Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
  • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
  • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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
  • C07D215/20—Oxygen atoms
  • C07D215/22—Oxygen atoms attached in position 2 or 4
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P33/00—Antiparasitic agents
• • 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
  • C07D401/10—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 carbon chain containing aromatic 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
  • C07D403/10—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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
  • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
  • C07D409/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

• TPP Target Product Profiles
• TCP Target Candidate Profiles
• the list is comprehensive and includes new oral medications that can be used for treatment of acute but uncomplicated malaria, as well as for severe and complicated disease where a fast ⁇ acting parenteral formulation would be appropriate.
• ELQ ⁇ 300 is an analog of Coenzyme Q 10 , a native ligand of electron transport chain enzymes.
• ELQ ⁇ 331 was accepted as a preclinical candidate by the MMV in October of 2020. Since this time, an oral formulation of ELQ ⁇ 331 has been developed by the MMV, and we recently described a low cost and scalable synthetic route to the core molecule ELQ ⁇ 300 adding to the feasibility of developing this drug for human use 10 . Thus, prodrug ELQ ⁇ 331 continues to move forward through the MMV clinical development pipeline. There remains a need for discovery and development of new ELQ compounds with improvements in intrinsic potency, selectivity, pharmacokinetic properties and/or efficacy.
• R 1a , R 1b , and R 1c is independently selected from the group of H, halogen, CN, C 1 ⁇ C 6 alkyl, and C 1 ⁇ C 6 alkoxy;
• a different embodiment provides a compound of Formula (III): wherein: R 1 is selected from the group of H, F, and Cl; R 3 , R 4 , and R 5 are each independently selected from the group of H, halogen, C 1 ⁇ C 4 alkyl, ⁇ O ⁇ C 1 ⁇ C 4 alkyl, C 1 ⁇ C 4 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 4 haloalkyl, ⁇ S ⁇ CF 3 , ⁇ SF 5 , CN, 2 ⁇ pyrrolidinone, ⁇ C(O)NH 2 , ⁇ C(O)NH(C 1 ⁇ C 4 alkyl), , ⁇ C(O)N(C 1 ⁇ C 4 alkyl) 2 , ⁇ C(O)NH(C 3 ⁇ C 6 cycloalkyl), ⁇ C(O)NH( ⁇ CH 2 ⁇ C 3 ⁇ C 6 cycloalkyl), C 3 ⁇ C 6 cycloalkyl, ⁇ O ⁇ C 3 ⁇
• R 1 is selected from the group of H, F, and Cl; and R 3 , R 4 , and R 5 are each independently selected from the group of H, halogen, C 1 ⁇ C 2 alkyl, ⁇ O ⁇ C 1 ⁇ C 2 alkyl, C 1 ⁇ C 2 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 2 haloalkyl, ⁇ S ⁇ CF 3 , ⁇ SF 5 , CN, 2 ⁇ pyrrolidinone, ⁇ C(O)NH 2 , ⁇ C(O)NH(C 1 ⁇ C 2 alkyl), , ⁇ C(O)N(C 1 ⁇ C 2 alkyl) 2 , ⁇ C(O)NH(C 3 ⁇ C 6 cycloalkyl), ⁇ C(O)NH( ⁇ CH 2 ⁇ C 3 ⁇ C 6 cycloalkyl), C 3 ⁇ C 6 cycloalkyl, ⁇ O ⁇ C 3 ⁇ C 6
• Two further embodiments provide, respectively, a compound of Formula (III ⁇ A2) and a compound of Formula (III ⁇ B2), wherein in each separate embodiment: each of R 1 , R 2 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n1, n2, n3, and the dashed lines are as defined above for Formulas (III ⁇ A2) and (III ⁇ B2); R 3 and R 4 are each independently selected from the group of H, halogen, C 1 ⁇ C 2 alkyl, ⁇ O ⁇ C 1 ⁇ C 2 alkyl, C 1 ⁇ C 2 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 2 haloalkyl, ⁇ S ⁇ CF 3 , ⁇ SF 5 , CN, 2 ⁇ pyrrolidinone, ⁇ C(O)NH 2 , ⁇ C(O)NH(C 1 ⁇ C 2 alkyl), , ⁇ C(O)N(C 1 ⁇ C 2 alkyl) 2 ,
• Two further embodiments provide, respectively, a compound of Formula (III ⁇ A2) and a compound of Formula (III ⁇ B2), wherein in each separate embodiment: each of R 1 , R 2 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n1, n2, n3, and the dashed lines are as defined above for Formulas (III ⁇ A2) and (III ⁇ B2); R 3 and R 4 are each independently selected from the group of H, halogen, methyl, methoxy, CH 2 F, CHF 2 , CF 3 , ⁇ O ⁇ CH 2 F, ⁇ O ⁇ CHF 2 , ⁇ O ⁇ CF 3 , ⁇ S ⁇ CF 3 , ⁇ SF 5 , CN, 2 ⁇ pyrrolidinone, ⁇ C(O)NH 2 , ⁇ C(O)NH(C 1 ⁇ C 2 alkyl), , ⁇ C(O)N(C 1 ⁇ C 2 alkyl) 2 , ⁇ C(O)NH(
• Two further embodiments provide, respectively, a compound of Formula (III ⁇ A2) and a compound of Formula (III ⁇ B2), wherein in each separate embodiment: each of R 1 , R 2 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , n1, n2, n3, and the dashed lines are as defined above for Formulas (III ⁇ A2) and (III ⁇ B2); R 3 and R 4 are each independently selected from the group of H, halogen, CH 2 F, CHF 2 , CF 3 , ⁇ O ⁇ CH 2 F, ⁇ O ⁇ CHF 2 , ⁇ O ⁇ CF 3 , and ⁇ S ⁇ CF 3 ; R 10 is selected from the group of H, F, methyl, methoxy, CH 2 F, CHF 2 , CF 3 , ⁇ O ⁇ CH 2 F, ⁇ O ⁇ CHF 2 , ⁇ O ⁇ CF 3 , and ⁇ S ⁇ CF 3 ; with the proviso that, when R 10 is H, at
• a further embodiment provides a compound of Formula (IV): wherein: R 1 is selected from the group of H, F, and Cl; and R 3 is selected from the group of halogen, C 1 ⁇ C 4 alkyl, ⁇ O ⁇ C 1 ⁇ C 4 alkyl, C 1 ⁇ C 4 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 4 haloalkyl, ⁇ S ⁇ CF 3 , ⁇ SF 5 , CN, 2 ⁇ pyrrolidinone, ⁇ C(O)NH 2 , ⁇ C(O)NH(C 1 ⁇ C 4 alkyl), , ⁇ C(O)N(C 1 ⁇ C 4 alkyl) 2 , ⁇ C(O)NH(C 3 ⁇ C 6 cycloalkyl), ⁇ C(O)NH( ⁇ CH 2 ⁇ C 3 ⁇ C 6 cycloalkyl), C 3 ⁇ C 6 cycloalkyl, ⁇ O ⁇ C 3 ⁇ C 6 cycloalkyl, and ⁇
• a further embodiment provides a compound of Formula (IV), wherein: R 1 is selected from the group of H, F, and Cl; and R 3 is selected from the group of halogen, C 1 ⁇ C 3 alkyl, ⁇ O ⁇ C 1 ⁇ C 3 alkyl, C 1 ⁇ C 3 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 3 haloalkyl, ⁇ S ⁇ CF 3 , ⁇ SF 5 , CN, ⁇ 2 ⁇ pyrrolidinone, C(O)NH 2 , ⁇ C(O)NH(C 1 ⁇ C 4 alkyl), , ⁇ C(O)N(C 1 ⁇ C 4 alkyl) 2 , ⁇ C(O)NH(C 3 ⁇ C 6 cycloalkyl), ⁇ C(O)NH( ⁇ CH 2 ⁇ C 3 ⁇ C 6 cycloalkyl), C 3 ⁇ C 6 cycloalkyl, ⁇ O ⁇ C 3 ⁇ C 6 cycloalkyl, and ⁇ S
• a further embodiment provides a compound of Formula (IV), wherein: R 1 is selected from the group of H, F, and Cl; and R 3 is selected from the group of halogen, C 1 ⁇ C 2 alkyl, ⁇ O ⁇ C 1 ⁇ C 2 alkyl, C 1 ⁇ C 2 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 2 haloalkyl, ⁇ S ⁇ CF 3 , ⁇ SF 5 , CN, 2 ⁇ pyrrolidinone, ⁇ C(O)NH 2 , ⁇ C(O)NH(C 1 ⁇ C 4 alkyl), , ⁇ C(O)N(C 1 ⁇ C 4 alkyl) 2 , ⁇ C(O)NH(C 3 ⁇ C 6 cycloalkyl), ⁇ C(O)NH( ⁇ CH 2 ⁇ C 3 ⁇ C 6 cycloalkyl), C 3 ⁇ C 6 cycloalkyl, ⁇ O ⁇ C 3 ⁇ C 6 cycloalkyl, and ⁇ S
• R 1 is Cl
• R 3 is selected from the group of F, Cl, C 1 ⁇ C 2 alkyl, ⁇ O ⁇ C 1 ⁇ C 2 alkyl, C 1 ⁇ C 2 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 2 haloalkyl, ⁇ SF 5 , and CN
• R 10 is selected from the group of H, halogen, C 1 ⁇ C 6 alkyl, ⁇ O ⁇ C 1 ⁇ C 6 alkyl, C 1 ⁇ C 4 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 4 haloalkyl, and ⁇ S ⁇ C 1 ⁇ C 4 haloalkyl; or a pharmaceutically acceptable salt thereof.
• R 1 is Cl
• R 3 is selected from the group of halogen, C 1 ⁇ C 2 alkyl, ⁇ O ⁇ C 1 ⁇ C 2 alkyl, C 1 ⁇ C 2 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 2 haloalkyl, ⁇ S ⁇ CF 3 , ⁇ SF 5 , CN, 2 ⁇ pyrrolidinone, ⁇ C(O)NH 2 , ⁇ C(O)NH(C 1 ⁇ C 4 alkyl), , ⁇ C(O)N(C 1 ⁇ C 4 alkyl) 2 , ⁇ C(O)NH(C 3 ⁇ C 6 cycloalkyl), ⁇ C(O)NH( ⁇ CH 2 ⁇ C 3 ⁇ C 6 cycloalkyl), C 3 ⁇ C 6 cycloalkyl, ⁇ O ⁇ C 3 ⁇ C 6 cycloalkyl, and ⁇ S ⁇ C 3 ⁇ C 6 cycloal
• An additional embodiment provides a compound of Formula (V), wherein: R 1 is Cl; and R 3 is selected from the group of F, Cl, C 1 ⁇ C 2 alkyl, ⁇ O ⁇ C 1 ⁇ C 2 alkyl, C 1 ⁇ C 2 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 2 haloalkyl, ⁇ SF 5 , and CN; R 10 is selected from the group of H, halogen, C 1 ⁇ C 6 alkyl, ⁇ O ⁇ C 1 ⁇ C 6 alkyl, C 1 ⁇ C 4 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 4 haloalkyl, and ⁇ S ⁇ C 1 ⁇ C 4 haloalkyl; or a pharmaceutically acceptable salt thereof.
• R 1 is selected from the group of H, F, and Cl; and R 3 , R 4 , and R 5 are each independently selected from the group of H, halogen, C 1 ⁇ C 2 alkyl, ⁇ O ⁇ C 1 ⁇ C 2 alkyl, C 1 ⁇ C 2 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 2 haloalkyl, ⁇ S ⁇ CF 3 , ⁇ SF 5 , CN, 2 ⁇ pyrrolidinone, ⁇ C(O)NH 2 , ⁇ C(O)NH(C 1 ⁇ C 2 alkyl), , ⁇ C(O)N(C 1 ⁇ C 2 alkyl) 2 , ⁇ C(O)NH(C 3 ⁇ C 6 cycloalkyl), ⁇ C(O)NH( ⁇ CH 2 ⁇ C 3 ⁇ C 6 cycloalkyl), C 3 ⁇ C 6 cycloalkyl, ⁇ O ⁇ C 3 ⁇ C 6
• R 1 is Cl
• R 3 , R 4 , and R 5 are each independently selected from the group of H, halogen, C 1 ⁇ C 4 alkyl, ⁇ O ⁇ C 1 ⁇ C 4 alkyl, C 1 ⁇ C 4 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 4 haloalkyl, ⁇ S ⁇ CF 3 , ⁇ SF 5 , CN, 2 ⁇ pyrrolidinone, ⁇ C(O)NH 2 , ⁇ C(O)NH(C 1 ⁇ C 4 alkyl), , ⁇ C(O)N(C 1 ⁇ C 4 alkyl) 2 , ⁇ C(O)NH(C 3 ⁇ C 6 cycloalkyl), ⁇ C(O)NH( ⁇ CH 2 ⁇ C 3 ⁇ C 6 cycloalkyl), C 3 ⁇ C 6 cycloalkyl, ⁇ O ⁇ C 3 ⁇ C 6 cycloalkyl, and
• a further embodiment provides a compound of Formula (VII), wherein: R 1 is selected from the group of H, F, and Cl; and R 3 , R 4 , and R 5 are each independently selected from the group of H, halogen, C 1 ⁇ C 3 alkyl, ⁇ O ⁇ C 1 ⁇ C 3 alkyl, C 1 ⁇ C 3 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 3 haloalkyl, ⁇ S ⁇ CF 3 , ⁇ SF 5 , CN, 2 ⁇ pyrrolidinone, ⁇ C(O)NH 2 , ⁇ C(O)NH(C 1 ⁇ C 3 alkyl), , ⁇ C(O)N(C 1 ⁇ C 3 alkyl) 2 , ⁇ C(O)NH(C 3 ⁇ C 6 cycloalkyl), ⁇ C(O)NH( ⁇ CH 2 ⁇ C 3 ⁇ C 6 cycloalkyl), C 3 ⁇ C 6 cycloalkyl, ⁇ O ⁇ C 3
• a further embodiment provides a compound of Formula (VII), wherein: R 1 is Cl; and R 3 , R 4 , and R 5 are each independently selected from the group of H, halogen, C 1 ⁇ C 3 alkyl, ⁇ O ⁇ C 1 ⁇ C 3 alkyl, C 1 ⁇ C 3 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 3 haloalkyl, ⁇ S ⁇ CF 3 , ⁇ SF 5 , CN, 2 ⁇ pyrrolidinone, ⁇ C(O)NH 2 , ⁇ C(O)NH(C 1 ⁇ C 3 alkyl), , ⁇ C(O)N(C 1 ⁇ C 3 alkyl) 2 , ⁇ C(O)NH(C 3 ⁇ C 6 cycloalkyl), ⁇ C(O)NH( ⁇ CH 2 ⁇ C 3 ⁇ C 6 cycloalkyl), C 3 ⁇ C 6 cycloalkyl, ⁇ O ⁇ C 3 ⁇ C 6 cycloalkyl,
• R 1 is Cl
• R 3 , R 4 , and R 5 are each independently selected from the group of H, halogen, methyl, methoxy, CH 2 F, CHF 2 , CF 3 , ⁇ O ⁇ CH 2 F, ⁇ O ⁇ CHF 2 , ⁇ O ⁇ CF 3 , ⁇ S ⁇ CF 3 , ⁇ SF 5 , CN, 2 ⁇ pyrrolidinone, ⁇ C(O)NH 2 , ⁇ C(O)NH(C 1 ⁇ C 2 alkyl), , ⁇ C(O)N(C 1 ⁇ C 2 alkyl) 2 , ⁇ C(O)NH(C 3 ⁇ C 6 cycloalkyl), ⁇ C(O)NH( ⁇ CH 2 ⁇ C 3 ⁇ C 6 cycloalkyl), C 3 ⁇ C 6 cycloalkyl, ⁇ O ⁇ C 3 ⁇ C 6 cycloalkyl, and ⁇ S ⁇ C 3 ⁇ C
• a different embodiment provides a compound of Formula (VIII): wherein: R 1 is selected from the group of H, F, and Cl; R 3 is selected from the group of H, halogen, C 1 ⁇ C 4 alkyl, ⁇ O ⁇ C 1 ⁇ C 4 alkyl, C 1 ⁇ C 4 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 4 haloalkyl, ⁇ S ⁇ CF 3 , ⁇ SF 5 , CN, 2 ⁇ pyrrolidinone, ⁇ C(O)NH 2 , ⁇ C(O)NH(C 1 ⁇ C 4 alkyl), , ⁇ C(O)N(C 1 ⁇ C 4 alkyl) 2 , ⁇ C(O)NH(C 3 ⁇ C 6 cycloalkyl), ⁇ C(O)NH( ⁇ CH 2 ⁇ C 3 ⁇ C 6 cycloalkyl), C 3 ⁇ C 6 cycloalkyl, ⁇ O ⁇ C 3 ⁇ C 6 cycloalkyl, and
• R 1 is Cl
• R 3 is selected from the group of halogen, C 1 ⁇ C 2 alkyl, ⁇ O ⁇ C 1 ⁇ C 2 alkyl, C 1 ⁇ C 2 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 2 haloalkyl, ⁇ SF 5 , and CN
• R 6 is C 1 ⁇ C 6 alkyl
• R 10 is selected from the group of H, halogen, C 1 ⁇ C 6 alkyl, ⁇ O ⁇ C 1 ⁇ C 6 alkyl, C 1 ⁇ C 4 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 4 haloalkyl, and ⁇ S ⁇ C 1 ⁇ C 4 haloalkyl; or a pharmaceutically acceptable salt thereof.
• R 1 is Cl
• R 3 is selected from the group of halogen, C 1 ⁇ C 2 alkyl, ⁇ O ⁇ C 1 ⁇ C 2 alkyl, C 1 ⁇ C 2 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 2 haloalkyl, ⁇ SF 5 , and CN
• R 6 is C 1 ⁇ C 4 alkyl
• R 10 is selected from the group of H, halogen, C 1 ⁇ C 6 alkyl, ⁇ O ⁇ C 1 ⁇ C 6 alkyl, C 1 ⁇ C 4 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 4 haloalkyl, and ⁇ S ⁇ C 1 ⁇ C 4 haloalkyl; or a pharmaceutically acceptable salt thereof.
• R 1 is Cl
• R 3 is selected from the group of halogen, C 1 ⁇ C 2 alkyl, ⁇ O ⁇ C 1 ⁇ C 2 alkyl, C 1 ⁇ C 2 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 2 haloalkyl, ⁇ SF 5 , and CN
• R 6 is ethyl
• R 10 is selected from the group of H, halogen, C 1 ⁇ C 6 alkyl, ⁇ O ⁇ C 1 ⁇ C 6 alkyl, C 1 ⁇ C 4 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 4 haloalkyl, and ⁇ S ⁇ C 1 ⁇ C 4 haloalkyl; or a pharmaceutically acceptable salt thereof.
• a different embodiment provides a compound of Formula (IX): wherein: R 1 is selected from the group of H, F, and Cl; R 3 is selected from the group of H, halogen, C 1 ⁇ C 4 alkyl, ⁇ O ⁇ C 1 ⁇ C 4 alkyl, C 1 ⁇ C 4 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 4 haloalkyl, ⁇ S ⁇ CF 3 , ⁇ SF 5 , CN, 2 ⁇ pyrrolidinone, ⁇ C(O)NH 2 , ⁇ C(O)NH(C 1 ⁇ C 4 alkyl), , ⁇ C(O)N(C 1 ⁇ C 4 alkyl) 2 , ⁇ C(O)NH(C 3 ⁇ C 6 cycloalkyl), ⁇ C(O)NH( ⁇ CH 2 ⁇ C 3 ⁇ C 6 cycloalkyl), C 3 ⁇ C 6 cycloalkyl, ⁇ O ⁇ C 3 ⁇ C 6 cycloalkyl, and
• R 1 is Cl
• R 3 is selected from the group of halogen, C 1 ⁇ C 2 alkyl, ⁇ O ⁇ C 1 ⁇ C 2 alkyl, C 1 ⁇ C 2 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 2 haloalkyl, ⁇ SF 5 , and CN
• R 6 is C 1 ⁇ C 6 alkyl
• R 10 is selected from the group of H, halogen, C 1 ⁇ C 6 alkyl, ⁇ O ⁇ C 1 ⁇ C 6 alkyl, C 1 ⁇ C 4 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 4 haloalkyl, and ⁇ S ⁇ C 1 ⁇ C 4 haloalkyl; or a pharmaceutically acceptable salt thereof.
• R 1 is Cl
• R 3 is selected from the group of halogen, C 1 ⁇ C 2 alkyl, ⁇ O ⁇ C 1 ⁇ C 2 alkyl, C 1 ⁇ C 2 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 2 haloalkyl, ⁇ SF 5 , and CN
• R 6 is C 1 ⁇ C 4 alkyl
• R 10 is selected from the group of H, halogen, C 1 ⁇ C 6 alkyl, ⁇ O ⁇ C 1 ⁇ C 6 alkyl, C 1 ⁇ C 4 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 4 haloalkyl, and ⁇ S ⁇ C 1 ⁇ C 4 haloalkyl; or a pharmaceutically acceptable salt thereof.
• Also provided herein is a method for treating malaria in a human subject comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• a method for inhibiting malaria in a human subject comprising administering to the human in need thereof a pharmaceutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• Methods for treating or inhibiting malaria in a human subject include the treatment or inhibition of infections caused by Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malariae.
• Such methods include bovine babesiosis, including infections caused by Babesia bovis and B. bigemina, and equine babesiosis, including infections caused by B. caballi and Theileria equi.
• alkyl refers to a straight or branched hydrocarbon.
• alkoxy groups include, but are not limited to, methoxy ( ⁇ O ⁇ CH 3 or ⁇ OMe), ethoxy ( ⁇ OCH 2 CH 3 or ⁇ OEt), n ⁇ propoxy ( ⁇ CH 2 ⁇ CH 2 ⁇ CH 3 ), isopropoxy ( ⁇ CH(CH 3 ) 2 ), n ⁇ butyl ( ⁇ CH 2 ⁇ CH 2 ⁇ CH 2 ⁇ CH 3 ), isobutoxy ( ⁇ CH 2 ⁇ CH(CH 3 ) 2 ), sec ⁇ butoxy (–CH(CH 3 )CH 2 ⁇ CH 3 ), t ⁇ butoxy ( ⁇ O ⁇ C(CH 3 ) 3 or ⁇ OtBu), and the like.
• cycloalkyl refers to a saturated or partially unsaturated ring having 3 to 6 carbon atoms (C 3 ⁇ C 6 cycloalkyl or C 3 ⁇ 6 cycloalkyl), as a monocycle, including cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl rings.
• halogen or “halo” refers and element or substituent selected from the group of F, Cl, Br, and I.
• prodrugs often have enhanced properties relative to the active agent pharmaceutical, such as, solubility and bioavailability
• the compounds disclosed herein can be delivered in prodrug form.
• prodrugs of the presently disclosed compounds methods of delivering prodrugs and compositions containing such prodrugs.
• Prodrugs of the disclosed compounds typically are prepared by modifying one or more functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to yield the parent compound.
• Prodrugs include compounds having a phosphonate and/or amino group functionalized with any group that is cleaved in vivo to yield the corresponding amino and/or phosphonate group, respectively.
• compounds and compositions may be provided as individual pure enantiomers or as stereoisomeric mixtures, including racemic mixtures.
• the compounds disclosed herein are synthesized in or are purified to be in substantially enantiopure form, such as in a 90% enantiomeric excess, a 95% enantiomeric excess, a 97% enantiomeric excess or even in greater than a 99% enantiomeric excess, such as in enantiopure form.
• the coccidiosis may be associated with infection of a pathogen selected from the group of E. christenseni, E. arloingi, E. caprina, and E. ninakohlyakimovae.
• the compounds and compositions described herein are also effective in the inhibition of fungal pathogens including Pneumocystis carinii, Aspergillus fumigatus, and others.
• the parasitic diseases may be caused by parasites that cause malaria.
• Particular species of parasites that are included within this group include all species that are capable of causing human or animal infection.
• compositions including therapeutic and prophylactic formulations
• pharmaceutically acceptable vehicles or carriers typically combined together with one or more pharmaceutically acceptable vehicles or carriers and, optionally, other therapeutic ingredients (for example, antibiotics, anti ⁇ inflammatories, or drugs that are used to reduce pruritus such as an antihistamine).
• other therapeutic ingredients for example, antibiotics, anti ⁇ inflammatories, or drugs that are used to reduce pruritus such as an antihistamine.
• the compositions disclosed herein may be advantageously combined and/or used in combination with other antimalarial agents as described above.
• compositions can be administered to subjects by a variety of mucosal administration modes, including by oral, rectal, intranasal, intrapulmonary, or transdermal delivery, or by topical delivery to other surfaces.
• the compositions can be administered by non ⁇ mucosal routes, including by intramuscular, subcutaneous, intravenous, intra ⁇ arterial, intra ⁇ articular, intraperitoneal, intrathecal, intracerebroventricular, or parenteral routes.
• the compound can be administered ex vivo by direct exposure to cells, tissues or organs originating from a subject.
• the antimalarial agent or combination of antimalarial agents may be administered to animals, such as chickens, as an additive to their prepared feed or grain.
• a pharmaceutically effective amount of a compound herein (including those of Formula (I) and all other formulas and individual compounds described herein), or a pharmaceutically acceptable salt thereof may be administered to a human in need thereof by injection.
• the injection may be subcutaneous. In other embodiments, the injection is intramuscular.
• Components of an injectable formulation may include additional polar compounds, such as those selected from the group of monoglycerides, diglycerides, free fatty acids, plant sterols, sesamin, and sesamolin. Some injectable formulations further comprise ethanol. In some embodiments, the injectable formulation comprises from about 5 weight % to about 10 weight% ethanol. In other embodiments, the injectable formulation comprises from about 7 weight % to about 8 weight% ethanol. In other embodiments, the injectable formulation comprises from about 7.25 weight % to about 7.75 weight% ethanol. In other embodiments, the injectable formulation comprises about 7.5 weight % ethanol. Additional components that may be used for intramuscular injections include vegetable oils, such as peanut oil, almond oil, olive oil, castor oil, and soybean oil.
• Useful controlled ⁇ release binders are materials that are metabolized slowly under physiological conditions following their delivery (for example, at a mucosal surface, or in the presence of bodily fluids).
• Appropriate binders include, but are not limited to, biocompatible polymers and copolymers well known in the art for use in sustained release formulations. Such biocompatible compounds are non ⁇ toxic and inert to surrounding tissues, and do not trigger significant adverse side effects, such as nasal irritation, immune response, inflammation, or the like. They are metabolized into metabolic products that are also biocompatible and easily eliminated from the body.
• Exemplary polymeric materials for use in the present disclosure include, but are not limited to, polymeric matrices derived from copolymeric and homopolymeric polyesters having hydrolyzable ester linkages.
• biodegradable or bioerodable polymers include, but are not limited to, such polymers as poly(epsilon ⁇ caprolactone), poly(epsilon ⁇ aprolactone ⁇ CO ⁇ lactic acid), poly(epsilon. ⁇ aprolactone ⁇ CO ⁇ glycolic acid), poly(beta ⁇ hydroxy butyric acid), poly(alkyl ⁇ 2 ⁇ cyanoacrilate), hydrogels, such as poly(hydroxyethyl methacrylate), polyamides, poly(amino acids) (for example, L ⁇ leucine, glutamic acid, L ⁇ aspartic acid and the like), poly(ester urea), poly(2 ⁇ hydroxyethyl DL ⁇ aspartamide), polyacetal polymers, polyorthoesters, polycarbonate, polymaleamides, polysaccharides, and copolymers thereof.
• polymers such as polymers as poly(epsilon ⁇ caprolactone), poly(epsilon ⁇ aprolactone ⁇ CO ⁇ lactic acid
• Sterile solutions can be prepared by incorporating the compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated herein, as required, followed by filtered sterilization.
• dispersions are prepared by incorporating the compound and/or other biologically active agent into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated herein.
• methods of preparation include vacuum drying and freeze ⁇ drying which yields a powder of the compound plus any additional desired ingredient from a previously sterile ⁇ filtered solution thereof.
• the implant comprises, respectively about 10% active drug/about 90% EVA, about 20% active drug/about 80% EVA, about 30% active drug/about 70% EVA, about 40% active drug/about 60% EVA, about 50% active drug/about 50% EVA, about 60% active drug/about 40% EVA, about 70% active drug/about 30% EVA, and about 80% active drug/about 20% EVA.
• Additional embodiments comprise methods in which the active drug described herein (a compound of Formula I, or a pharmaceutically acceptable salt thereof) is administered to a subject in need thereof in a continuous release, sustained release, or timed release gel formulation, such as a hydrogel formulation.
• Examples of useful gel carriers include those described in Sarah Gordon’s chapter Gels as Vaccine Delivery Systems at pages 203 ⁇ 220 in Subunit Vaccine Delivery, Springer New York 2015 (Print ISBN: 1 ⁇ 4939 ⁇ 1416 ⁇ 2), US Pat. No. 10,272,140 (Yu et al.), US Pat. No. 9,526,787 (Ko et al.), and Bobbala et al., AAPS J. 2016 Jan, 18(1), pp. 261 ⁇ 269.
• Oral gel, gel ⁇ bead, or gel droplet formulations may also be used for delivering effective amounts of the compounds herein, or pharmaceutically acceptable salts thereof, to animals, such as poultry.
• Examples of gel formulations that may be used with the active drugs described herein include those described in U.S. Pat.
• accepted screening methods are employed to determine risk factors associated with a parasitic infection to determine the status of an existing disease or condition in a subject.
• These screening methods include, for example, preparation of a blood smear from an individual suspected of having malaria. The blood smear is then fixed in methanol and stained with Giemsa and examined microscopically for the presence of Plasmodium infected red blood cells.
• These and other routine methods allow the clinician to select patients in need of therapy using the methods and pharmaceutical compositions of the disclosure.
• the administration of the compound of the disclosure can be for either prophylactic or therapeutic purpose. When provided prophylactically, the compound is provided in advance of any symptom.
• a therapeutically effective amount is also one in which any toxic or detrimental side effects of the compound and/or other biologically active agent is outweighed in clinical terms by therapeutically beneficial effects.
• a non ⁇ limiting range for a therapeutically effective amount of a compound and/or other biologically active agent within the methods and formulations of the disclosure is about 0.01 mg/kg body weight to about 20 mg/kg body weight, such as about 0.05 mg/kg to about 5 mg/kg body weight, or about 0.2 mg/kg to about 2 mg/kg body weight. Dosage can be varied by the attending clinician to maintain a desired concentration at a target site (for example, the lungs or systemic circulation).
• kits include a container or formulation that contains one or more of the conjugates described herein.
• this component is formulated in a pharmaceutical preparation for delivery to a subject.
• the conjugate is optionally contained in a bulk dispensing container or unit or multi ⁇ unit dosage form.
• Optional dispensing means can be provided, for example a pulmonary or intranasal spray applicator.
• Packaging materials optionally include a label or instruction indicating for what treatment purposes and/or in what manner the pharmaceutical agent packaged therewith can be used. Initially, ELQ ⁇ 596 was prepared using a previously reported approach. 12 The 4 ⁇ OEt ⁇ quinolone 1 was prepared according to the literature (Scheme 1, below) and reacted with pinacol ester 2 as previously described 12 .
• a method for the preparation of a compound of Formula (I): wherein R 1 is selected from the group of H, F, and Cl, and R 3 , R 4 , and R 5 are as defined above, the method comprising: a) a first step of reacting a compound of the formula: , wherein R 1 is selected from the group of H, F, and Cl, with an optionally substituted 2 ⁇ ([1,1' ⁇ biphenyl] ⁇ 4 ⁇ yl) ⁇ 4,4,5,5 ⁇ tetramethyl ⁇ 1,3,2 ⁇ dioxaborolane compound of the formula to form a first step product compound of the formula: ; and b) a second step of treating the first step product compound with an acidic medium to form the compound of Formula (I).
• R 1 is selected from the group of H, F, and Cl
• R 3 , R 4 , and R 5 are each independently selected from the group of H, halogen, C 1 ⁇ C 2 alkyl, ⁇ O ⁇ C 1 ⁇ C 2 alkyl, C 1 ⁇ C 2 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 2 haloalkyl, ⁇ SF 5 , and CN.
• R 1 is selected from the group of H, F, and Cl
• R 3 , R 4 , and R 5 are each independently selected from the group of H, F, C 1 ⁇ C 2 alkyl, ⁇ O ⁇ C 1 ⁇ C 2 alkyl, C 1 ⁇ C 2 fluoroalkyl, ⁇ O ⁇ C 1 ⁇ C 2 fluoroalkyl, ⁇ SF 5 , and CN.
• Another embodiment provides a compound of Formula (XI), wherein R 1 is selected from the group of H, F, and Cl, and R 3 , R 4 , and R 5 are each independently selected from the group of H, F, C 1 ⁇ C 2 fluoroalkyl, ⁇ O ⁇ C 1 ⁇ C 2 fluoroalkyl, and ⁇ SF 5 .
• R 1 is selected from the group of H, F, and Cl
• R 3 , R 4 , and R 5 are each independently selected from the group of H, F, C 1 ⁇ C 2 fluoroalkyl, ⁇ O ⁇ C 1 ⁇ C 2 fluoroalkyl, and ⁇ SF 5 .
• p ⁇ TsOH catalytic para ⁇ toluenesulfonic acid
• bis ⁇ acylated 7a and 7b were converted to ⁇ keto ester intermediates 8a and 8b, which existed as mixtures of keto and enol tautomers as determined by 1 H ⁇ NMR.
• concentration the crude reaction mixture contained mainly ⁇ keto esters 8a or 8b and catalytic p ⁇ TsOH, which was required in the next reaction and can be used without further purification.
• R 3 , R 4 , and R 5 are each independently selected from the group of H, halogen, C 1 ⁇ C 4 alkyl, ⁇ O ⁇ C 1 ⁇ C 4 alkyl, C 1 ⁇ C 4 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 4 haloalkyl, ⁇ S ⁇ CF 3 , ⁇ SF 5 , CN, 2 ⁇ pyrrolidinone, ⁇ C(O)NH 2 , ⁇ C(O)NH(C 1 ⁇ C 4 alkyl), , ⁇ C(O)N(C 1 ⁇ C 4 alkyl) 2 , ⁇ C(O)NH(C 3 ⁇ C 6 cycloalkyl), and ⁇ C(O)NH( ⁇ CH 2 ⁇ C 3 ⁇ C 6 cycloalkyl).
• a further embodiment provides a compound of Formula (A), wherein R 3 , R 4 , and R 5 are each independently selected from the group of H, halogen, methyl, methoxy, CH 2 F, CHF 2 , CF 3 , ⁇ O ⁇ CH 2 F, ⁇ O ⁇ CHF 2 , ⁇ O ⁇ CF 3 , ⁇ S ⁇ CF 3 , ⁇ SF 5 , CN, 2 ⁇ pyrrolidinone, ⁇ C(O)NH 2 , ⁇ C(O)NH(C 1 ⁇ C 2 alkyl), , ⁇ C(O)N(C 1 ⁇ C 2 alkyl) 2 , ⁇ C(O)NH(C 3 ⁇ C 6 cycloalkyl), ⁇ C(O)NH( ⁇ CH 2 ⁇ C 3 ⁇ C 6 cycloalkyl);
• Another embodiment provides a compound of Formula (A), wherein R 3 , R 4 , and R 5 are each independently selected from the group of H, halogen, methyl, methoxy
• An additional embodiment provides a compound of Formula (XII), wherein R 1 is selected from the group of H, F, and Cl; and R 3 , R 4 , and R 5 are each independently selected from the group of halogen, C 1 ⁇ C 2 alkyl, ⁇ O ⁇ C 1 ⁇ C 2 alkyl, C 1 ⁇ C 2 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 2 haloalkyl, ⁇ SF 5 , 2 ⁇ pyrrolidinone, and CN, and Z is selected from the group of H, F, and OMe.
• Two separate embodiments provide, respectively, a compound of Formula (XI ⁇ 1) and a compound of Formula (XI ⁇ 2): wherein, in each embodiment, R 1 is selected from the group of H, F, and Cl; and R 3 is selected from the group of halogen, C 1 ⁇ C 4 alkyl, ⁇ O ⁇ C 1 ⁇ C 4 alkyl, C 1 ⁇ C 4 haloalkyl, ⁇ O ⁇ C 1 ⁇ C 4 haloalkyl, ⁇ S ⁇ CF 3 , ⁇ SF 5 , CN, 2 ⁇ pyrrolidinone, ⁇ C(O)NH 2 , ⁇ C(O)NH(C 1 ⁇ C 4 alkyl), , ⁇ C(O)N(C 1 ⁇ C 4 alkyl) 2 , ⁇ C(O)NH(C 3 ⁇ C 6 cycloalkyl), and ⁇ C(O)NH( ⁇ CH 2 ⁇ C 3 ⁇ C 6 cycloalkyl) , and Z is selected from the group of
• Additional embodiments are provided corresponding to each embodiment for a compound of Formula (X ⁇ 1) and a compound of Formula (XI ⁇ 2) as just described, wherein R 3 is as defined and R 1 is Cl. Additional embodiments are also provided corresponding to each embodiment for a compound of Formula (X ⁇ 1) and a compound of Formula (XI ⁇ 2) as just described, wherein R 3 is as defined and R 1 is F.
• Scheme 5 Synthesis of 3 ⁇ (4 ⁇ bromophenyl) ⁇ 4,6 ⁇ dichloro ⁇ 7 ⁇ methoxy ⁇ 2 ⁇ methylquinoline 13 from ⁇ ketoester 8a.
• ELQ ⁇ 596 The ability of ELQ ⁇ 596 to inhibit cytochrome bc 1 activity from P. falciparum mitochondria was assessed. As shown in Table 5, ELQ ⁇ 596 showed potent inhibitory action of the P. falciparum cytochrome bc 1 complex, with an IC 50 value of 0.1 nM. This value is much lower than IC 50 values previously cited for either atovaquone or ELQ ⁇ 300. Notice that the prodrug ELQ ⁇ 598 exhibits only feeble inhibitory activity against the parasite enzyme. We also evaluated ELQ ⁇ 596 for inhibition of the human host cytochrome bc 1 complex isolated from human liver tissue and found no detectable inhibition at a concentration of 10,000 nM.
• GC ⁇ MS was obtained using an Agilent Technologies 7890B gas chromatograph (30 m, DBS column set at either 100°C or 200°C for 2 min, then at 30°C/min to 300°C with inlet temperature set at 250°C) with an Agilent Technologies 5977A mass ⁇ selective detector operating at 70 eV. Flash chromatography over silica gel column was performed using an Isolera One flash chromatography system from Biotage, Uppsala, Sweden. 1 H ⁇ NMR spectra were obtained using a Bruker 400 MHz Avance NEO NanoBay NMR spectrometer operating at 400.14 MHz. The NMR raw data were analyzed using the iNMR Spectrum Analyst software.
• chloromethyl ethyl carbonate (2.0 eq, 0.00069 mol, 0.095 g) was added as a solution in 1mL DMF.
• the reaction was allowed to stir at 60°C, sealed with a needle vented septum, for 24 hours, whereupon TLC indicated that reaction was complete.
• the cooled reaction mixture was vacuum filtered to remove solids, and the solvent was removed from the filtrate under reduced pressure with heating.
• the residue was taken up in 50 mL ethyl acetate and stirred, resulting in precipitation of tetrabutyl ammonium iodide; this was removed by vacuum filtration, and the solvent was removed from the filtrate under reduced pressure with warming.
• the impure mixture (0.45g) was used without further purification in the following reaction. 6 ⁇ Chloro ⁇ 3 ⁇ (2' ⁇ chloro ⁇ [1,1' ⁇ biphenyl] ⁇ 4 ⁇ yl) ⁇ 7 ⁇ methoxy ⁇ 2 ⁇ methylquinolin ⁇ 4(1H) ⁇ one (ELQ ⁇ 713) 4,6 ⁇ Dichloro ⁇ 3 ⁇ (2' ⁇ chloro ⁇ [1,1' ⁇ biphenyl] ⁇ 4 ⁇ yl) ⁇ 7 ⁇ methoxy ⁇ 2 ⁇ methylquinoline (0.15 g of impure material, see above) was heated at 110°C in 10 mL glacial acetic acid with anhydrous potassium acetate (0.34g, 0.0035 mol) for 24 hours.
• the desired product was recovered by vacuum filtration, rinsing with excess water followed by 2 x 3 mL acetone. The resulting solid (34 mg) was recrystallized from N,N ⁇ dimethylformamide (2 mL). The desired product was obtained as a gray powder (17 mg, 22%, 1 H ⁇ NMR (400 MHz; DMSO ⁇ d 6 ): ⁇ 11.68 (s, 1H), 8.02 (s, 1H), 7.38 ⁇ 7.26 (m, 8H), 7.09 (s, 1H), 3.97 (s, 3H), 2.31 (s, 3H), 2.27 (s, 3H)).
• HPLC analyses were performed using an Agilent 1260 Infinity instrument with detection at 254 nm and a Phenomenex, Luna® 5 ⁇ m C8(2) 100 ⁇ reverse phase LC column 150 x 4.6 mm at 40°C, and eluted with a gradient of A/B at 25% : 75% to A/B at 10% : 90% (A:0.05% formic acid in milliQ water, B: 0.05% formic acid in methanol). All compounds were at least >95% pure for in vitro testing and >98% pure for in vivo testing as determined by GC ⁇ MS, 1 H ⁇ NMR and HPLC.
• ELQ ⁇ 652 ((6 ⁇ chloro ⁇ 7 ⁇ methoxy ⁇ 2 ⁇ methyl ⁇ 3 ⁇ (3' ⁇ (trifluoromethoxy) ⁇ [1,1' ⁇ biphenyl] ⁇ 4 ⁇ yl)quinolin ⁇ 4 ⁇ yl)oxy)methyl ethyl carbonate (ELQ ⁇ 652): Following the general procedure C, using a mixture of ELQ ⁇ 604 (150 mg, 0.33 mmol, 1 eq), TBAI (244 mg, 0.66 mmol, 2 eq), dry K 2 CO 3 (92 mg, 0.66 mmol, 2 eq) and chloromethyl ethylcarbonate (91.7 mg, 0.66 mmol, 2 eq) in DMF (15 ml) to give crude ELQ ⁇ 652 (193 mg).
• ELQ ⁇ 671 ((6 ⁇ chloro ⁇ 7 ⁇ methoxy ⁇ 2 ⁇ methyl ⁇ 3 ⁇ (3' ⁇ (trifluoromethyl) ⁇ [1,1' ⁇ biphenyl] ⁇ 4 ⁇ yl)quinolin ⁇ 4 ⁇ yl)oxy)methyl ethyl carbonate (ELQ ⁇ 671): Following the general procedure C, using a mixture of ELQ ⁇ 646 (150 mg, 0.34 mmol, 1 eq), TBAI (251 mg, 0.68 mmol, 2 eq), dry K 2 CO 3 (95 mg, 0.68 mmol, 2 eq) and chloromethyl ethylcarbonate (95 mg, 0.68 mmol, 2 eq) in DMF (30 ml) to give crude ELQ ⁇ 671 (188 mg).
• ELQ ⁇ 699 ((3 ⁇ (3',5' ⁇ bis(trifluoromethyl) ⁇ [1,1' ⁇ biphenyl] ⁇ 4 ⁇ yl) ⁇ 6 ⁇ chloro ⁇ 7 ⁇ methoxy ⁇ 2 ⁇ methylquinolin ⁇ 4 ⁇ yl)oxy)methyl ethyl carbonate (ELQ ⁇ 699): Following the general procedure C, using a mixture of ELQ ⁇ 689 (511 mg, 1.0 mmol, 1 eq), TBAI (738 mg, 2.0 mmol, 2 eq), dry K 2 CO 3 (278 mg, 2.0 mmol, 2 eq) and chloromethyl ethylcarbonate (278 mg, 2.0 mmol, 2 eq) in DMF (50 ml) to give crude ELQ ⁇ 699 (707 mg).
• ELQ ⁇ 711 ((6 ⁇ chloro ⁇ 7 ⁇ methoxy ⁇ 2 ⁇ methyl ⁇ 3 ⁇ (2' ⁇ (trifluoromethoxy) ⁇ [1,1' ⁇ biphenyl] ⁇ 4 ⁇ yl)quinolin ⁇ 4 ⁇ yl)oxy)methyl ethyl carbonate (ELQ ⁇ 711): Following the general procedure C, using a mixture of ELQ ⁇ 702 (230 mg, 0.5 mmol, 1 eq), TBAI (369 mg, 1.0 mmol, 2 eq), dry K 2 CO 3 (139 mg, 1.0 mmol, 2 eq) and chloromethyl ethylcarbonate (139 mg, 2.0 mmol, 2 eq) in DMF (25 ml) to give crude ELQ ⁇ 711 (737 mg).
• ELQ ⁇ 749 ((6 ⁇ chloro ⁇ 7 ⁇ methoxy ⁇ 3 ⁇ (2' ⁇ methoxy ⁇ 4' ⁇ (trifluoromethoxy) ⁇ [1,1' ⁇ biphenyl] ⁇ 4 ⁇ yl) ⁇ 2 ⁇ methylquinolin ⁇ 4 ⁇ yl)oxy)methyl ethyl carbonate (ELQ ⁇ 749): Following the general procedure C, using a mixture of ELQ ⁇ 744 (980 mg, 2.0 mmol, 1 eq), TBAI (1.48 g, 4.0 mmol, 2 eq), dry K 2 CO 3 (556 mg, 4.0 mmol, 2 eq) and chloromethyl ethylcarbonate (556 mg, 4.0 mmol, 2 eq) in DMF (100 ml) to give crude ELQ ⁇ 749 (737 mg).
• ELQ ⁇ 696 ((3 ⁇ (3',5' ⁇ bis(trifluoromethyl) ⁇ [1,1' ⁇ biphenyl] ⁇ 4 ⁇ yl) ⁇ 6 ⁇ fluoro ⁇ 7 ⁇ methoxy ⁇ 2 ⁇ methylquinolin ⁇ 4 ⁇ yl)oxy)methyl ethyl carbonate (ELQ ⁇ 696): Following the general procedure C, using a mixture of ELQ ⁇ 694 (495 mg, 1.0 mmol, 1 eq), TBAI (738 g, 2.0 mmol, 2 eq), dry K 2 CO 3 (278 mg, 2.0 mmol, 2 eq) and chloromethyl ethylcarbonate (278 mg, 2.0 mmol, 2 eq) in DMF (50 ml) to give crude ELQ ⁇ 696 (816 mg) .
• ELQ ⁇ 698 ((3 ⁇ (4' ⁇ cyclohexyl ⁇ [1,1' ⁇ biphenyl] ⁇ 4 ⁇ yl) ⁇ 6 ⁇ fluoro ⁇ 7 ⁇ methoxy ⁇ 2 ⁇ methylquinolin ⁇ 4 ⁇ yl)oxy)methyl ethyl carbonate (ELQ ⁇ 698): Following the general procedure C, using a mixture of ELQ ⁇ 697 (442 mg, 1.0 mmol, 1 eq), TBAI (738 g, 2.0 mmol, 2 eq), dry K 2 CO 3 (278 mg, 2.0 mmol, 2 eq) and chloromethyl ethylcarbonate (278 mg, 2.0 mmol, 2 eq) in DMF (50 ml) to give crude ELQ ⁇ 698 (816 mg) .
• ELQ ⁇ 761 ((5,7 ⁇ difluoro ⁇ 2 ⁇ methyl ⁇ 3 ⁇ (4' ⁇ (trifluoromethoxy) ⁇ [1,1' ⁇ biphenyl] ⁇ 4 ⁇ yl)quinolin ⁇ 4 ⁇ yl)oxy)methyl ethyl carbonate (ELQ ⁇ 761): Following the general procedure C, using a mixture of ELQ ⁇ 601 (431 mg, 1.0 mmol, 1 eq), TBAI (738 g, 2.0 mmol, 2 eq), dry K 2 CO 3 (278 mg, 2.0 mmol, 2 eq) and chloromethyl ethylcarbonate (278 mg, 2.0 mmol, 2 eq) in DMF (50 ml) to give crude ELQ ⁇ 761 (521 mg) .
• the crude ELQ ⁇ 707 was dissolved in DCM (5 ml) cooled at 4 o C for 12 h, filtered and the filtrate was purified by flash chromatography using ethyl acetate/DCM (6/4) followed by crystallization in ethyl acetate/hexane to give pure ELQ ⁇ 707 (397 mg, yield 69%) as a yellow crystal.
• the product was purified by flash chromatography using ethyl acetate/DCM (6/4) followed by crystallization in ethyl acetate/hexane to give pure ELQ ⁇ 735 (235 mg, yield 59 %) as a white crystal.
• Aqueous sodium hydroxide (0.54 mL of a 10% solution, thus 3.3 eq, 0.0015 mol, 0.06 g NaOH) was added while stirring at room temperature. After 105 minutes, the reaction was concentrated to 2 mL, then poured into 80 mL of water. This mixture was allowed to stir overnight, followed by vacuum filtration; after rinsing with water and allowing to remain on suction for 1 hour, the resulting white powder was additionally rinsed with dichloromethane (3 x 0.5 mL).
• ELQ ⁇ 773 ((3 ⁇ (3',4' ⁇ bis(trifluoromethyl) ⁇ [1,1' ⁇ biphenyl] ⁇ 4 ⁇ yl) ⁇ 6 ⁇ chloro ⁇ 7 ⁇ methoxy ⁇ 2 ⁇ methylquinolin ⁇ 4 ⁇ yl)oxy)methyl ethyl carbonate (ELQ ⁇ 773): Following the general procedure C, using a mixture of ELQ ⁇ 750 (256 mg, 0.5 mmol, 1 eq), TBAI (370 mg, 1.0 mmol, 2 eq), dry K 2 CO 3 (139 mg, 1.0 mmol, 2 eq) and chloromethyl ethylcarbonate (139 mg, 1.0 mmol, 2 eq) in DMF (25 ml) to give crude ELQ ⁇ 773 (370 mg).
• ELQ ⁇ 774 ((3 ⁇ (2',4' ⁇ bis(trifluoromethyl) ⁇ [1,1' ⁇ biphenyl] ⁇ 4 ⁇ yl) ⁇ 6 ⁇ chloro ⁇ 7 ⁇ methoxy ⁇ 2 ⁇ methylquinolin ⁇ 4 ⁇ yl)oxy)methyl ethyl carbonate (ELQ ⁇ 774): Following the general procedure C, using a mixture of ELQ ⁇ 763 (256 mg, 0.5 mmol, 1 eq), TBAI (370 mg, 1.0 mmol, 2 eq), dry K 2 CO 3 (139 mg, 1.0 mmol, 2 eq) and chloromethyl ethylcarbonate (139 mg, 1.0 mmol, 2 eq) in DMF (25 ml) to give crude ELQ ⁇ 774 (305 mg).
• the drug was incubated at 37 °C and 1 ⁇ M concentration in murine liver microsomes (Corning) for 45 minutes at a protein concentration of 0.5 mg/mL in potassium phosphate buffer at pH 7.4 containing 1.0 mM EDTA.
• the metabolic reaction was initiated by addition of NADPH and quenched with ice ⁇ cold acetonitrile at 0, 5, 15, 25, and 45 minutes.
• the culture medium used was RPMI ⁇ 1640 with 25 mg/L gentamicin sulfate, 45 mg/L Albumax II, 10 mM glucose, and 25 mM HEPES buffer. Cultures were maintained at less than 10% parasitemia by transfer of infected cells to fresh erythrocytes and culture medium every 3 or 4 days.
• the P. falciparum strains used in these experiments include the following: D6 (MRA ⁇ 285/BEI Resources, deposited by Dr. Dennis Kyle) with modest resistance to mefloquine but generally drug sensitive; Dd2 (MRA ⁇ 150/BEI Resources, deposited by Dr.
• the plates were incubated at room temperature for an hour in the dark.
• the fluorescence signal correlating to parasite DNA, was measured using a SpectraMax iD3 iD5 Multi ⁇ Mode Microplate Reader, with excitation and emission wavelength bands centered at 497 and 520 nm, respectively.
• the 50% inhibitory concentrations (IC 50 ) were determined by non ⁇ linear regression analysis using GraphPad Prism software. Drugs were assayed in quadruplicate and the results were averaged during analysis to give a final IC 50 value together with standard deviations and 95% confidence intervals. Atovaquone and ELQ ⁇ 300 were used as internal controls to verify cross ⁇ resistance and parasite strain integrity.
• the P. yoelii 4 ⁇ day test monitors suppression of patent infection in female CF1 mice.
• the test began with the inoculation (iv) of parasitized erythrocytes (3.5 x 10 4 /P. yoelli) (from a donor animal) on the first day of the experiment (D0). After 24 hr, test drugs (including ELQ ⁇ 596 and prodrug ELQ ⁇ 598) were administered daily by gavage for 4 successive days.
• ELQ ⁇ 331 served as a positive control in these studies to directly compare with prodrug ELQ ⁇ 598.
• ELQ ⁇ 598 was evaluated for liver stage activity in vivo at the Portland VA with a Perkin ⁇ Elmer IVIS instrument. This well ⁇ characterized assay uses in vivo imaging to demonstrate liver stage activity in a murine model. In brief, luciferase/GFP expressing P.
• yoelii sporozoites were reared Anopheles stephensii at the OHSU insectary (Dr. Brandon Wilder). Mice were inoculated with 10,000 sporozoites via tail vein injection of CF1 mice treated with or without drug (dissolved in PEG400) one hour after inoculation. In vivo imaging assessments were taken at 24 ⁇ , 48 ⁇ , and 72 ⁇ hours post ⁇ injection and the luciferase signal from drug treated mice was compared to the luciferase signal derived from vehicle treated mice. Imaging of any luciferase expressing liver stage parasites followed the administration of 150 mg/kg luciferin i.p.
• mice were anesthetized with isoflurane gas when imaging began. Additional monitoring of blood stage infection was conducted after IVIS assessment for a 30 ⁇ day period to confirm true causal prophylaxis against P. yoelii challenge.
• Outcomes from this assay included full causal prophylaxis where all animals showed a negative liver stage signal, partial causal prophylaxis where less than 100% of the animals exhibited a negative liver signal, suppressive prophylaxis where a positive liver stage signal was observed followed by a negative blood stage signal, and a delay in patency where blood stage parasitemia was delayed in drug ⁇ treated animals compared to vehicle animals. Testing involved the use of 4 animals per group for statistical accuracy. ELQ ⁇ 331 was used as a positive control. Isolation of Plasmodium falciparum Mitochondria and Ubiquinol ⁇ Cytochrome c Oxidoreductase Assay. Human cytochrome bc 1 assays.

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