyl, heteroaryl, cycloalky !alkyl, arylalkyl, arylalkenyl, arylalkynyl, heterocyclylalkyl, heteroaryla!kyl, heteroarylalkenyl, or heteroarylalkynyl, wherein each cycloalkyl, aryl, heteroaryl, and heterocyclyl portion is optionally substituted with one or more R7;
R4 is each independently H, alkyl, wherein each alkyl is optionally substituted with one or more R5;
R5 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CF3, -OCF3, -CN, -alkyl-CN, -
C OM ! . -CONHR6, -CONR6R6, -COR6, -COOH, -M l·. -M UR. -NO2, ~NR6R6, -NR6COR6, - (alkylene)NR6COR6, -N3, -OH, OR6, -COOR6, -OSQ3R6, oxo, R6, -SH, -SO2R6, -SO3H, -
Figure imgf000212_0001
R6 is each independently alkyl, alkenyl, alkynyl, haloalkyl, haloalkenyl, haloalkynyl; or alternatively two R6 on the same N atom can together form a 3-6 membered N- heterocydyl;
R7 is each independently I, Br, Cl, F, -CFI2F, -CHF2, -CF3, -OCF3, -CN, -alkyl-CN, -
COM ! . -CONHR6, -CONR6R6, -COOH, -\! l·. -M UR. -NO2, -MR!R. -N3, -OH, OR6, -
COOR6, -OSO3R6, oxo, R6, -SH, -SQ2R6, -SQ3H, -SQ3R6, -SR6, cycloalkyl, heterocyclyl aryl, or heteroaryl, wherein each cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R5;
m is 0, 1, or 2; and
wherein the compound is not AyV’-(l-phenyl-l//-l,2,4-triazole-3,5-diyl)dibenzamide, 7V-(3- benzamido-l -phenyl- l -l,2,4-triazol-5-yl)furan-2-carboxamide, /V-(5-cinnamamido-l- phenyl-li/-l,2,4-triazol-3-yl)benzamide, N-(l -phenyl-5-(phenylamino)~li/-l,2,4~triazol~3~ yljbenzamide, 4-fluoro-/V-(5-(4-methoxybenzamido)-l -phenyl- lH-12, 4-triazol-3- y l)benzami de, NN'-( 1 -phenyl- Hi- 1 ,2,4-tri azole-3, 5 -dry l)bi s(4-methy lbenzamide), N-{5 -((2- chlorobenzyl)amino)~l -phenyl- 1 -1, 2, 4-triazol-3-yl)-2-fluorobenzamide, /V-(3-benzamido-l- phenyl~li/-l,2,4-triazol-5-yl)-4-fluorobenz.amide, iV-(3-benzamido-l-phenyl-li -l,2,4- triazol-5-yl)-4-nitrobenzamide, Ai-(3-benzamido-l-phenyl-li:/-l,2,4-tiiazol-5-yl)-3- nitrobenzamide, and 4-((3 -benzamido- 1 -pheny 1 - III- 1 ,2,4-triazol-5 -y 1 lcarbamoy l)benzoic acid.
136. The compound of claim 135, wherein the compound has the structure of formula (IIIA):
Figure imgf000212_0002
or a pharmaceutically acceptable salt or solvate thereof, wherein:
M1 and M2 are each independently selected from -NR4-, -NR4C(0)~ or -C(0)NR4-, provided that M1 and M2 are not both -NR4-;
R1 and R2 are each independently phenyl, optionally substituted with one or more R5; wherein at least one of R1 or R2 is substituted with -(Ci-Ce. alkylene)NHCO(Ci-Cio alkyl) or -(C1-C6 alkyl ene)N(Ci-Cs alkyl)CO(Ci-Cio nlkvi );
Figure imgf000213_0001
R4 is each independently H or C1-C3 alkyl;
R5 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CFs, -Ci-Cc, alkyl, alkynyl, -CN, -
(C1-C3 alkylene)-CN, -NH2, -NO2, -Ns, -OH, -OCF3, -OMe, -NMe2, -NEta, -C(0)0(Ci
Ce alkyl), -CO(Ci~Cio alkyl), -NHCO(Ci-Cio alkyl), -N(CI-CJ alkyl)CO(Ci-Cio alkyl),
(Ci-Ce alkylene)NHCO(Ci-Cio alkyl), or -(Ci-Ce alkylene)N(Ci-C3 alkyl)CO(Ci-Cio alkyl);
R7a, R7b, R7'·, and R7e is each independently H, I, Br, Cl, F, -CH2F, -CHF2, -CF3, -OCF3, -
Ns, -CN, -OH, methyl, ethyl, propyl, C1-C3 haloalkyl, C1-C3 alkoxy, or C1-C3 haloalkoxy; and
R7c is H, I, Br, Cl, F, -CH2F, -CHF2, -CFs, -OCF3, -N3, -CN, -OH, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C1-C3 haloalkoxy, 4-6 membered heterocyclyl, or 5-6 membered heteroaryl, wherein the heterocyclyl and heteroaryl is optionally substituted with one or more R5.
137. The compound of claim 138, wherein at least one of R1 or R2 is substituted with -(Ci- C3 alkylene)NHCO(Ci-C8 alkyl) or -(C1-C3 alkylene)N(Cl-C3 alkyl)CO(Ci-C8 alkyl).
138. The compound of 138, wherein at least one of R1 or R2 is substituted with - CH2NHCO(C I-C8 alkyl) or -CHiNCCi-Cs alkyi)CO(Ci~Cg alkyl).
139. The compound of any one of claims 136-138, wherein R7a, R7b, R7c, R7e, and R7e is each independently H, I, Br, Cl, F, -CH2F, -CHF2, -CF3, -OCF3, -N3, -CN, -OH, methyl, ethyl, propyl, -CºCH; -CN, -NH2, -NO’. -N3, -OH, -OCF3, -OMe, -NMe2, or -NEt2.
140. The compound of claim 136, wherein the compound is
Figure imgf000214_0001
or
or a pharmaceutically acceptable salt thereof.
141. The compound of claim 135, wherein the compound has the structure of formula (TUB):
Figure imgf000214_0002
or a pharmaceutically acceptable salt or solvate thereof, wherein:
!VT and M2 are each independently selected from -NR4-, -NR4C(0)- or -C(0)NR4-, provided that M1 and M2 are not both -NR4-;
R1 and R2 are each independently phenyl, optionally substituted with one or more R5;
R3 is phenyl, substituted with one or more R7;
R4 is each independently H or C1-C3 alkyl;
R5 is each independently I, Br, Cl, F, -CH2F, -CHF2, -CFs, -Ci-Ce alkyl, alkynyl, -CN, - (C1-C3 alkylene)-CN, -NFb, -NO?., -Ns, -OH, -OCFs, -OMe, -NMer, -NEt?., -C(0)0(Ci- Ce alkyl), -CO(Ci-Cio alkyl), -NHCO(Ci-Cio alkyl), -NiCi-CN alkyl)CO(Ci-Cio alkyl), -(Ci-Ce alkyl ene)NHCO(Ci-C 10 alkyl), or -(C1-C6 alkylene)N(Ci-C3 alkyl)CO(Ci-Cio alkyl); and
wherein at least one R’' is heterocyclyl substituted with -CO(Ci-Cio alkyl), which is optionally further substituted with one or more R5.
142. The compound of claim 141, w herein R3 is phenyl, substituted with 6-membered heterocyclyl and wherein the 6-membered heterocyclyl is substituted with -CO(Ci-Cio alkyl).
143. The compound of claim 141, wherein R3 is phenyl substituted with a piperidine or a piperazine, wherein the piperidine or the piperazine is substituted with -CO(Ci-Cio alkyl).
144. The compound of any one of claims 141 -143, wherein R1 and R2 are each independently phenyl, optionally substituted with one or more substitutent selected from 1, Br, Cl, F, -CH2F, -CHI x -CFs, -OCFs, -Ns, -CN, -OH, methyl, ethyl, propyl, -C ( 1 1: -CN, -NH2, -NO2, -Ns, - OH, -OCF3, -OMe, -NMe2, or -NEt2.
145. The compound of claim 141, wherein the compound is
Figure imgf000215_0001
pharmaceutically acceptable salt thereof.
146. A pharmaceutical composition comprising a pharmaceutically acceptable carrier or a pharmaceutically acceptable excipient and a compound of any one of claims 135-145.
147. The pharmaceutical composition of claim 146, further comprising one additional therapeutically active agent.
148. A method of modulating a Parkin ligase, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 135-145.
149. A method of treating a disease or a condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 135-145.
150. The method of claim 149, wherein the disease or the condition is cancer.
151. The method of claim 150, wherein the cancer is Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, Adrenocortical Carcinoma, AIDS-Related Cancers, Kaposi Sarcoma, Lymphoma, Anal Cancer, Appendix Cancer, Astrocytomas, Childhood Atypical Teratoid''Rhabdoid Tumor, Basal Cell Carcinoma, Skin Cancer (Nonmelanoma), Childhood Bile Duct Cancer, Extrahepatic Bladder Cancer, Bone Cancer, Ewing Sarcoma Family of Tumors, Osteosarcoma and Malignant Fibrous Histiocytoma, Brain Stem Glioma, Brain Tumors, Embryonal Tumors, Germ Cell Tumors, Craniopharyngioma, Ependymoma, Bronchial Tumors, Burkitt Lymphoma (Non-Hodgkin Lymphoma), Carcinoid Tumor, Gastrointestinal Carcinoma of Unknown Primary, Cardiac (Heart) Tumors, Lymphoma, Primary, Cervical Cancer, Childhood Cancers, Chordoma, Chronic Lymphocytic Leukemia, Chronic Myelogenous Leukemia, Chronic Myeloproliferative Neoplasms Colon Cancer, Colorectal Cancer, Cutaneous T-Cell Lymphoma, Ductal Carcinoma In Situ, Endometrial Cancer, Ependymoma, Esophageal Cancer, Esthesioneuroblastoma, Ewing Sarcoma, Extracranial Germ Cell Tumor, Extragonadal Germ Cell Tumor, Extrahepatic Bile Duct Cancer, Eye Cancer, Intraocular Melanoma, Retinoblastoma, Fibrous Histiocytoma of Bone, Malignant, and Osteosarcoma, Gallbladder Cancer, Gastric (Stomach) Cancer, Gas trointestinal Carcinoid Tumor, Gastrointestinal Stromal Tumors, Extragonadal Cancer, Ovarian Cancer, Testicular Cancer, Gestational Trophoblastic Disease, Glioma, Brain Stem Cancer, Hairy Cell Leukemia, Head and Neck Cancer, Heart Cancer, Hepatocellular (Liver) Cancer, Histiocytosis, Langerhans Ceil Cancer, Hodgkin Lymphoma, Hypopharyngea! Cancer, Intraocular Melanoma, Islet Cell Tumors, Pancreatic Neuroendocrine Tumors, Kaposi Sarcoma, Kidney Cancer, Renal Cell Cancer, Wilms Tumor and Other Childhood Kidney Tumors, Langerhans Cell Histiocytosis, Laryngeal Cancer, Leukemia, Chronic Lymphocytic Cancer, Chronic Myelogenous Cancer, Hair ' Cell Cancer, Lip and Oral Cavity Cancer, Liver Cancer (Primary), Lobular Carcinoma In Situ (LCIS), Lung Cancer, Non-Small Cell Cancer, Small Cell Cancer, Lymphoma, Cutaneous T-Ce!l (Mycosis Fungoides and Sezary Syndrome), Hodgkin Cancer, Non-Hodgkin Cancer, Macroglobulinemia, Waldenstrom, Male Breast Cancer, Malignant Fibrous Histiocytoma of Bone and Osteosarcoma, Melanoma, Intraocular (Eye) Cancer, Merkel Cell Carcinoma, Mesothelioma, Malignant, Metastatic Squamous Neck Cancer with Occult Primary', Midline Tract Carcinoma involving NUT Gene, Mouth Cancer, Multiple Endocrine Neoplasia Syndromes, Multiple Myeloma/Plasma Cell Neoplasm, Mycosis Fungoides, Myelodysplastic Syndromes, Myelodysplastic/Myeloproliferative Neoplasms, Myelogenous Leukemia, Chronic, Myeloid Leukemia, Acute, Myeloma Multiple, Chronic Myeloproliferative Neoplasms, Nasal Cavity and Paranasal Sinus Cancer, Nasopharyngeal Cancer, Neuroblastoma, Non-Hodgkin Lymphoma, Non-Small Cell Lung Cancer, Oral Cancer, Oral Cavity Cancer, Lip and Oropharyngeal Cancer, Osteosarcoma and Malignant Fibrous Histiocytoma of Bone, Epithelial Cancer, Low Malignant Potential Tumor, Pancreatic Cancer, Pancreatic Neuroendocrine Tumors (Islet Cell Tumors), Papillomatosis, Paraganglioma, Parathyroid Cancer, Penile Cancer, Pharyngeal Cancer, Pheochromocytoma, Pituitary- Tumor, Plasma Cell Neoplasm/Multiple Myeloma, P!europulmonary Blastema, Primary Central Nervous System Lymphoma, Rectal Cancer, Renal Cell (Kidney) Cancer, Retinoblastoma, Rhabdomyosarcoma, Salivary Gland Cancer, Sarcoma, Ewing Cancer, Kaposi Cancer, Osteosarcoma (Bone Cancer), Soft Tissue Cancer, Uterine Cancer, Sezary Syndrome, Skin Cancer, Childhood Melanoma, Merkel Ceil Carcinoma, Nonmelanoma, Small Cell Lung Cancer, Small Intestine Cancer, Soft Tissue Sarcoma, Squamous Cell Carcinoma, Skin Cancer (Nonmelanoma), Childhood Squamous Neck Cancer with Occult Primary', Metastatic Cancer, Stomach (Gastric) Cancer, T-Cell Lymphoma, Cutaneous Cancer, Testicular Cancer, Throat Cancer, Thymoma and Thymic Carcinoma, Thyroid Cancer, Transitional Cell Cancer of the Renal Pelvis and Ureter, Unknown Primary, Carcinoma of Childhood, Unusual Cancers of Childhood, Urethral Cancer, Uterine Cancer, Endometrial Cancer, Uterine Sarcoma, Vaginal Cancer, Vulvar Cancer, Waldenstrom Macroglobuhnemia, Wilms Tumor, or Women's Cancers.
152. The method of claim 150, wherein the cancer is colon cancer, lung cancer, or ovarian cancer.
153. The method of claim 148 or 149, wherein the compound has one of the following structures:
Figure imgf000217_0001
; or a p armaceu ca y accep a e sa hereof.
154. A method of treating Parkinson’s Disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-81, 96- 125, and 135-145.
155. A method of slowing the progeression of Parkinson’s Disease comprising
administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-81, 96-125, and 135-145.
156. A method of restoring dopamine neuronal balance in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-81, 96-125, and 135-145.
157. A method of delaying or preventing dopamine neuron loss in a subject in need thereof, comprising administering to the subject in need thereof a therapeutically effective amount of a compound of any one of claims 1-81, 96-125, and 135-145.
158. A method of increasing mitophagy of damaged mitochondria in a subject in need thereof, comprising administering to the subject need thereof a therapeutically effective amount of a compound of any one of claims 1-81, 96-125, and 135-145.
159. The method of any one of claims 154-158, the compound is
Figure imgf000218_0001
pharmaceutically acceptable salt thereof.
160. The method of any one of claims 154-158, the compound is selected from Table 1, Table 2, Table 3 A and/or Table 3B
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Citations (2)

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Publication number Priority date Publication date Assignee Title
US4323566A (en) * 1979-03-02 1982-04-06 Glaxo Group Limited Triazole acylamines, pharmaceutical compositions thereof and method of use thereof
WO2017210694A1 (en) * 2016-06-03 2017-12-07 An2H Discovery Limited Triazole benzamide derivatives and the compositions and methods of treatment regarding the same

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Publication number Priority date Publication date Assignee Title
US4323566A (en) * 1979-03-02 1982-04-06 Glaxo Group Limited Triazole acylamines, pharmaceutical compositions thereof and method of use thereof
WO2017210694A1 (en) * 2016-06-03 2017-12-07 An2H Discovery Limited Triazole benzamide derivatives and the compositions and methods of treatment regarding the same

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Title
BAGAL ET AL.: "Heterocyclic nitro compounds III. Reactions of nitro-1, 2, 4-triazoles with aliphatic amines", CHEMISTRY OF HETEROCYCLIC COMPOUNDS, vol. 6, February 1970 (1970-02-01), pages 249 - 253, XP055616415 *
DATABASE Pubchem compound 7 October 2017 (2017-10-07), "3-N,5-N,1-Trimethyl-1,2,4-triazole-3,5-dicarboxamide. GYBCPUTUQAVKHMUHFFFAOYSA-N", XP055616433, retrieved from NCBI Database accession no. 130008745 *
DATABASE Pubchem compound 9 October 2017 (2017-10-09), "N-[3-(Dimethylamino)-1H-1,2,4-triazol-5-yl]acetamide. JSSNUYBUPFERQS-UHFFFAOYSA-N", XP055616417, retrieved from NCBI Database accession no. 130741852 *
DATABASE Pubchem compound U.S. National Library of Medicine; 26 March 2005 (2005-03-26), "N-[3-(Propanoylamino)-1H-1,2,4-triazol-5- yl]propanamide", XP055616427, retrieved from NCBI Database accession no. 332816 *

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