WO2018026811A2 - Antifungal agents - Google Patents

Antifungal agents Download PDF

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Publication number
WO2018026811A2
WO2018026811A2 PCT/US2017/044894 US2017044894W WO2018026811A2 WO 2018026811 A2 WO2018026811 A2 WO 2018026811A2 US 2017044894 W US2017044894 W US 2017044894W WO 2018026811 A2 WO2018026811 A2 WO 2018026811A2
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WO
WIPO (PCT)
Prior art keywords
phenyl
trifluoromethyl
amino
acetamide
trifluoromethy
Prior art date
Application number
PCT/US2017/044894
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French (fr)
Other versions
WO2018026811A3 (en
Inventor
Ching-Shih Chen
Ying-Lien CHEN
Yee-Chun Chen
Appaso JADHAV
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Ohio State Innovation Foundation
Academia Sinica
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Publication of WO2018026811A2 publication Critical patent/WO2018026811A2/en
Publication of WO2018026811A3 publication Critical patent/WO2018026811A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/42—Radicals substituted by singly-bound nitrogen atoms having hetero atoms attached to the substituent nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/402—1-aryl substituted, e.g. piretanide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/33—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • 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
    • C07D401/04—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
    • 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
    • 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

Definitions

  • Fungal infections continue to be major causes of morbidity and mortality, particularly for vulnerable subjects with compromised or suppressed immune systems. Since these subjects are often under inpatient care, a significant number of severe systemic fungal infections, such as aspergillosis, candidiasis, cryptococcosis, histoplasmosis, and the like are often acquired in hospital settings. Subjects at significant risk of fungal infection may include, for example, chemotherapy and other oncology patients with immune suppression, transplant recipients receiving immunosuppressant anti-rejection therapy, subjects with HIV infection or other immune-compromised diseases, bum patients, and the like.
  • Treatments exist for systemic fungal infections such as candidiasis and aspergillosis, but are limited by low efficacy, side effects, expense, and drug resistance.
  • Known antifungal drug classes include: azoles, such as fluconazole, itraconazole, and voriconazole; polyenes, such as Amphotericin B, nystatin, and natamycin; echinocandins such as caspofungin; and allylamines such as terbinafine.
  • azoles such as fluconazole, itraconazole, and voriconazole
  • polyenes such as Amphotericin B, nystatin, and natamycin
  • echinocandins such as caspofungin
  • allylamines such as terbinafine.
  • Currently, only certain azoles, polyenes, and echinocandins are approved to treat systemic fungal infections.
  • Each of the currently approved antifungal drugs have one or more significant drawbacks, such as a lack of broad-spectrum activity, low activity, poor oral bioavailability, undesirable side-effects, expense, and drug-drug interactions. Further, systemic administration of many antifungal drugs in effective concentrations, such as amphotericin B, may be toxic, damaging the liver and other organs.
  • a method of antifungal treatment may include providing a subject that may have a fungal infection or may be at risk of the fungal infection.
  • the method may include administering a compound to the subject in an amount effective to mitigate the fungal infection in the subject, the compound being represented by Structural Formula (I): (I)
  • R 1 may be H, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro.
  • R 2 may be H and R 3 may be: sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl, a ⁇ - amino carbonyl, a ⁇ -amino carbonyl, an ⁇ - ⁇ -unsaturated carbonyl, guanidine, or urea.
  • the aniline nitrogen of Structural Formula (I), R 2 , and R 3 together may form an optionally substituted heterocyclic group.
  • Ar may be an optionally substituted aryl or heteroaryl group consisting of 1, 2, 3, or 4 rings that may be one or more of linked and fused.
  • Het may be a heteroaryl group including a first ring that may be a nitrogen-containing, five or six-membered heteroaryl group.
  • the first ring may be optionally fused to one or more of a second ring and a third ring to form a bicyclic or tricyclic heteroaryl group characterized by 8, 9, 10, 11 , 12, or 13 ring atoms among the first ring, the second ring, and the third ring.
  • R 1 and phenyl ring A may be bonded to the first ring, and Ar may be bonded to the first ring, the second ring, or the third ring.
  • the fungus is not one of: Candida albicans, Cryptococcus neoformans, Cryptococcus gattii, Candida tropicalis, Candida krusei, Candida glabrata, Candida dubliniesis, and Candida parapsilosis .
  • a pharmaceutical composition may include a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition may include a compound represented by Structural Formula (I):
  • R 1 may be H, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro.
  • R 2 may be H and R 3 may be: sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl, a ⁇ - amino carbonyl, a ⁇ -amino carbonyl, an ⁇ - ⁇ -unsaturated carbonyl, guanidine, or urea; or, R 2 , R 3 , and the aniline nitrogen of Structural Formula (I) may together form an optionally substituted heterocyclic group.
  • Ar may be an optionally substituted aryl or heteroaryl group consisting of 1, 2, 3, or 4 rings that may be one or more of linked and fused.
  • Het may be a heteroaryl group including a first ring that may be a nitrogen-containing, five or six-membered heteroaryl group.
  • the first ring may be optionally fused to one or more of a second ring and a third ring to form a bicyclic or tricyclic heteroaryl group characterized by 8, 9, 10, 11, 12, or 13 ring atoms.
  • R 1 and phenyl ring A may be bonded to the first ring, and Ar may be bonded to the first ring, the second ring, or the third ring.
  • the pharmaceutical composition may include an antifungal drug.
  • a kit is provided.
  • the kit may include a compound and instructions.
  • the instructions may direct a user to provide a subject that may have a fungal infection or may be at risk of the fungal infection.
  • the instructions may direct the user to administer the compound to the subject in an amount effective to mitigate the fungal infection.
  • the compound may be represented by Structural Formula (I):
  • R 1 may be H, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro.
  • R 2 may be H and R 3 may be: sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl, a ⁇ - amino carbonyl, a ⁇ -amino carbonyl, an ⁇ - ⁇ -unsaturated carbonyl, guanidine, or urea; or, R 2 , R 3 , and the aniline nitrogen of Structural Formula (I) may together form an optionally substituted heterocyclic group.
  • Ar may be an optionally substituted aryl or heteroaryl group consisting of 1, 2, 3, or 4 rings that may be one or more of linked and fused.
  • Het may be a heteroaryl group including a first ring that may be a nitrogen-containing, five or six-membered heteroaryl group.
  • the first ring may be optionally fused to one or more of a second ring and a third ring to form a bicyclic or tricyclic heteroaryl group characterized by 8, 9, 10, 11, 12, or 13 ring atoms.
  • R 1 and phenyl ring A may be bonded to the first ring, and Ar may be bonded to the first ring, the second ring, or the third ring.
  • the kit may further include an antifungal drug and the instructions may direct the user to co-administer the compound and the antifungal drug to the subject.
  • R 1 ' may be H, cycloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro.
  • Ar' may be optionally substituted and may be one of: tetracene, phenalenyl, pyrenyl, chrysenyl, phenanthrolinyl, acridinyl, phenazinyl, carbazolyl, dibenzofuranyl, quinolinyl, isoquinolinyl, quinoxalyl, quinazolinyl, bipyridyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, and indenyl.
  • R 2 ' may be H, and R 3 ' may be sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl other than glycine, a ⁇ -amino carbonyl, a ⁇ -amino carbonyl, or an ⁇ - ⁇ -unsaturated carbonyl.
  • the aniline nitrogen of Structural Formula ( ⁇ ), R 2 , and R 3 may together form an optionally substituted heterocyclic group.
  • FIG. 1A depicts a range of disclosed compounds by chemical structure that include a pyrrole group.
  • FIG. IB depicts a range of disclosed compounds by chemical structure that include a pyrrole group.
  • FIG. 1C depicts a range of disclosed compounds by chemical structure that include a pyrrole group.
  • FIG. ID depicts a range of disclosed compounds by chemical structure that include a pyrrole group.
  • FIG. 2A depicts a range of disclosed compounds by chemical structure that include an indole group.
  • FIG. 2B depicts a range of disclosed compounds by chemical structure that include an indole group.
  • FIG. 2C depicts a range of disclosed compounds by chemical structure that include an indole group.
  • FIG. 3 depicts a range of disclosed compounds by chemical structure that include indazole or pyridine groups.
  • FIG. 4A depicts a range of disclosed compounds by chemical structure that include an imidazole group.
  • FIG. 4B depicts a range of disclosed compounds by chemical structure that include an imidazole group.
  • FIG. 4C depicts a range of disclosed compounds by chemical structure that include an imidazole group.
  • FIG. 5A depicts a synthetic scheme for compounds having a pyrrole group, e.g., the pyrrole compounds of FIGs. 1A, IB, 1C, and ID.
  • FIG. 5B depicts a synthetic scheme for compounds having a biphenyl group, e.g., the compounds of FIGs. 1A, IB, 1C, and ID.
  • FIG. 6 depicts a synthetic scheme for compounds having an imidazole group, e.g., the compounds of FIGS. 4A, 4B, and 4C.
  • FIG. 7A depicts a synthetic scheme for compounds having a pyridine group, e.g., the pyridine compounds of FIG. 3.
  • FIG. 7B depicts a synthetic scheme for compounds having a naphthalene group, e.g., the naphthalene compounds of FIGs. 1A, IB, 1C, and ID.
  • FIG. 7C depicts a synthetic scheme for compounds having an indole group, e.g., the indole compounds of FIGs. 2A, 2B, and 2C.
  • FIG. 7D depicts a synthetic scheme for compounds having an indazole group, e.g., the indazole compounds of FIG. 3.
  • FIG. 8A is a table of minimum inhibitory concentration (MIC) results in ⁇ g/mL for various compounds.
  • FIG. 8B is a table of minimum inhibitory concentration (MIC) results in ⁇ g/mL for various compounds.
  • Described herein are compounds, methods, pharmaceutical compositions, and kits directed to antifungal therapy. Without wishing to be bound by theory, it is believed that the compounds may act to inhibit fungal enzymes that facilitate fungal replication, for example, phosphoinositide-dependent kinase- 1, and the like. As shown by the data in the Examples and FIGs., the antifungal activity of the compounds is tolerant of a wide diversity of fungal species, being effective against Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton rubrum, and Fusarium solani. Accordingly, the antifungal activity of the described compounds, methods, pharmaceutical compositions, and kits may be generally applicable to most or all of human and animal fungal pathogens.
  • a method of antifungal treatment may include providing a subject that may have a fungal infection or may be at risk of the fungal infection.
  • the method may include administering a compound to the subject in an amount effective to mitigate the fungal infection in the subject, the compound being represented by Structural Formula (I):
  • R 1 may be H, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro.
  • R 2 may be H and R 3 may be: sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl, a ⁇ - amino carbonyl, a ⁇ -amino carbonyl, an ⁇ - ⁇ -unsaturated carbonyl, guanidine, or urea.
  • the aniline nitrogen of Structural Formula (I), R 2 , and R 3 together may form an optionally substituted heterocyclic group.
  • Ar may be an optionally substituted aryl or heteroaryl group consisting of 1, 2, 3, or 4 rings that may be one or more of linked and fused.
  • Het may be a heteroaryl group including a first ring that may be a nitrogen-containing, five or six-membered heteroaryl group.
  • the first ring may be optionally fused to one or more of a second ring and a third ring to form a bicyclic or tricyclic heteroaryl group characterized by 8, 9, 10, 11 , 12, or 13 ring atoms among the first ring, the second ring, and the third ring.
  • R 1 and phenyl ring A may be bonded to the first ring, and Ar may be bonded to the first ring, the second ring, or the third ring.
  • the fungus is not one of: Candida albicans, Cryptococcus neoformans, Cryptococcus gattii, Candida tropicalis, Candida krusei, Candida glabrata, Candida dubliniesis, and Candida parapsilosis .
  • the subject may be infected by the fungus.
  • the method may include administering the compound to the subject in an amount effective to mitigate one or more symptoms of the fungal infection in the subject.
  • the subj ect may be at risk of the fungal infection.
  • the method may include administering the compound to the subject in an amount effective to mitigate the fungal infection of the subject.
  • the subject may suffer from infection by the fungus or may be at risk of suffering from infection by the fungus.
  • the infection may be of one or more of: skin, nail, hoof, hair, fur, scale, mucosal membrane, blood, lymph, brain, lung, heart, liver, pancreas, spleen, kidney, bladder, stomach, and intestine.
  • the subject may suffer from or may be at risk of suffering from a systemic infection by the fungus.
  • the subject may be one or more of: suffering from cancer; undergoing chemotherapy; undergoing immune suppression therapy; a transplant recipient; suffering from an immuno-deficiency, and a burn patient.
  • the subject may be a human, dog, cat, cow, horse, sheep, pig, bird, amphibian, or fish.
  • the fungus may include phosphoinositide-dependent kinase- 1, and the compound may be effective to modulate the phosphoinositide-dependent kinase- 1 effective to mitigate the fungal infection in the subject.
  • the administering may be one or more of: oral administration, intraperitoneal administration, intravenous administration, and intranasal administration.
  • the amount of the composition administered to the subject may refer to the amount of a compound, e.g., active ingredient, administered to the subject.
  • the amount of the composition or compound may include about 2.5 mg per kg of subject weight.
  • the amount of the composition administered to the subject may include less than about5 mg per kg of subject weight.
  • the amount of the composition administered to the subject may include in mg/kg at least about one or more of: 0.01, 0.05, 0.1, 0.3, 0.5, 0.7, 1.0, 1.25, 1.5, 1.8, 2.0, 2.3, 2.5, 3.0, 5.0, 10, 15, 20, 25, 50, 75, and 100, or any value or range between any of the preceding values, e.g., about 2.75; between about 0.5 and about 2.5, between about 3 and about 10, and the like.
  • the amount of the composition administered to the subject may include a range in mg/kg between about one or more of: 1 and 5, 1 and 10, 1 and 15, 5 and 10, 5 and 15, and 5 and 20.
  • the amount of the composition administered to the subject may include any amount described herein, and may be administered as a single dose.
  • the amount of the composition may be administered in a dosage of one or more of: a single dose, a daily dose, a weekly dose, a biweekly dose, a monthly dose, an annual dose, and the like.
  • One or more of the amount of the composition and the dosage administered to the subject may be determined upon one or more of: stage of the infection, progression of the infection, and response to treatment with the composition.
  • One or more of the stage of the infection, the progression of the infection, and the response to treatment with the composition may be analyzed or monitored, for example, by IF A via cell and/or tissue extraction.
  • the compound may be administered by one or more of oral administration, intraperitoneal administration, intravenous administration, and intranasal administration.
  • the amount of the composition administered to the subject may be between about 1 and about 100 mg per kg of subject weight.
  • the amount of the composition administered to the subject may be in a range in mg/kg between one or more of about: 1 and 5, 1 and 10, 1 and 15, 5 and 10, 5 and 15, and 5 and 20.
  • the subject may be administered the compound in a dosage of one or more of: a single dosage, a daily dosage, a weekly dosage, a monthly dosage, and an annual dosage.
  • the fungus may belong to any taxonomic group that includes human or animal pathogens.
  • the fungus may be one of Aspergillus; Candida; Cryptococcus; Fusarium; Trichophyton; and the like.
  • the fungus may include Aspergillus, e.g., A. fumigatus, A. flavus, A. clavi, A. nidulans, and A. terreus, A. niger, A. aculeatus, A. avenaceus, A. casiellus, A. candidus, A, carneus, A. clavato-nanicus, A. clavatus, A. conicus, A.
  • deflectus A. granulosus, A. janus, A. japonicas, A. lentulus, A. ochraceus, A. oryzae, A. protuberus, A. restrictus, A. sclerotiorum, A. sydowii, A. tamarii, A. tubingenis, A. unguis, A. calidoustus, A. versicolor, A. flscheranus, A. thermomutatus , A. hiratsukae, A. nidulans, A, tetrazonus, A. flavipes, A. niveus, A. chevalieri, A. glaucus, A. hollandicus, A.
  • the fungus may include, for example, Candida, e.g., C. rugosa, C. albicans, C. tropicalis, C. krusei, C. glabrata, C. dubliniesis, C. parapsilosis , and the like.
  • the fungus may include, for example, Cryptococcus, e.g., C. neoformans, C. gattii, C.
  • the fungus may include, for example, Fusarium, e.g., F. solani, F. oxysporum, F. verticillioides, F. proliferatum, and the like.
  • the fungus may include, for example, Trichophyton, e.g., T. rubrum, T. concentricum, T. mentagrophytes var. interdigitale, T. mentagrophytes var. erinacei, T. equinum, T. flavescens, T. megnini, T. redellii, T. schoenleinii, T. simii, T. soudanense, T. tonsurans, T. verrucosum, T. violaceum, T. yaoundei, and the like.
  • the fungus may be one of: Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton rubrum, and Fusarium solani.
  • the method may include co-administering an antifungal to the subject.
  • the antifungal drug may include, for example, one or more of: amphotericin B, candicidin, filipin, hamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, Miconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, efinaconazole, epoxiconazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, voriconazole, abafungin, amorolfin,
  • the compound may be represented by Structural Formula (II): (II) ,
  • R 1 may be C1-C4 alkyl or C1-C4 haloalkyl
  • Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl, and Ar may be optionally substituted with one or more of: halogen, C1-C4 haloalkyl, C1-C4 alkyl, C1-C4 alkoxy, nitrile, and nitro
  • R 4 and R 5 may each independently be: H, C1-C6 alkyl, C 3 -C6 cycloalkyl, or C1-C6 haloalkyl; and n may be an integer from 1-6.
  • the compound may be represented by Structural Formula (III):
  • R 1 may be CF 3 ;
  • Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl; and Ar may be optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 haloalkyl;
  • the compound of the method may be one of compounds III-l to 111-39 (FIG. 1A, IB, 1C, and ID): 2-amino-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-pyrrol- 1 -yl)phenyl)acetamide (III-l); 2-amino-N-(4-(2-(phenanthren-3-yl)-4-(trifluoromethyl)-lH- pyrrol- 1 -yl)phenyl)acetamide (III-2); 2-amino-N-(4-(2-(naphthalen-2-yl)-4-(trifluoromethyl)- lH-pyrrol-l-yl)phenyl)acetamide (UI-3); 2-amino-N-(4-(2-(naphthalen-l-yl)-4-(trifluoromethyl)- lH-pyrrol-l-yl)phenyl)acetamide (UI
  • the compound may be represented by Structural Formula (IV):
  • R 1 may be C1-C4 alkyl or C1-C4 haloalkyl
  • Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, naphthyl, pyridyl, or pyrrolyl, and Ar may be optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, nitrile, or SO2-C1-C4 alkyl
  • R 4 and R 5 may optionally be H or C1-C4 alkyl.
  • the compound may be represented by Structural Formula (V):
  • R 1 may be C1-C4 alkyl or C1-C4 haloalkyl
  • Ar may be l-(4-CF 3 )-phenyl, l-(4-CN)- phenyl, 1 -(4-Me)-phenyl, 5-(2-CF 3 )-pyridyl, l-(4-S0 2 Me)-phenyl, 9-anthracenyl, l-(4-OMe)- phenyl, 1 -(4-F)-phenyl, 1 -(4- ⁇ Bu)-phenyl, l-(4-Et)-phenyl, l-(4-zPr)-phenyl, or N-Me-3-pyrrolyl;
  • the compound of the method may be one of compounds V-l to V-22 (FIG. 2A, 2B, and 2C): 2-amino-N-(4-(3-isopropyl-6-(4-(trifluoromethyl)phenyl)-lH-indol-l- yl)phenyl)acetamide (V-l); 2-amino-N-(4-(3-isopropyl-6-(4-(methylsulfonyl)phenyl)-lH-indol- 1 -yl)phenyl)acetamide (V-2); 3-(l -(4-(2-aminoacetamido)phenyl)-6-(4-(trifluoromethyl)phenyl)- lH-indol-3-yl)-N-methylpropanamide (V-3); N-(4-(3-isopropyl-6-(4-(trifluoromethyl)phenyl)-
  • the compound may be represented by Structural Formula (VI):
  • R 1 may be C1-C4 alkyl, C2-C6 cycloalkyl, or C1-C4 haloalkyl
  • Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl, and Ar may be optionally substituted with haloalkyl
  • R 4 and R 5 may be optionally H or C1-C4 alkyl.
  • the compound may be represented by Structural Formula (VII):
  • R 1 may be CF 3 or cyclopropyl
  • Ar may be CF 3 -phenyl
  • the compound may be one of compounds VII-1 to VII-4 (FIG. 3): 2- amino-N-(4-(3 -(trifluoromethy l)-6-(4-(trifluoromethy l)pheny 1)- lH-indazol- 1 - yl)phenyl)acetamide (VII-1); 2-amino-N-(4-(3-cyclopropyl-6-(4-(trifluoromethyl)phenyl)-lH- indazol-l-yl)phenyl)acetamide (VII-2); N-(4-(3-cyclopropyl-6-(4-(trifluoromethyl)phenyl)-lH- indazol-l-yl)phenyl)aminosulfonamide (VII-3); or N-(4-(3 -(trifluoromethy l)-6-(4- (trifluoromethyl)phenyl)- lH-in
  • the compound may be represented by Structural Formula (VIII):
  • R 1 may be C1-C4 alkyl, C 2 -C6 cycloalkyl, or C1-C4 haloalkyl
  • Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl, and Ar may be optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 haloalkyl
  • R 4 and R 5 may be optionally H or C1-C4 alkyl.
  • the compound may be represented by Structural Formula (IX):
  • R 1 may be CF 3 ;
  • Ar may be phenanthryl; and
  • R 2 may be H and R 3 may be
  • the compound may be (FIG. 3) 2-amino-N-(4-(6- (phenanthren-2-yl)-4-(trifluoromethyl)pyridin-2-yl)phenyl)acetamide (IX- 1) or N-(4-(6- (phenanthren-2-yl)-4-(trifluoromethyl)pyridin-2-yl)phenyl)aminosulfonamide (IX-2).
  • the compound may be represented by Structural Formula (X):
  • R 1 may be C1-C4 alkyl, C 2 -C6 cycloalkyl, or C1-C4 haloalkyl
  • Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl, and Ar may be optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 haloalkyl
  • R 4 and R 5 may be optionally H or C 1 -C4 alkyl.
  • the compound may be represented by Structural Formula (XI):
  • R 1 may be CF 3 ;
  • Ar may be anthracenyl, phenanthryl, CF 3 -biphenyl, CF 3 -phenyl, or Br- phenyl;
  • the compound of the method may be one of compounds XI- 1 to XI-
  • the compound may be represented by Structural Formula (XII):
  • R 1 may be C1-C4 alkyl, C2-C6 cycloalkyl, C1-C4 haloalkyl, or an optionally alkylated alkyl amide
  • Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl, and Ar may be optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 haloalkyl
  • R 2 may be H and R 3 R 2 ' may be H, and R ' may be sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl other than glycine, a ⁇ -amino carbonyl, a ⁇ -amino carbonyl, or an ⁇ - ⁇ -unsaturated carbonyl; or, R 2 , R 3 , and
  • R 4 and R 5 may be optionally H or C1-C4 alkyl.
  • the compound may be represented by Structural Formula (XIII):
  • the compound may be 3-(l-(4-(2- aminoacetamido)phenyl)-5-(4'-(trifluoromethyl)-[l, -biphenyl]-4-yl)-lH-pyrazol-3-yl)-N- methylpropanamide:
  • Het may be one of: pyrrole, imidazole, triazole, tetrazole, oxazole, thiazole, indole, indazole, benzimidazole, benzoxazole, benzothiazole, carbazole, quinoline, isoquinoline, quinoxaline, quinazoline, pyridine, pyrazine, pyrimidine, and triazine.
  • R 1 may be ⁇ , C1-C4 alkyl, C 3 -C6 cycloalkyl, C1-C4 haloalkyl, C 3 -C6 halocycloalkyl, halogen, nitrile, alkyl amide, or nitro.
  • R 1 may be CF 3 , isopropyl, cyclopropyl, or -(CH 2 ) 2 C(0)NH(CH 3 ).
  • R 2 may be H.
  • R 3 together with the aniline nitrogen of Structural Formula (I) to which R 3 may be bonded, may represent an amide-bonded: glycine, alanine, serine, threonine, cysteine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tyrosine, tryptophan, aspartic acid, glutamic acid, asparagine, glutamine, histidine, lysine, or arginine.
  • the compound may be represented by Structural Formula (XIV):
  • R 4 and R 5 may each be independently: H, C1-C6 alkyl, C 3 -C6 cycloalkyl, or Ci- Ce haloalkyl; and n may be an integer from 1-6.
  • R 2 , R 3 , and the aniline nitrogen of Structural Formula (I) together may form an optionally substituted triazole or tetrazole.
  • the triazole may be substituted with an alkylamino group.
  • Ar may be an optionally substituted: phenyl, pyridinyl, pyrazinyl, pyrimidinyl, naphthalenyl, quinolinyl, isoquinolinyl, quinoxalyl, quinazolinyl, biphenyl, bipyridinyl, phenanthrenyl, phenanthrolinyl, anthracenyl, tetracenyl, phenalenyl, pyrenyl, chrysenyl, acridinyl, phenazinyl, carbazolyl, fluorenyl, dibenzofuran, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, indenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, or tetrazolyl.
  • Ar may be optionally substituted, for example, with one or more of: C1-C6 alkyl, C 3 -C6 cycloalkyl, C1-C6 haloalkyl, C 3 -C6 halocycloalkyl, nitrile, C1-C6 alkylsulfone, alkyl sulfoxide, Ci-C 6 O-alkyl, O-phenyl, Ci-C 6 NH-alkyl, C 2 -Ci 2 N-alkyl 2 , hydroxyl, NH 2 , halogen, dioxole, dioxolane, N0 2 , aldehyde, C 2 -C7 alkyl or aryl ketone, C 2 -C7 alkyl or aryl ester, C 2 -C7 alkyl or aryl amide, guanidine, amidine, N-OH amidine, urea, imide, oxime, hydrazone, and hydra
  • Ar may be optionally substituted with one or more of: methyl, ethyl, isopropyl, tertbutyl, CF 3 , CN, methoxy, S(0)2-Ci-C4 alkyl, Br, and F.
  • Candida albicans Cryptococcus neoformans, Cryptococcus gattii, Candida tropicalis, Candida krusei, Candida glabrata, Candida dubliniesis, and Candida parapsilosis.
  • the compound when the fungus is one of: Candida albicans, Cryptococcus neoformans, Cryptococcus gattii, Candida tropicalis, Candida krusei, Candida glabrata, Candida dubliniesis, and Candida parapsilosis, the compound may be represented by Structural Formula ( ⁇ ):
  • R 1 ' may be H, cycloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro;
  • Ar' may be optionally substituted and may be one of: tetracene, phenalenyl, pyrenyl, chrysenyl, phenanthrolinyl, acridinyl, phenazinyl, carbazolyl, dibenzofuranyl, quinolinyl, isoquinolinyl, quinoxalyl, quinazolinyl, bipyridyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, and indenyl;
  • R 2 ' may be H, and R 3 ' may be sulfonamide, sulfinamide, alkylamino sulfone, al
  • the fungus is not one of: Candida albicans, Cryptococcus neoformans, Cryptococcus gattii, Candida tropicalis, Candida krusei, Candida glabrata, Candida dubliniesis, and Candida parapsilosis.
  • R 1 ' may be trihalomethyl;
  • Ar' may be 2-phenanthrenyl;
  • R 2 ' may be H, and
  • R 1 ' may be trihalomethyl, H, methyl, ethyl, or halo;
  • Ar' may be 2- phenanthrenyl;
  • R 2 ' may be H, and
  • R 1 ' may be trifluoromethyl
  • Ar' may be phenyl, biphenyl, naphthyl, anthracenyl, phenanthryl, or fluorenyl
  • R 2 ' may be H
  • R 1 ' may be one of alkyl and haloalkyl
  • Ar may be one of: phenyl, biphenyl, naphthyl, anthracenyl, phenanthryl, and fluorenyl; wherein Ar may be optionally substituted with one or more of: halo, C1-C4 alkyl, C1-C4 haloalkyl, azido, C1-C4 azidoalkyl, aryl, alkylaryl, haloaryl, haloalkylaryl, and combinations thereof;
  • R 2 ' may be H; and R 3 ' may be one of N- carboxamide, N-amidine, N-acetamidine, N-aminoacetamide, N-guanidine, and N-urea.
  • R 2 ' may be H, methyl, or ethyl, and each H bonded to a nitrogen in R 3 ' may optionally be methyl or ethyl.
  • the compound may be represented by Structural Formula ( ⁇ ).
  • R 1 ' may be H, cycloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro.
  • Ar' may be optionally substituted and may be one of: tetracene, phenalenyl, pyrenyl, chrysenyl, phenanthrolinyl, acridinyl, phenazinyl, carbazolyl, dibenzofuranyl, quinolinyl, isoquinolinyl, quinoxalyl, quinazolinyl, bipyridyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, and indenyl.
  • R 2 " may be H and R 3 ' may be sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl other than glycine, a ⁇ -amino carbonyl, a ⁇ -amino carbonyl, or an ⁇ - ⁇ -unsaturated carbonyl.
  • R 2 ', R 3 ', and the aniline nitrogen of Structural Formula ( ⁇ ) together may form an optionally substituted heterocyclic group.
  • the fungus may be any fungus described herein.
  • the fungus may be one of: Candida albicans, Cryptococcus neoformans, Cryptococcus gattii, Candida tropicalis, Candida krusei, Candida glabrata, Candida dubliniesis, and Candida parapsilosis .
  • a compound is provided.
  • the compound may be represented by Structural Formula (I):
  • R 1 may be H, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro.
  • R 2 may be H and R 3 may be: sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl, a ⁇ - amino carbonyl, a ⁇ -amino carbonyl, an ⁇ - ⁇ -unsaturated carbonyl, guanidine, or urea; or, the aniline nitrogen of Structural Formula (I), R 2 , and R 3 may together form an optionally substituted heterocyclic group;
  • Ar may be an optionally substituted aryl or heteroaryl group consisting of 1, 2, 3, or 4 rings that may be one or more of linked and fused;
  • Het may be a heteroaryl group including a first ring that may be
  • R 1 ' may be H, cycloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro
  • Ar' may be optionally substituted and may be one of: tetracene, phenalenyl, pyrenyl, chrysenyl, phenanthrolinyl, acridinyl, phenazinyl, carbazolyl, dibenzofuranyl, quinolinyl, isoquinolinyl, quinoxalyl, quinazolinyl, bipyridyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, and indenyl;
  • R 2 ' may be H, and R 3 ' may be sulfonamide, sulfinamide, alkylamino sulfone, al
  • the compound may include any aspect of the compound as described in the method herein.
  • R 4 and R 5 may each independently be: H, C1-C6 alkyl, C3-C6 cycloalkyl, or Ci-Ce haloalkyl; and n may be an integer from 1-6.
  • the compound may be represented by Structural Formula (III), wherein: R 1 may be CF 3 ; Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl; and Ar may be optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, or Ci- C4 haloalkyl; Ar may be 2-phenanthryl, 3 -phenanthryl, 9-anthracenyl, 4-biphenyl, 4-(4'-CF 3 )- biphenyl, 4-(3',5'-dimethyl)-biphenyl, 4-(3',5'-dimethoxy)-biphenyl, phenyl, l-(4-CF 3 )-phenyl, 1 - naphthyl, or 2-naphthyl; and R 2 may be H and R 3 may be S0 2 NH 2
  • the compound may be one of compounds III-l to 111-39 (FIG. 1A, IB,
  • the compound may be represented by Structural Formula
  • R 1 may be C1-C4 alkyl or C1-C4 haloalkyl
  • Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, naphthyl, pyridyl, or pyrrolyl, and Ar may be optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, nitrile, or S0 2 -Ci-C4 alkyl
  • R 4 and R 5 may optionally be H or C1-C4 alkyl.
  • the compound may be one of compounds V-l to V-22 (FIG. 2A, 2B, and 2C).
  • the compound may be represented by Structural Formula
  • R 1 may be C1-C4 alkyl, C 2 -C6 cycloalkyl, or C1-C4 haloalkyl
  • Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl, and Ar may be optionally substituted with haloalkyl
  • R 4 and R 5 may be optionally H or C1-C4 alkyl.
  • the compound may be one of compounds VII- 1 to VII-4 (FIG. 3).
  • R 4 and R 5 may be optionally H or C1-C4 alkyl.
  • the compound may be (FIG.
  • the compound may be represented by Structural Formula
  • R 1 may be C1-C4 alkyl, C 2 -C6 cycloalkyl, or C1-C4 haloalkyl
  • Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl, and Ar may be optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 haloalkyl
  • R 4 and R 5 may be optionally H or C1-C4 alkyl.
  • the compound may be one of compounds XI-1 to XI-21 (FIG. 4A, 4B, 4C, and 2C).
  • the compound may be represented by Structural Formula (XII), wherein R 1 may be C 1 -C4 alkyl, C 2 -C6 cycloalkyl, C 1 -C4 haloalkyl, or an optionally alkylated alkyl amide; Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl, and Ar may be optionally substituted with halogen, C 1 -C4 alkyl, C 1 -C4 alkoxy, or C 1 -C4 haloalkyl; and R may be H and R 3 R 2 ' may be H, and R ' may be sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl other than glycine, a ⁇ -amino carbonyl, a ⁇ - amino carbon
  • R 4 and R 5 may be optionally H or C 1 -C4 alkyl.
  • the compound may be 3-(l-(4-(2-aminoacetamido)phenyl)-5-(4'-(trifluoromethyl)-[l, -biphenyl]-4- yl)-lH-pyrazol-3-yl)-N-methylpropanamide (compound XIII- 1).
  • Het may be one of: pyrrole, imidazole, triazole, tetrazole, oxazole, thiazole, indole, indazole, benzimidazole, benzoxazole, benzothiazole, carbazole, quinoline, isoquinoline, quinoxaline, quinazoline, pyridine, pyrazine, pyrimidine, and triazine.
  • R 1 may be H, C 1 -C4 alkyl, C 3 -C6 cycloalkyl, C 1 -C4 haloalkyl, C 3 -C 6 halocycloalkyl, halogen, nitrile, alkyl amide, or nitro.
  • R 1 may be CF 3 , isopropyl, cyclopropyl, or -(CH 2 ) 2 C(0)NH(CH 3 ).
  • R 2 may be H.
  • R 3 together with the aniline nitrogen of Structural Formula (I) to which R 3 may be bonded, may represent an amide-bonded: glycine, alanine, serine, threonine, cysteine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tyrosine, tryptophan, aspartic acid, glutamic acid, asparagine, glutamine, histidine, lysine, or arginine.
  • the compound may be represented by Structural Formula (XIV), wherein: R 4 and R 5 may each be independently: H, C1-C6 alkyl, C 3 -C6 cycloalkyl, or Ci- Ce haloalkyl; and n may be an integer from 1-6.
  • R 2 , R 3 , and the aniline nitrogen of Structural Formula (I) together may form an optionally substituted triazole or tetrazole.
  • the triazole may be substituted with an alkylamino group.
  • Ar may be an optionally substituted: phenyl, pyridinyl, pyrazinyl, pyrimidinyl, naphthalenyl, quinolinyl, isoquinolinyl, quinoxalyl, quinazolinyl, biphenyl, bipyridinyl, phenanthrenyl, phenanthrolinyl, anthracenyl, tetracenyl, phenalenyl, pyrenyl, chrysenyl, acridinyl, phenazinyl, carbazolyl, fluorenyl, dibenzofuran, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, indenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, or tetrazolyl.
  • Ar may be optionally substituted, for example, with one or more of: Ci-C 6 alkyl, C 3 -C 6 cycloalkyl, Ci-C 6 haloalkyl, C 3 -C 6 halocycloalkyl, nitrile, Ci-C 6 alkylsulfone, alkyl sulfoxide, Ci-C 6 O-alkyl, O-phenyl, Ci-C 6 NH-alkyl, C 2 -Ci 2 N-alkyl 2 , hydroxyl, NH 2 , halogen, dioxole, dioxolane, N0 2 , aldehyde, C 2 -C7 alkyl or aryl ketone, C 2 -C7 alkyl or aryl ester, C 2 -C7 alkyl or aryl amide, guanidine, amidine, N-OH amidine, urea, imide, oxime, hydrazone, and hydrazide.
  • Ar may be optionally substituted with one or more of: methyl, ethyl, isopropyl, fertbutyl, CF 3 , CN, methoxy, S(0) 2 -Ci-C4 alkyl, Br, and F.
  • a pharmaceutical composition may include a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition may include a compound represented by Structural Formula (I):
  • R 1 may be H, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro.
  • R 2 may be H and R 3 may be: sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl, a ⁇ - amino carbonyl, a ⁇ -amino carbonyl, an ⁇ - ⁇ -unsaturated carbonyl, guanidine, or urea; or, R 2 , R 3 , and the aniline nitrogen of Structural Formula (I) may together form an optionally substituted heterocyclic group.
  • Ar may be an optionally substituted aryl or heteroaryl group consisting of 1, 2, 3, or 4 rings that may be one or more of linked and fused.
  • Het may be a heteroaryl group including a first ring that may be a nitrogen-containing, five or six-membered heteroaryl group.
  • the first ring may be optionally fused to one or more of a second ring and a third ring to form a bicyclic or tricyclic heteroaryl group characterized by 8, 9, 10, 1 1, 12, or 13 ring atoms.
  • R 1 and phenyl ring A may be bonded to the first ring, and Ar may be bonded to the first ring, the second ring, or the third ring.
  • the com ound may be represented by Structural Formula ( ⁇ ):
  • R 1 ' may be H, cycloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro.
  • Ar' may be optionally substituted and may be one of: tetracene, phenalenyl, pyrenyl, chrysenyl, phenanthrolinyl, acridinyl, phenazinyl, carbazolyl, dibenzofuranyl, quinolinyl, isoquinolinyl, quinoxalyl, quinazolinyl, bipyridyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, and indenyl.
  • R 2 ' may be H, and R 3 ' may be sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl other than glycine, a ⁇ -amino carbonyl, a ⁇ -amino carbonyl, or an ⁇ - ⁇ -unsaturated carbonyl.
  • the aniline nitrogen of Structural Formula ( ⁇ ), R 2 , and R 3 may together form an optionally substituted heterocyclic group.
  • the pharmaceutical composition may further include an antifungal, e.g., the antifungal drugs (other than the compound) described herein for the method.
  • an antifungal e.g., the antifungal drugs (other than the compound) described herein for the method.
  • the compound may include any aspect of the compound or compound of the method as described herein.
  • the compound of the pharmaceutical composition may be one of compounds III-l to III-39 (FIG. 1A, IB, 1C, and ID), V-l to V-22 (FIG. 2A, 2B, and 2C), VII-1 to VII-4 (FIG. 3), IX-1 and IX-2 (FIG. 3), XI-1 to XI-21 (FIG. 4A, 4B, 4C, and 2C), or XIII-1
  • a kit may include a compound and instructions.
  • the instructions may direct a user to provide a subject that may have a fungal infection or may be at risk of the fungal infection.
  • the instructions may direct the user to administer the compound to the subject in an amount effective to mitigate the fungal infection.
  • the compound may be represented by Structural Formula (I):
  • R 1 may be H, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro.
  • R 2 may be H and R 3 may be: sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl, a ⁇ - amino carbonyl, a ⁇ -amino carbonyl, an ⁇ - ⁇ -unsaturated carbonyl, guanidine, or urea; or, R 2 , R 3 , and the aniline nitrogen of Structural Formula (I) may together form an optionally substituted heterocyclic group.
  • Ar may be an optionally substituted aryl or heteroaryl group consisting of 1, 2, 3, or 4 rings that may be one or more of linked and fused.
  • Het may be a heteroaryl group including a first ring that may be a nitrogen-containing, five or six-membered heteroaryl group.
  • the first ring may be optionally fused to one or more of a second ring and a third ring to form a bicyclic or tricyclic heteroaryl group characterized by 8, 9, 10, 11, 12, or 13 ring atoms.
  • R 1 and phenyl ring A may be bonded to the first ring, and Ar may be bonded to the first ring, the second ring, or the third ring.
  • R 1 ' may be H, cycloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro.
  • Ar' may be optionally substituted and may be one of: tetracene, phenalenyl, pyrenyl, chrysenyl, phenanthrolinyl, acridinyl, phenazinyl, carbazolyl, dibenzofuranyl, quinolinyl, isoquinolinyl, quinoxalyl, quinazolinyl, bipyridyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, and indenyl.
  • R 2 ' may be H, and R 3 ' may be sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl other than glycine, a ⁇ -amino carbonyl, a ⁇ -amino carbonyl, or an ⁇ - ⁇ -unsaturated carbonyl.
  • the aniline nitrogen of Structural Formula ( ⁇ ), R 2 , and R 3 may together form an optionally substituted heterocyclic group.
  • the kit may further include an antifungal, e.g., the antifungal drugs described herein for the method.
  • an antifungal e.g., the antifungal drugs described herein for the method.
  • the compound may include any aspect of the compound, the compound of the method, or the compound of the pharmaceutical composition as described herein.
  • the compound of the pharmaceutical composition may be one of compounds III-l to 111-39 (FIG. 1A, IB, 1C, and ID), V-l to V-22 (FIG. 2A, 2B, and 2C), VII-1 to VII-4 (FIG. 3), IX-1 and IX-2 (FIG. 3), XI-1 to XI-21 (FIG. 4A, 4B, 4C, 2C), or XIII-1.
  • the compound in the kit may be provided in the form of the pharmaceutical composition.
  • the instructions in the kit may direct the user to carry out any aspect of the method as described herein.
  • FIGS. 5A-8B The following examples and results are illustrated in FIGS. 5A-8B. All commercially available reagents were used without further purification unless otherwise stated. Anhydrous tetrahydrofuran (THF) was obtained by distilling commercial reagent over CaH 2 and anhydrous dimethylformamide (DMF) was obtained by distillation over P2O5 under reduced pressure. Silica gel for column chromatography 230 - 400 mesh, was purchased from Fisher Scientific, Pittsburg, PA. Routine X H and 1 C nuclear magnetic resonance spectra were recorded on the DPX 300 or Ascend 400 (Bruker, Billerica, MA).
  • THF tetrahydrofuran
  • DMF dimethylformamide
  • Silica gel for column chromatography 230 - 400 mesh was purchased from Fisher Scientific, Pittsburg, PA. Routine X H and 1 C nuclear magnetic resonance spectra were recorded on the DPX 300 or Ascend 400 (Bruker, Billerica, MA).
  • Electrospray ionization mass spectrometry analyses were performed with a maXis 4G mass spectrometer (Bruker, Billerica, MA). All compounds for bioassay were identified with X H NMR, 1 C NMR and FIRMS, and purities confirmed to be higher than 95%.
  • the purities of all tested compounds were determined by a Hitachi Elite LaChrom HPLC system, including a Versa Grad Prep 36 pump, an L-2400 UV detector, an L-2200 auto sampler and a 250 ⁇ 4.6 mm Phenomenex Luna 5 ⁇ C18 column (Hitachi High-Technologies Science America, Inc., Northridge, CA).
  • EXAMPLE 1 2-amino-A ⁇ -(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)- 1H- pyrrol- 1- yl)phenyl)acetamide (III-l) [0086]
  • the synthetic sequence described below is illustrated in FIG. 5A.
  • Derivatives of compound III-l were prepared from precursor (lg) by various "step h" methods (A-E).
  • Method A as depicted in FIG. 5A, prepared compounds such as III-l, III-2, and III- 10.
  • Method B as described below, prepared compounds such as III- 16.
  • Method C as described below, prepared compounds such as 111-36.
  • Method D as described below, prepared compounds such as 111-33.
  • Method E as described below, prepared compounds such as 111-28, 111-26, 111-22, III- 18, III- 27, 111-24, 111-30, and 111-20
  • step a N-bromosuccinimide (0.121 g, 0.68mmol) was added to a solution of 2-acetylphenanthrene (5.0 g, 22.69 mmol), triethyl orthoformate (6.72 g, 45.39 mmol), and absolute EtOH (50 mL). The resulting solution was stirred at room temperature for 5 to 6 h. The reaction was monitored by TLC. Upon completion, a cold aqueous solution of NaOH (10%, 15 mL) was added and the mixture was extracted with EtjO (3 ⁇ 50 mL). The organic extracts were washed with water (3 ⁇ 25 mL) and dried over anhydrous Na 2 SC>4. The solvent was removed under reduced pressure. The crude product was purified by TEA-coated silica flash chromatography to afford 2-(l,l-diethoxyethyl)phenanthrene (la) (5.4 g) in 82% yield.
  • step b See FIG. 5A, step b.
  • 2-(l,l-diethoxyethyl)phenanthrene (la) 7.0 g, 23.77 mmol
  • chloroform 50 mL
  • pyridine 3.76 g, 47.55 mmol
  • a solution of trifluoroacetic anhydride 9.98 g, 47.55 mmol
  • the reaction was stirred at room temperature for 5 to 6 h.
  • the reaction was monitored by TLC. Upon completion of the reaction, ice cold water was added and the mixture was extracted with DCM.
  • step c See FIG. 5A, step c.
  • trimethylsilyl cyanide 5.0 g, 14.5 mmol
  • triethylamine 0.073 g, 0.726 mmol
  • acetonitrile 20 mL
  • Z -4-ethoxy- 1,1,1 - trifluoro-4-(phenanthren-2-yl)but-3-en-2-one
  • step d L1AIH4 (0.753 g, 19.0 mmol) was suspended in dry ether (50 mL) under an inert atmosphere and cooled to 0-5 °C.
  • step e To a solution of (Z)-2-(aminomethyl)-4-ethoxy- 1,1,1 -trifluoro- 4-(phenanthren-2-yl)but-3-en-2-ol (Id) (3.0 g, 7.99 mmol). acetonitrile (20 mL), and water (1.5 mL) was added 5% aq. HCl (1.15 mL, 32.0 mmol). The resulting solution was stirred at 80 °C for 12 h and monitored by TLC. Upon completion, water and 3% NaHCC (20 mL) were added.
  • step f To a solution of 2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH- pyrrole (le) (2.0 g, 6.42 mmol) in DMF (20 mL), was added 4-fluoronitrobenzene (1.35 g, 9.63 mmol) and K2CO 3 (1.77g, 12.8mmol). The resulting mixture was stirred at 120 °C for 12 h. The reaction was monitored by TLC. Upon completion, ice cold water was added and the solution was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SC>4.
  • step g To a solution of l-(4-nitrophenyl)-2-(phenanthren-2-yl)-4- (trifluoromethyl)-lH-pyrrole (If) (1.0 g, 2.31 mmol) in EtOAc (20 ml) and MeOH (10 mL) was added 10 % Pd/C (122 mg, 1.15 mmol). 70 PSI of H 2 gas was applied to the mixture using a Parr apparatus for 3h.
  • Compound III-2 was prepared from a phenanthren-3-yl derivative of (lg) according to Method (A).
  • the phenanthren-3-yl derivative was prepared according to the scheme in FIG. 5A, beginning with l-(phenanthren-3-yl)ethan-l-one.
  • Compound III-10 was prepared from lg according to Method A using N-Boc, N- methyl glycine.
  • the crude product was purified by silica gel flash chromatography (DCM:Methanol:NH 4 OH, 96:2:2) to afford the corresponding compounds 111-18, 111-20, 111-22, 111-24, 111-26, 111-27, 111-28, and 111-30 in 54- 83% yields.
  • step a A mixture of 4-bromoacetophenone (11.8 g, 59 mmol), 4- trifluoromethyl phenyl boronic acid (11.4 g, 60 mmol), palladium (II) acetate (250 mg, 2 mol %), potassium carbonate (20.3 g, 147 mmol), and tetrabutyl ammonium bromide (20.1 g, 62 mmol), was flushed with argon. Water (500 mL) was introduced using a syringe.
  • step b N-bromosuccinimide (0.094 g, 0.52 mmol) was added to a solution of l-(4'-(trifluoromethyl)-[l, -biphenyl]-4-yl)ethanone (7.0 g, 26.44 mmol), triethyl orthoformate (7.70 g, 52.88 mmol), and absolute EtOH (70 mL). The resulting solution was stirred at room temperature for 6 h. The reaction was monitored by TLC. Upon completion, a cold aqueous solution of NaOH (10%, 15 mL) was added and the mixture was extracted with Et ⁇ O (3 x 50 mL).
  • step d See FIG. 5B, step d.
  • trimethylsilyl cyanide (2.49 g, 25.10 mmol) and triethylamine (0.095 g, 0.965 mmol) in acetonitrile (20 mL) was added (Z)-4-ethoxy- 1,1,1- trifluoro-4-(4'-(trifluoromethyl)-[l, -biphenyl]-4-yl)but-3-en-2-one (7.50 g, 19.31 mmol) as a solution in acetonitrile (20 mL) at 0°C.
  • step e LiAlH 4 (0.857 g, 22.56 mmol) was suspended in dry ether (40 mL) under an inert atmosphere and cooled to 0-5 °C.
  • step f To a solution of (Z)-2-(aminomethyl)-4-ethoxy- 1,1,1 -trifluoro- 4-(4'-(trifluoromethyl)-[l,r-biphenyl]-4-yl)but-3-en-2-ol (3.0 g, 7.15 mmol) acetonitrile (20 mL), and water (1.5 mL) was added HC1 (1.3 mL, 35.76 mmol). The resulting solution was stirred at 80 °C for 12 h and monitored by TLC. Upon completion, water and saturated NaHCCb (20 mL) were added.
  • step g To a solution of 4-(trifluoromethyl)-2-(4'-(trifluoromethyl)- [l,l'-biphenyl]-4-yl)-lH-pyrrole (2.0 g, 5.62 mmol) in DMF (20 mL) was added 4- fluoronitrobenzene (1.19 g, 8.44 mmol) and K2CO 3 (1.55g, 11.25 mmol). The resulting mixture was stirred at 120 °C for 12 h. Upon completion, ice cold water was added and the solution was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SC>4.
  • step i A mixture of 4-(4-(trifluoromethyl)-2-(4'-(trifluoromethyl)-[l,r- biphenyl]-4-yl)-lH-pyrrol-l-yl)aniline (1.0 equiv), propiolic acid (1.2 equiv) and 2-(li- benotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU) (1.5 equiv) in DCM was stirred at room temperature for 48 h (monitored by TLC; DCM:MeOH). The resulting mixture was diluted with DCM, and washed with water and brine. The organic phase was dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM:MeOH) to afford compound 111-32 (82 mg) in 74 % yield.
  • DCM:MeOH 2-(li- benotriazo
  • Compound XI-6 was prepared according to Method A, as described above, using N- Boc, N-methyl glycine.
  • Compound IX-1 was prepared according to Method A as described above. To a solution of /-butyloxycarbonyl ( i BOC)-glycine (46 mg, 0.26 mmol) and 4-(6-(phenanthren-2-yl)- 4-(trifluoromethyl)pyridin-2-yl)aniline (3d) (100 mg, 0.24 mmol) in dry THF (10 mL) was added l-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (71 mg, 0.36 mmol). The resulting mixture was stirred at 25 °C for 12 h, and then concentrated under reduced pressure. The residue was suspended in water and extracted with EtOAc.
  • the organic phase was dried over anhydrous Na 2 SC>4, filtered, and concentrated under reduced pressure to give the Boc- protected intermediate.
  • the intermediate (0.110 g, 0.73 mmol) was dissolved in EtOAc (10 mL) and cone. HCl (1.0 mL) was added. The resulting solution was stirred at room temperature for 2 h, and then concentrated under reduced pressure.
  • Compound III-3 and its derivatives were prepared as shown in FIG. 7B, such as III- 4, III-ll, 111-12, 111-17, 111-19, 111-24, 111-26, and 111-29
  • step a N-bromosuccinimide (0.168 g, 0.94 mmol) was added to a solution of 2-acetylnaphthalene (8.0 g, 47.0 mmol), triethyl orthoformate (13.93 g, 94.00 mmol), and absolute EtOH (80 mL). The resulting solution was stirred at room temperature for 6 h. The reaction was monitored by TLC. Upon completion, a cold aqueous solution of NaOH (10%, 15 mL) was added and the mixture was extracted with Et ⁇ O (3 ⁇ 50 mL). The organic extracts were washed with water (3 ⁇ 25 mL) and dried over anhydrous Na 2 SC>4. The solvent was removed under reduced pressure. The crude product was purified by TEA-coated silica flash chromatography to afford 2-(l,l-diethoxyethyl)naphthalene (9.76 g) in 85% yield.
  • step b To a solution of 2-(l,l-diethoxyethyl)naphthalene (15.0 g, 61.39 mmol) in chloroform (60 mL) was added pyridine (9.7 g, 122.7 mmol) and the resulting solution was stirred at 0 °C for 5 min. A solution of trifluoroacetic anhydride (25.8 g, 122.7 mmol) in 40 mL of chloroform was added dropwise over 15 min. The resulting solution was stirred at room temperature for 5 to 6 h. The reaction was monitored by TLC.
  • step c To a solution of trimethylsilyl cyanide (6.13 g, 61.75 mmol) and triethylamine (0.240 g, 0.237 mmol) in acetonitrile (40 mL) was added (Z)-4-ethoxy- 1,1,1 - trifluoro-4-(naphthalen-2-yl)but-3-en-2-one (7.50 g, 19.31 mmol) as a solution in acetonitrile (20 mL) at 0°C.
  • step d LiAlH 4 (2.0 g, 53.11 mmol) was suspended in dry ether (40 mL) under an inert atmosphere and cooled to 0-5 °C.
  • step e To a solution of (Z)-2-(aminomethyl)-4-ethoxy- 1,1,1 -trifluoro- 4-(naphthalen-2-yl)but-3-en-2-ol (4.0 g, 12.31 mmol) acetonitrile (20 mL), and water (1.5 mL) was added con. HC1 (1.5 mL). The resulting solution was stirred at 80 °C for 12 h and monitored by TLC. Upon completion, water and saturated NaHCC (20 mL) were added. The solution was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over anhydrous Na2S04.
  • step f To a solution of 2-(naphthalen-2-yl)-4-(trifluoromethyl)-lH- pyrrole (1.0 g, 3.82 mmol) in DMF (20 mL), was added 4-fluoronitrobenzene (0.809 g, 5.74 mmol) and K2CO 3 (1.05 g, 7.52 mmol). The resulting mixture was stirred at 120 °C for 12 h. Upon completion, ice cold water was added and the solution was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na 2 S0 4 .
  • step g To a solution of 2-(naphthalen-2-yl)-l-(4-nitrophenyl)-4- (trifluoromethyl)-lH-pyrrole (1.0 g, 2.84 mmol) in EtOAc (20 ml) and MeOH (10 mL) was added 10 % Pd/C (0.150 g, 1.41 mmol) 70 PSI of H 2 gas was applied to the mixture using a Pan- apparatus for 3h.
  • EXAMPLE 6 2-amino-N-(4-(3-isopropyl-6-(4-(trifluoromethyl)phenyl)-lH-indol-l- yl)phenyl)acetamide (V-l): Compounds represented by formula V were prepared from compound 3d, as shown in FIG. 7C, such as compounds V-l to V-17.
  • step c A solution of 6-bromo-3-isopropyl-l-(4-nitrophenyl)-lH-indole (1.9 g, 5.2 mmol), (4-(trifluoromethyl)phenylboronic acid (1.2 g, 6.3 mmol), and 2M.
  • step d See FIG. 7C, step d.
  • 3-isopropyl-l-(4-nitrophenyl)-6-(4- (trifluoromethyl)phenyl)-lH-indole (1.8 g, 4.24 mmol) in (20 ml) of Ethyl acetate and (10 mL) of methanol was added 10 % Palladium on carbon (0.225 g, 2.12 mmol), The reaction was carried out at 70 PSI H 2 gas on the Par apparatus for 3h.
  • step a To a solution of l-(4-bromo-2-fluorophenyl)-2,2,2- trifluoroethanol (1.09 g, 3.99 mmol) in ethyl acetate (30 mL) was added 2-iodoxy benzoic acid (2.28 g, 7.97 mmol). The reaction was heated to reflux overnight. The reaction was cooled to room temperature and diluted with hexanes (30 mL). The mixture was filtered through Celite and the filtrate was concentrated to give l-(4-bromo-2-fluorophenyl)-2,2,2-trifluoroethan-l-one (1.03 g, 95%) as pale yellow oil.
  • step b A solution of Hydrazine hydrate (3.5 mL, 45 mmol), and l-(4- bromo-2-fluorophenyl)-2,2,2-trifluoroethanone (1.00 g, 3.69 mmol) in 1-butanol (15 mL). The reaction was heated to reflux for 6 hours, then cooled to room temperature and left stirring overnight. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated.
  • 6-Bromo-l-(4-nitrophenyl)-3-(trifluoromethyl)-lH-indazole [00143] See FIG. 7D, step c.
  • a solution of 6-bromo-3-(trifluoromethyl)-lH-indazole (1.0 g, 3.77 mmol), 4-fluoronitrobenzene (0.800 g, 5.66 mmol) and K 2 C0 3 (1.02 g, 7.54 mmol) in DMF (10 mL) was stirred at 120°C temperature for 12 h.
  • the reaction was monitored by TLC and after completion of reaction, ice cold water was added, the product were extracted with ethyl acetate (3x 50 mL) dried over anhydrous Na2SC>4.
  • step e To a solution of l-(4-nitrophenyl)-3-(trifluoromethyl)-6-(4- (trifluoromethyl)phenyl)-lH-indazole compound (0.280 g, 0.62 mmol) in (10 ml) of Ethyl acetate and (5 mL) of methanol was added 10 % Palladium on carbon (0.035 g, 0.31 mmol), The reaction was carried out at 70 PSI H 2 gas on the Par apparatus for 2h.
  • step f See FIG. 7D, step f.
  • i-butyloxycarbonyl (i BOC)-glycine 0.035 g, 0.20 mmol
  • 4-(3-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)-lH-indazol-l-yl)aniline 0.080 g, 0.19 mmol
  • 10 ml of dry tetrahydrofuran was added l-[3-(dimethylamino)propyl]-3- ethylcarbodiimidehydrochloride (53 mg, 0.27 mmol), stirred at 25 °C for 12 h, and concentrated to dryness under rotary evaporator.
  • Boc protected intermediate (0.110 g, 0.20 mmol) was dissolved in 9 ml of ethyl acetate containing 1.0 ml of concentrated HCl solution, stirred at room temperature for 2 h, and concentrated to dryness under vacuum.
  • C. albicans and C. neoformans were used to determine the MICs of yeast pathogens, such as C. albicans and C. neoformans .
  • Two-fold serial dilutions of compounds were prepared in 2 of RPMI 1640 medium, and the final concentrations of the antifungal agents ranged from 0.125 to 64 ⁇ g/mL after the addition of the inoculum.
  • C. albicans and C. neoformans were incubated in liquid YPD medium overnight at 37°C, washed twice with ddH 2 0, and adjusted to 0.0005 OD/mL at 600 nm wave length.
  • 98 of the inoculum was added to the RPMI 1640 medium containing serial concentrations of the antifungal agents.
  • the microtitration plates (Becton Dickinson #353072) were then incubated at 35°C for 24 hr (C. albicans) or 48 hr (C. neoformans).
  • the MIC was defined as the lowest concentration of the antifungal agents that completely inhibited growth of C. albicans and C. neoformans in the microtitration wells as detected by the unaided eye and by spectrophotometer.
  • Example 8 Screening The Disclosed Anti-Fungal Compounds For Toxicity and Therapeutic Activity In Vivo
  • C. albicans SC5314 may be cultured in liquid YPD broth overnight at 37°C and washed twice with sterile PBS buffer.
  • Candida cells may be counted with a hemocytometer, and resuspended in sterile PBS buffer at 5x10 6 cells per mL. Dilutions of the cells may be plated onto YPD and may be incubated at 37°C for 24 hr in order to determine CFU and viability.
  • Groups of five mice may be inoculated with C. albicans via tail-vein injection of 10 6 cells (in 200 ⁇ ).
  • Compounds may be prepared as 10-fold stock in DMSO and diluted with ddH 2 0 (0.5% methylcellulose (w/v) + 0.1% Tween-80 (v/v)) into 4.26 mg/ml and 1.42 mg/ml to make the final concentration for mice dose at 30 and 10 mg/kg.
  • the diluted compounds may be sonicated for 1 hr to make homogeneous solution (in 200 ⁇ ), administered via oral gavage (22 gauge) after 4, 24, 48, and 72 hr following Candida infection.
  • the conditions of the mice may be monitored twice daily, and moribund mice may be euthanized by cervical dislocation.
  • Kaplan-Meier survival curves may be generated with Prism 5.03 (GraphPad software, La Jolla, CA, USA), and P values may be evaluated by a Log-rank (Mantel-Cox) test. A P value of ⁇ 0.05 may be considered significant.
  • the mice orally receive a disclosed antifungal compound at 10 or 30 mg/kg may exhibit less toxicity compared with known antifungal compounds, such as ketoconazole. Meanwhile, the therapeutic activity of a specific disclosed compound against C. albicans infection may be determined according to the respective survival curves.
  • the disclosed anti-parasitic compounds may also be counterscreened for toxicity to J774 macrophages and HepG2 hepatocellular carcinoma cells.
  • J774 cells (10 3 in 100 ⁇ ) or HepG2 cells (5 * 10 3 in 100 ⁇ ) may be incubated for 72 h with serial dilutions of compounds in DMEM (for J774 cells) or RPMI medium (for HepG2 cells) supplemented with 10% fetal bovine serum. MTT may then be added and absorbance at 570 nm may provide an assessment of cell proliferation. Determination of IC5 0 values in each assay may permit the calculation of a selectivity index (SI, e.g., target fungus IC50 vs. mammalian cell line/ICso vs., e.g., target fungi in genera such as Aspergillus, Candida, Cryptococcus , Histoplasma, and the like) for each target compound.
  • SI selectivity index
  • an "alkyl” group includes straight chain and branched chain alkyl groups having a number of carbon atoms, for example, from 1 to 12, 1 to 10, 1 to 8, 1 to 6, or 1 to 4.
  • straight chain alkyl groups include groups such as methyl, ethyl, ⁇ -propyl, n- butyl, ft-pentyl, w-hexyl, w-heptyl, and w-octyl groups.
  • branched alkyl groups include, e.g., isopropyl, iso-butyl, sec-butyl, fert-butyl, neopentyl, isopentyl, and 2,2- dimethylpropyl groups.
  • Representative substituted alkyl groups may be substituted one or more times with substituents such as those listed above and include, without limitation, haloalkyl (e.g., trifluoromethyl), hydroxyalkyl, thioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, or carboxyalkyl.
  • an "alkoxy” group means a hydroxyl group (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of a substituted or unsubstituted alkyl group.
  • linear alkoxy groups include, e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy.
  • branched alkoxy groups include, e.g., isopropoxy, seobutoxy, fert-butoxy, isopentoxy, or isohexoxy.
  • cycloalkoxy groups include, e.g., cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy.
  • Representative substituted alkoxy groups may be substituted one or more times.
  • a "cycloalkyl” group includes mono-, bi- or tricyclic alkyl groups having from 3 to 12 carbon atoms in each ring, for example, 3 to 10, 3 to 8, or 3 to 4, 5, or 6 carbon atoms.
  • Exemplary monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like.
  • a cycloalkyl group may have a number of ring carbons of from 3 to 8, 3 to 7, 3 to 6, or 3 to 5.
  • Bi- and tricyclic ring systems may include both bridged cycloalkyl groups and fused rings, e.g., bicyclo[2.1.1]hexane, adamantyl, decalinyl, and the like.
  • Substituted cycloalkyl groups may be substituted one or more times with non-hydrogen and non-carbon groups as defined above.
  • Substituted cycloalkyl groups may include rings that may be substituted with straight or branched chain alkyl groups.
  • Representative substituted cycloalkyl groups may be mono-substituted or substituted more than once, for example, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups.
  • a heterocycloalkyl means an aromatic carbocyclic ring having one or more ring carbon atoms replaced by a heteroatom (e.g., N, S, or O).
  • Non-aromatic heterocyclic rings may have 4, 5, 6, 7, or 8 ring atoms. Examples include oxazolinyl, thiazolinyl, oxazolidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahyrothiophenyl, morpholino, thiomorpholino, pyrrolidinyl, piperazinyl, piperidinyl, thiazolidinyl, and the like.
  • an "aryl” group means a carbocyclic aromatic hydrocarbon.
  • Aryl groups herein include monocyclic, bicyclic and tricyclic ring systems.
  • Aryl groups include, e.g., phenyl, azulenyl, heptalenyl, biphenyl, fluorenyl, phenanthrenyl, anthracenyl, indenyl, indanyl, pentalenyl, naphthyl, and the like, for example, phenyl, biphenyl, and naphthyl.
  • Aryl groups may contain, for example, 6 to 14, 6 to 12, or 6 to 10 ring carbons.
  • the aryl groups may be phenyl or naphthyl.
  • aryl groups may include groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl or tetrahydronaphthyl), an "aryl" group, unless stated to be substituted or optionally substituted, does not include aryl groups that have other groups, such as alkyl or halo groups, bonded to one of the ring members. Rather, groups such as tolyl may be referred to as substituted aryl groups.
  • Representative substituted aryl groups may be mono-substituted or substituted more than once.
  • monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6- substituted phenyl or naphthyl, which may be substituted with substituents such as those above.
  • an "aralkyl” group means an alkyl group in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group.
  • aralkyl groups contain 7 to 16 carbon atoms, 7 to 14 carbon atoms, or 7 to 10 carbon atoms.
  • Substituted aralkyl groups may be substituted at the alkyl, the aryl or both the alkyl and aryl portions of the group.
  • Representative aralkyl groups include, e.g., benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-indanylethyl. Substituted aralkyls may be substituted one or more times.
  • a "heteroaryl” group means a carbocyclic aromatic ring having one or more ring carbon atoms replaced by a heteroatom (e.g., N, S, or O).
  • Heteroaryl groups may include, for example, imidazolyl, isoimidazolyl, thienyl, furanyl, pyridyl, pyrimidyl, pyranyl, pyrazolyl, pyrrolyl, pyrazinyl, thiazoyl, isothiazolyl, oxazolyl, isooxazolyl, 1,2,3-trizaolyl, 1,2,4- triazolyl, and tetrazolyl.
  • Heteroaryl groups also include fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings.
  • heteroaryl groups may include benzothienyl, benzofuranyl, indolyl, quinolinyl, benzothiazolyl, benzoisothiazolyl, benzooxazolyl, benzoisooxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl and isoindolyl.
  • Groups described herein having two or more points of attachment may be designated by use of the suffix, "ene.”
  • divalent alkyl groups may be alkylene groups
  • divalent aryl groups may be arylene groups
  • divalent heteroaryl groups may be heteroarylene groups, and so forth.
  • certain polymers may be described by use of the suffix "ene" in conjunction with a term describing the polymer repeat unit.
  • substituted means a compound or group that may be substituted or unsubstituted.
  • substituted refers to an organic group (e.g., an alkyl group) in which one or more bonds to a hydrogen atom contained therein may be replaced by a bond to non-hydrogen or non-carbon atoms.
  • Substituted groups also include groups in which one or more bonds to a carbon or hydrogen atom may be replaced by one or more bonds, including double or triple bonds, to a heteroatom.
  • a substituted group may be substituted with one or more substituents, unless otherwise specified. In some embodiments, a substituted group may be substituted with 1, 2, 3, 4, 5, or 6 substituents.
  • substituent groups include: halogens (F, CI, Br, and I); hydroxyl; alkoxy, alkenoxy, aryloxy, aralkyloxy, heterocyclyloxy, and heterocyclylalkoxy groups; carbonyls (oxo); carboxyls; esters; urethanes; oximes; hydroxylamines; alkoxyamines; aralkoxy amines; thiols; sulfides; sulfoxides; sulfones; sulfonyls; sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitro groups; or nitriles.
  • halogens F, CI,
  • a "per"- substituted compound or group is a compound or group having all or substantially all substitutable positions substituted with the indicated substituent.
  • 1,6-diiodo perfluoro hexane indicates a compound of formula C 6 F12I2, where all the substitutable hydrogens have been replaced with fluorine atoms.
  • suitable substituents for an alkyl group, cycloalkyl group, heterocycloalkyl group, or an aryl group ring carbon are those which do not substantially interfere with the activity of the disclosed compounds. Examples include -OH, halogen (-Br, -, - I and -F), -OR A , -0(CO)R A , -(CO)R A , -CN, -N0 2 , -C0 2 H, -SO 3 H, -NH 2 , -NHR A , -N(R A R B ), - (CO)OR A , -(CO)H, -CONH 2 , -CONHR A , -CON(R A R B ), -NHCOR A , -NRCOR A , -NHCONH 2 , - NHCONR A H, -NHCON(R A R B ), -NR c CONH 2 , -NR c CONH 2 , -
  • Each of R A -R D may independently be an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group, for example, an alkyl, benzylic or aryl group. Further, -NR A R D , taken together, may form a substituted or unsubstituted non-aromatic heterocyclic group. A non-aromatic heterocyclic group, benzylic group or aryl group may also have an aliphatic or substituted aliphatic group as a substituent.
  • a substituted aliphatic group may also have a non-aromatic heterocyclic ring, a substituted a non- aromatic heterocyclic ring, benzyl, substituted benzyl, aryl or substituted aryl group as a substituent.
  • a substituted aliphatic, non-aromatic heterocyclic group, substituted aryl, or substituted benzyl group may have more than one substituent.
  • Suitable substituents for heteroaryl ring nitrogen atoms having three covalent bonds to other heteroaryl ring atoms may include -OH and Ci to C 10 alkoxy. Substituted heteroaryl ring nitrogen atoms that have three covalent bonds to other heteroaryl ring atoms are positively charged, which may be balanced by counteranions such as chloride, bromide, formate, acetate and the like. Examples of other suitable counteranions may include counteranions found in the described pharmacologically acceptable salts.
  • Suitable substituents for heteroaryl ring nitrogen atoms having two covalent bonds to other heteroaryl ring atoms include alkyl, substituted alkyl (including haloalkyl), phenyl, substituted phenyl, -S(0) 2 -(alkyl), -S(0) 2 -NH(alkyl), -S(0) 2 -NH(alkyl) 2 , and the like.
  • compositions described herein may react with any of a number of organic or inorganic acids to form a salt.
  • compounds disclosed herein that possess a sufficiently acidic functional group may react with any of a number of organic or inorganic bases to form a salt.
  • Acids commonly employed to form acid addition salts from compounds with basic groups may include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p- bromophenyl-sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p- bromophenyl-sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • salts may include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenyl
  • Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like.
  • bases useful in preparing the salts of the described compounds may include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, and the like.
  • An "effective amount” is the quantity of compound in which a beneficial clinical outcome may be achieved when the compound is administered to a subject suffering from the described fungus.
  • a "beneficial clinical outcome” may include one or more of: a reduction in number of fungal cells in a subject; a reduction in the rate of fungal growth in a subject; a reduction in fungal metabolism or consumption of a subject's bodily resources; a reduction in biomarkers, toxins, proteins, peptides, and other biomolecules associated with infection of the subject by the fungus; a reduction in inflammatory, allergic, toxic, disfigurement, or other effects on the subject by the fungus; a reduction in the severity of the symptoms associated with the fungus and/or an increase in the longevity or health of the subject compared with the absence of the treatment.
  • the precise amount of compound administered to a subject may depend on the species, lifecycle, and course of the fungal infection.
  • the precise amount of compound administered to a subject may also depend on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. A skilled artisan may determine appropriate dosages depending on these and other factors. Effective amounts of the disclosed compounds typically range between about 1 mg/mm 2 per day and about 10 grams/mm 2 per day, and preferably between 10 mg/mm 2 per day and about 5 grams/mm 2 .
  • the disclosed compounds and pharmaceutical compositions may be administered by any suitable route, including, for example, orally in tablets, pills, gelcaps, lozenges, or suspensions; by parenteral administration.
  • Parenteral administration can include, for example, systemic administration, such as by intramuscular, intravenous, subcutaneous, or intraperitoneal injection.
  • the compounds may also be administered, for example, orally (e.g., dietary); topically, in the form of creams, sprays, patches, and the like; by inhalation (e.g., intrabronchial, intranasal, or oral inhalation of an aerosol formulation, by intranasal drops, and the like); via absorption through mucus membranes (e.g., tissues such as oral, nasal, rectal, vaginal, and the like) via, for example, creams, lozenges, sprays, drops, suppositories, and the like); depot preparations; coatings on sutures, bandages, medical devices, and the like.
  • oral or parenteral administration are exemplary modes of administration.
  • the disclosed compounds may be administered to the subject in conjunction with an acceptable pharmaceutical carrier as part of a pharmaceutical composition for treatment of infection by the described fungus.
  • Formulation of the compound to be administered may vary according to the route and vehicle of administration selected (e.g., solution for injection, capsule or tablet for ingestion, and the like).
  • Suitable pharmaceutical carriers may contain inert ingredients that do not interact with the described compound. Standard pharmaceutical formulation techniques may be employed, such as those described in Remington's Pharmaceutical Sciences, 22 nd ed., Mack Publishing Company, Easton, PA, 2012.
  • Suitable pharmaceutical carriers for parenteral administration may include, for example, sterile water, physiological saline, bacteriostatic saline (e.g., saline containing about 0.9% mg/ml benzyl alcohol, and the like), phosphate-buffered saline, Hank's solution, Ringer's-lactate and the like.
  • Methods for encapsulating compositions (such as in a coating of hard gelatin or cyclodextrin) or tableting compositions are known in the art (Baker, et al, "Controlled Release of Biological Active Agents," John Wiley and Sons, New York, 1986).
  • a "subject” may be any animal subject to infection by the described fungi, e.g., the subject may be a mammal, bird, marsupial, fish, or amphibian.
  • the subject may be a mammal, such as a human.
  • the subject may also be a domestic or wild animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like), laboratory animals (e.g., rats, mice, guinea pigs, and the like), birds, fish, marsupials, and the like.
  • the term "about” in conjunction with a number is intended to include ⁇ 10% of the number. In other words, “about 10” may mean from 9 to 11. Where the term “about” is used with respect to a number that is an integer, the term “about” may mean ⁇ 10% of the number, or ⁇ 5, ⁇ 4, ⁇ 3, ⁇ 2, or ⁇ 1 of the number.

Abstract

Described herein are methods employing substituted phenyl-heteroaryl-aryl compounds, and corresponding kits directed to antifungal therapy. The antifungal activity is tolerant of a wide diversity of fungal species, being effective against Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton rubrum, and Fusarium solani. Accordingly, the antifungal methods and kits may be generally applicable to a wide range of fungal pathogens.

Description

ANTIFUNGAL AGENTS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from U.S. Provisional Patent Application No. : 62/369,558 filed on August 1, 2016, the entire contents of which are incorporated herein by reference.
BACKGROUND
[0002] Fungal infections continue to be major causes of morbidity and mortality, particularly for vulnerable subjects with compromised or suppressed immune systems. Since these subjects are often under inpatient care, a significant number of severe systemic fungal infections, such as aspergillosis, candidiasis, cryptococcosis, histoplasmosis, and the like are often acquired in hospital settings. Subjects at significant risk of fungal infection may include, for example, chemotherapy and other oncology patients with immune suppression, transplant recipients receiving immunosuppressant anti-rejection therapy, subjects with HIV infection or other immune-compromised diseases, bum patients, and the like.
[0003] Treatments exist for systemic fungal infections, such as candidiasis and aspergillosis, but are limited by low efficacy, side effects, expense, and drug resistance. Known antifungal drug classes include: azoles, such as fluconazole, itraconazole, and voriconazole; polyenes, such as Amphotericin B, nystatin, and natamycin; echinocandins such as caspofungin; and allylamines such as terbinafine. Currently, only certain azoles, polyenes, and echinocandins are approved to treat systemic fungal infections. Each of the currently approved antifungal drugs have one or more significant drawbacks, such as a lack of broad-spectrum activity, low activity, poor oral bioavailability, undesirable side-effects, expense, and drug-drug interactions. Further, systemic administration of many antifungal drugs in effective concentrations, such as amphotericin B, may be toxic, damaging the liver and other organs.
[0004] The present application appreciates that developing treatments for fungal infections may be a challenging endeavor.
SUMMARY
[0005] In one embodiment, a method of antifungal treatment is provided. The method may include providing a subject that may have a fungal infection or may be at risk of the fungal infection. The method may include administering a compound to the subject in an amount effective to mitigate the fungal infection in the subject, the compound being represented by Structural Formula (I): (I)
Figure imgf000004_0001
and pharmaceutically acceptable salts thereof. R1 may be H, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro. R2 may be H and R3 may be: sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl, a β- amino carbonyl, a γ-amino carbonyl, an α-β-unsaturated carbonyl, guanidine, or urea. Alternatively, the aniline nitrogen of Structural Formula (I), R2, and R3 together may form an optionally substituted heterocyclic group. Ar may be an optionally substituted aryl or heteroaryl group consisting of 1, 2, 3, or 4 rings that may be one or more of linked and fused. Het may be a heteroaryl group including a first ring that may be a nitrogen-containing, five or six-membered heteroaryl group. The first ring may be optionally fused to one or more of a second ring and a third ring to form a bicyclic or tricyclic heteroaryl group characterized by 8, 9, 10, 11 , 12, or 13 ring atoms among the first ring, the second ring, and the third ring. R1 and phenyl ring A may be bonded to the first ring, and Ar may be bonded to the first ring, the second ring, or the third ring. In some embodiments, when the compound is 2-amino-N-[4-[5-phenanthren-2-yl-3- (trifluoromethyl)pyrazol-l-yl]phenyl]acetamide, the fungus is not one of: Candida albicans, Cryptococcus neoformans, Cryptococcus gattii, Candida tropicalis, Candida krusei, Candida glabrata, Candida dubliniesis, and Candida parapsilosis .
[0006] In one embodiment, a pharmaceutical composition is provided. The pharmaceutical composition may include a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition may include a compound represented by Structural Formula (I):
(I)
Figure imgf000004_0002
[0007] and pharmaceutically acceptable salts thereof. R1 may be H, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro. R2 may be H and R3 may be: sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl, a β- amino carbonyl, a γ-amino carbonyl, an α-β-unsaturated carbonyl, guanidine, or urea; or, R2, R3, and the aniline nitrogen of Structural Formula (I) may together form an optionally substituted heterocyclic group. Ar may be an optionally substituted aryl or heteroaryl group consisting of 1, 2, 3, or 4 rings that may be one or more of linked and fused. Het may be a heteroaryl group including a first ring that may be a nitrogen-containing, five or six-membered heteroaryl group. The first ring may be optionally fused to one or more of a second ring and a third ring to form a bicyclic or tricyclic heteroaryl group characterized by 8, 9, 10, 11, 12, or 13 ring atoms. R1 and phenyl ring A may be bonded to the first ring, and Ar may be bonded to the first ring, the second ring, or the third ring. The pharmaceutical composition may include an antifungal drug. In another embodiment, a kit is provided. The kit may include a compound and instructions. The instructions may direct a user to provide a subject that may have a fungal infection or may be at risk of the fungal infection. The instructions may direct the user to administer the compound to the subject in an amount effective to mitigate the fungal infection. The compound may be represented by Structural Formula (I):
(I)
Figure imgf000005_0001
and pharmaceutically acceptable salts thereof. R1 may be H, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro. R2 may be H and R3 may be: sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl, a β- amino carbonyl, a γ-amino carbonyl, an α-β-unsaturated carbonyl, guanidine, or urea; or, R2, R3, and the aniline nitrogen of Structural Formula (I) may together form an optionally substituted heterocyclic group. Ar may be an optionally substituted aryl or heteroaryl group consisting of 1, 2, 3, or 4 rings that may be one or more of linked and fused. Het may be a heteroaryl group including a first ring that may be a nitrogen-containing, five or six-membered heteroaryl group. The first ring may be optionally fused to one or more of a second ring and a third ring to form a bicyclic or tricyclic heteroaryl group characterized by 8, 9, 10, 11, 12, or 13 ring atoms. R1 and phenyl ring A may be bonded to the first ring, and Ar may be bonded to the first ring, the second ring, or the third ring. When the compound is represented by Structural Formula (Γ):
Figure imgf000006_0001
one or more of the following may be present. The kit may further include an antifungal drug and the instructions may direct the user to co-administer the compound and the antifungal drug to the subject. R1' may be H, cycloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro. Ar' may be optionally substituted and may be one of: tetracene, phenalenyl, pyrenyl, chrysenyl, phenanthrolinyl, acridinyl, phenazinyl, carbazolyl, dibenzofuranyl, quinolinyl, isoquinolinyl, quinoxalyl, quinazolinyl, bipyridyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, and indenyl. R2' may be H, and R3' may be sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl other than glycine, a β-amino carbonyl, a γ-amino carbonyl, or an α-β-unsaturated carbonyl. Alternatively, the aniline nitrogen of Structural Formula (Γ), R2, and R3 may together form an optionally substituted heterocyclic group.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] The accompanying figures, which are incorporated in and constitute a part of the specification, illustrate example compositions, methods, and kits, and are used merely to illustrate example embodiments.
[0009] FIG. 1A depicts a range of disclosed compounds by chemical structure that include a pyrrole group.
[0010] FIG. IB depicts a range of disclosed compounds by chemical structure that include a pyrrole group.
[0011] FIG. 1C depicts a range of disclosed compounds by chemical structure that include a pyrrole group.
[0012] FIG. ID depicts a range of disclosed compounds by chemical structure that include a pyrrole group.
[0013] FIG. 2A depicts a range of disclosed compounds by chemical structure that include an indole group.
[0014] FIG. 2B depicts a range of disclosed compounds by chemical structure that include an indole group. [0015] FIG. 2C depicts a range of disclosed compounds by chemical structure that include an indole group.
[0016] FIG. 3 depicts a range of disclosed compounds by chemical structure that include indazole or pyridine groups.
[0017] FIG. 4A depicts a range of disclosed compounds by chemical structure that include an imidazole group.
[0018] FIG. 4B depicts a range of disclosed compounds by chemical structure that include an imidazole group.
[0019] FIG. 4C depicts a range of disclosed compounds by chemical structure that include an imidazole group.
[0020] FIG. 5A depicts a synthetic scheme for compounds having a pyrrole group, e.g., the pyrrole compounds of FIGs. 1A, IB, 1C, and ID.
[0021] FIG. 5B depicts a synthetic scheme for compounds having a biphenyl group, e.g., the compounds of FIGs. 1A, IB, 1C, and ID.
[0022] FIG. 6 depicts a synthetic scheme for compounds having an imidazole group, e.g., the compounds of FIGS. 4A, 4B, and 4C.
[0023] FIG. 7A depicts a synthetic scheme for compounds having a pyridine group, e.g., the pyridine compounds of FIG. 3.
[0024] FIG. 7B depicts a synthetic scheme for compounds having a naphthalene group, e.g., the naphthalene compounds of FIGs. 1A, IB, 1C, and ID.
[0025] FIG. 7C depicts a synthetic scheme for compounds having an indole group, e.g., the indole compounds of FIGs. 2A, 2B, and 2C.
[0026] FIG. 7D depicts a synthetic scheme for compounds having an indazole group, e.g., the indazole compounds of FIG. 3.
[0027] FIG. 8A is a table of minimum inhibitory concentration (MIC) results in μg/mL for various compounds.
[0028] FIG. 8B is a table of minimum inhibitory concentration (MIC) results in μg/mL for various compounds.
DETAILED DESCRIPTION
[0029] Described herein are compounds, methods, pharmaceutical compositions, and kits directed to antifungal therapy. Without wishing to be bound by theory, it is believed that the compounds may act to inhibit fungal enzymes that facilitate fungal replication, for example, phosphoinositide-dependent kinase- 1, and the like. As shown by the data in the Examples and FIGs., the antifungal activity of the compounds is tolerant of a wide diversity of fungal species, being effective against Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton rubrum, and Fusarium solani. Accordingly, the antifungal activity of the described compounds, methods, pharmaceutical compositions, and kits may be generally applicable to most or all of human and animal fungal pathogens.
[0030] In various embodiments, a method of antifungal treatment is provided. The method may include providing a subject that may have a fungal infection or may be at risk of the fungal infection. The method may include administering a compound to the subject in an amount effective to mitigate the fungal infection in the subject, the compound being represented by Structural Formula (I):
Figure imgf000008_0001
and pharmaceutically acceptable salts thereof. R1 may be H, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro. R2 may be H and R3 may be: sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl, a β- amino carbonyl, a γ-amino carbonyl, an α-β-unsaturated carbonyl, guanidine, or urea. Alternatively, the aniline nitrogen of Structural Formula (I), R2, and R3 together may form an optionally substituted heterocyclic group. Ar may be an optionally substituted aryl or heteroaryl group consisting of 1, 2, 3, or 4 rings that may be one or more of linked and fused. Het may be a heteroaryl group including a first ring that may be a nitrogen-containing, five or six-membered heteroaryl group. The first ring may be optionally fused to one or more of a second ring and a third ring to form a bicyclic or tricyclic heteroaryl group characterized by 8, 9, 10, 11 , 12, or 13 ring atoms among the first ring, the second ring, and the third ring. R1 and phenyl ring A may be bonded to the first ring, and Ar may be bonded to the first ring, the second ring, or the third ring. In some embodiments, when the compound is 2-amino-N-[4-[5-phenanthren-2-yl-3- (trifluoromethyl)pyrazol-l-yl]phenyl]acetamide, the fungus is not one of: Candida albicans, Cryptococcus neoformans, Cryptococcus gattii, Candida tropicalis, Candida krusei, Candida glabrata, Candida dubliniesis, and Candida parapsilosis .
[0031] In several embodiments, the subject may be infected by the fungus. The method may include administering the compound to the subject in an amount effective to mitigate one or more symptoms of the fungal infection in the subject. The subj ect may be at risk of the fungal infection. The method may include administering the compound to the subject in an amount effective to mitigate the fungal infection of the subject. The subject may suffer from infection by the fungus or may be at risk of suffering from infection by the fungus. The infection may be of one or more of: skin, nail, hoof, hair, fur, scale, mucosal membrane, blood, lymph, brain, lung, heart, liver, pancreas, spleen, kidney, bladder, stomach, and intestine. The subject may suffer from or may be at risk of suffering from a systemic infection by the fungus. The subject may be one or more of: suffering from cancer; undergoing chemotherapy; undergoing immune suppression therapy; a transplant recipient; suffering from an immuno-deficiency, and a burn patient. The subject may be a human, dog, cat, cow, horse, sheep, pig, bird, amphibian, or fish.
[0032] In various embodiments, the fungus may include phosphoinositide-dependent kinase- 1, and the compound may be effective to modulate the phosphoinositide-dependent kinase- 1 effective to mitigate the fungal infection in the subject.
[0033] In several embodiments, the administering may be one or more of: oral administration, intraperitoneal administration, intravenous administration, and intranasal administration. The amount of the composition administered to the subject may refer to the amount of a compound, e.g., active ingredient, administered to the subject. The amount of the composition or compound may include about 2.5 mg per kg of subject weight. The amount of the composition administered to the subject may include less than about5 mg per kg of subject weight. The amount of the composition administered to the subject may include in mg/kg at least about one or more of: 0.01, 0.05, 0.1, 0.3, 0.5, 0.7, 1.0, 1.25, 1.5, 1.8, 2.0, 2.3, 2.5, 3.0, 5.0, 10, 15, 20, 25, 50, 75, and 100, or any value or range between any of the preceding values, e.g., about 2.75; between about 0.5 and about 2.5, between about 3 and about 10, and the like. For example, the amount of the composition administered to the subject may include a range in mg/kg between about one or more of: 1 and 5, 1 and 10, 1 and 15, 5 and 10, 5 and 15, and 5 and 20.
[0034] In some embodiments, the amount of the composition administered to the subject may include any amount described herein, and may be administered as a single dose. In some embodiments, the amount of the composition may be administered in a dosage of one or more of: a single dose, a daily dose, a weekly dose, a biweekly dose, a monthly dose, an annual dose, and the like. One or more of the amount of the composition and the dosage administered to the subject may be determined upon one or more of: stage of the infection, progression of the infection, and response to treatment with the composition. One or more of the stage of the infection, the progression of the infection, and the response to treatment with the composition may be analyzed or monitored, for example, by IF A via cell and/or tissue extraction.
[0035] The compound may be administered by one or more of oral administration, intraperitoneal administration, intravenous administration, and intranasal administration. The amount of the composition administered to the subject may be between about 1 and about 100 mg per kg of subject weight. The amount of the composition administered to the subject may be in a range in mg/kg between one or more of about: 1 and 5, 1 and 10, 1 and 15, 5 and 10, 5 and 15, and 5 and 20. The subject may be administered the compound in a dosage of one or more of: a single dosage, a daily dosage, a weekly dosage, a monthly dosage, and an annual dosage.
[0036] In several embodiments, the fungus may belong to any taxonomic group that includes human or animal pathogens. For example, the fungus may be one of Aspergillus; Candida; Cryptococcus; Fusarium; Trichophyton; and the like. For example, the fungus may include Aspergillus, e.g., A. fumigatus, A. flavus, A. clavi, A. nidulans, and A. terreus, A. niger, A. aculeatus, A. avenaceus, A. casiellus, A. candidus, A, carneus, A. clavato-nanicus, A. clavatus, A. conicus, A. deflectus, A. granulosus, A. janus, A. japonicas, A. lentulus, A. ochraceus, A. oryzae, A. protuberus, A. restrictus, A. sclerotiorum, A. sydowii, A. tamarii, A. tubingenis, A. unguis, A. calidoustus, A. versicolor, A. flscheranus, A. thermomutatus , A. hiratsukae, A. nidulans, A, tetrazonus, A. flavipes, A. niveus, A. chevalieri, A. glaucus, A. hollandicus, A. reptans, A. alliaceus, A. fennelliae, A. spinosus, A. coreanus, A. fumisynnematus , A. viridinutans , A. fumigatiafflnis , A. udagawae, and the like. The fungus may include, for example, Candida, e.g., C. rugosa, C. albicans, C. tropicalis, C. krusei, C. glabrata, C. dubliniesis, C. parapsilosis , and the like. The fungus may include, for example, Cryptococcus, e.g., C. neoformans, C. gattii, C. albidus, C. uniguttulatus , and the like. The fungus may include, for example, Fusarium, e.g., F. solani, F. oxysporum, F. verticillioides, F. proliferatum, and the like. The fungus may include, for example, Trichophyton, e.g., T. rubrum, T. concentricum, T. mentagrophytes var. interdigitale, T. mentagrophytes var. erinacei, T. equinum, T. flavescens, T. megnini, T. redellii, T. schoenleinii, T. simii, T. soudanense, T. tonsurans, T. verrucosum, T. violaceum, T. yaoundei, and the like.
[0037] In some embodiments, the fungus may be one of: Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton rubrum, and Fusarium solani.
[0038] In some embodiments, the method may include co-administering an antifungal to the subject. The antifungal drug may include, for example, one or more of: amphotericin B, candicidin, filipin, hamycin, natamycin, nystatin, rimocidin, bifonazole, butoconazole, clotrimazole, econazole, fenticonazole, isoconazole, ketoconazole, Miconazole, miconazole, omoconazole, oxiconazole, sertaconazole, sulconazole, tioconazole, albaconazole, efinaconazole, epoxiconazole, fluconazole, isavuconazole, itraconazole, posaconazole, propiconazole, ravuconazole, terconazole, voriconazole, abafungin, amorolfin, butenafine, naftifine, terbinafine, anidulafungin, caspofungin, micafungin, benzoic acid, ciclopirox, 5-fluorocytosine, griseofulvin, haloprogin, tolnaftate, undecylenic acid, crystal violet; and the like; and the like.
[0039] In various embodiments of the method, the compound may be represented by Structural Formula (II): (II)
Figure imgf000011_0001
,
wherein: R1 may be C1-C4 alkyl or C1-C4 haloalkyl; Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl, and Ar may be optionally substituted with one or more of: halogen, C1-C4 haloalkyl, C1-C4 alkyl, C1-C4 alkoxy, nitrile, and nitro; R2 may be H and R3 may be SO2NH2, C(=0)CH2NH2, C(=0)CH2N(CH3)2, C(=0)C(cyclopropyl)NH2, C(=0)C(CH3)2NH2„ C(=0)C≡CH, C(=0)CH2NH(CH3), C(=0)CH(NH2)CH(CH3)2, C(=0)CH(NH2)CH2CH(CH3)2, C(=0)CH(CH2Ph)NH2, C(=0)CH(CH3)NH(CH3),
C(=0)CH[CH2CH(CH3)2]NH(CH3), C(=0)CH(CH2Ph)NH(CH3), C(=0)CH(CH2Ph)N(CH3)2; or, R2, R3, and the aniline nitrogen of Structural Formula (II) may together form:
Figure imgf000011_0002
wherein R4 and R5 may each independently be: H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; and n may be an integer from 1-6.
[0040] In some embodiments of the method, the compound may be represented by Structural Formula (III):
(III)
Figure imgf000011_0003
wherein: R1 may be CF3; Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl; and Ar may be optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 haloalkyl; Ar may be 2-phenanthryl, 3-phenanthryl, 9-anthracenyl, 4-biphenyl, 4-(4'-CF3)- biphenyl, 4-(3',5'-dimethyl)-biphenyl, 4-(3',5'-dimethoxy)-biphenyl, phenyl, l-(4-CF3)-phenyl, 1- naphthyl, or 2-naphthyl; and R2 may be H and R3 may be S02NH2, C(=0)CH2NH2, C(=0)CH2N(CH3)2, C(=0)C(cyclopropyl)NH2, C(=0)C(CH3)2NH2i, C(=0)C≡CH, C(=0)CH2NH(CH3), C(=0)CH(NH2)CH(CH3)2, C(=0)CH(NH2)CH2CH(CH3)2,
C(=0)CH(CH2Ph)NH2, C(=0)CH(CH3)NH(CH3), C(=0)CH[CH2CH(CH3)2]NH(CH3), C(=0)CH(CH2Ph)NH(CH3), C(=0)CH(CH2Ph)N(CH3)2; or, R2, R3, and the aniline nitrogen of Structural Formula (III) may together form:
Figure imgf000012_0001
[0041] For example, the compound of the method may be one of compounds III-l to 111-39 (FIG. 1A, IB, 1C, and ID): 2-amino-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-pyrrol- 1 -yl)phenyl)acetamide (III-l); 2-amino-N-(4-(2-(phenanthren-3-yl)-4-(trifluoromethyl)-lH- pyrrol- 1 -yl)phenyl)acetamide (III-2); 2-amino-N-(4-(2-(naphthalen-2-yl)-4-(trifluoromethyl)- lH-pyrrol-l-yl)phenyl)acetamide (UI-3); 2-amino-N-(4-(2-(naphthalen-l-yl)-4-
(trifluoromethyl)-lH-pyrrol-l-yl)phenyl)acetamide (III-4); 2-amino-N-(4-(4-(trifluoromethyl)-2- (4-(trifluoromethyl)phenyl)-lH-pyrrol-l-yl)phenyl)acetamide (III-5); N-(4-(2-([l,l'-biphenyl]-4- yl)-4-(trifluoromethyl)- lH-pyrrol- 1 -yl)phenyl)-2-aminoacetamide (III-6); 2-amino-N-(4-(4- (trifluoromethyl)-2-(4'-(trifluoromethyl)-[ 1 , 1 '-biphenyl] -4-yl)-lH-pyrrol- 1 -yl)phenyl)acetamide (III-7); 2-amino-N-(4-(2-(3',5'-dimethyl-[l,r-biphenyl]-4-yl)-4-(trifluoromethyl)-lH-pyrrol-l- yl)phenyl)acetamide (IU-8); 2-amino-N-(4-(2-(3',5'-dimethoxy-[l,r-biphenyl]-4-yl)-4- (trifluoromethyl)-lH-pyrrol-l-yl)phenyl)acetamide (III-9); 2-(methylamino)-N-(4-(2- (phenanthren-2-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 -y l)pheny l)acetamide (III- 10); 2- (methylamino)-N-(4-(2-(naphthalen-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l-yl)phenyl)acetamide (III- 11); 2-(methylamino)-N-(4-(2-(naphthalen-l-yl)-4-(trifluoromethyl)-lH-pyrrol-l- yl)phenyl)acetamide (111-12); N-(4-(2-([l,r-biphenyl]-4-yl)-4-(trifluoromethyl)-lH-pyrrol-l- yl)phenyl)-2-(methylamino)acetamide (111-13); N-(4-(2-(3',5'-dimethyl-[l,r-biphenyl]-4-yl)-4- (trifluoromethyl)-lH-pyrrol-l-yl)phenyl)-2-(methylamino)acetamide (111-14); N-(4-(2-(3',5'- dimethoxy-[ 1 , 1 '-biphenyl]-4-yl)-4-(trifluoromethyl)- lH-pyrrol- 1 -yl)phenyl)-2- (methylamino)acetamide (III- 15); 2-(dimethylamino)-N-(4-(2-(phenanthren-2-yl)-4- (trifluoromethyl)-lH-pyrrol-l-yl)phenyl)acetamide (111-16); 2-(dimethylamino)-N-(4-(2- (naphthalen-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l-yl)phenyl)acetamide (III- 17); (5)-2-amino-N- (4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l-yl)phenyl)-3-phenylpropanamide (III- 18); (5)-2-(methylamino)-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)- lH-pyrrol- 1 - yl)phenyl)-3-phenylpropanamide (111-19); (5)-2-(methylamino)-N-(4-(2-(naphthalen-2-yl)-4- (trifluoromethyl)-lH-pyrrol-l-yl)phenyl)-3-phenylpropanamide (111-20); (^)-2-
(dimethylamino)-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l-yl)phenyl)-3- phenylpropanamide (111-21); (i?)-2-amino-4-methyl-N-(4-(2-(phenanthren-2-yl)-4-
(trifluoromethyl)-lH-pyrrol-l-yl)phenyl)pentanamide (111-22); (i?)-4-methyl-2-(methylamino)- N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l-yl)phenyl)pentanamide (111-23); (5 -4-methy l-2-(methy lamino)-N-(4-(2-(naphthalen-2-yl)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)pentanamide (111-24); (i?)-2-amino-3-methyl-N-(4-(2-(phenanthren-2-yl)-4- (trifluoromethyl)-lH-pyrrol-l-yl)phenyl)butanamide (111-25); (i?)-2-amino-3-methyl-N-(4-(2- (naphthalen-2-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 -y l)pheny l)butanamide(III-26); C^)-2- (methy lamino)-N-(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)propanamide (111-27); 2-amino-2-methyl-N-(4-(2-(phenanthren-2-yl)-4-
(trifluoromethyl)-lH-pyrrol-l-yl)phenyl)propanamide (111-28); 2-amino-2-methyl-N-(4-(2- (naphthalen-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l-yl)phenyl)propanamide (111-29); 1-amino-N- (4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l-yl)phenyl)cyclopropane-l- carboxamide (111-30); 1 -amino-N-(4-(4-(trifluoromethyl)-2-(4'-(trifluoromethyl)-[ 1 , 1 '-biphenyl]- 4-yl)-lH-pyrrol-l-yl)phenyl)cyclopropane-l-carboxamide (111-31); N-(4-(4-(trifluoromethyl)-2- (4'-(trifluoromethy 1)- [1,1 '-biphenyl] -4-y 1)- lH-py rrol- 1 -y l)pheny l)propiolamide (111-32); NN- dime l-l-(l-(4-(2-(phenanthren-2-yl)-4-(trifluorome l)-lH-pyrrol-l-yl)phenyl)-lH-l,2,3- triazol-4-yl)methanamine (111-33); l-(l-(4-(2-(anthracen-9-yl)-4-(trifluoromethyl)-lH-pyrrol-l- yl)phenyl)-lH-l,2,3-triazol-4-yl)-N,N-dimethylmethanamine (UI-34); NN-dimethyl-l-(l-(4-(4- (trifluoromethy l)-2-(4'-(trifluoromethy l)-[ 1 , 1 '-biphenyl] -4-y 1)- lH-pyrrol- 1 -y l)pheny 1)- 1H- 1 ,2,3- triazol-4-yl)methanamine (111-35); N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l- yl)phenyl)aminosulfonamide (111-36); N-(4-(2-(phenanthren-3-yl)-4-(trifluoromethyl)- 1H- pyrrol- 1 -yl)phenyl)aminosulfonamide (111-37); N-(4-(2-(anthracen-9-yl)-4-(trifluoromethyl)- 1H- pyrrol-l-yl)phenyl)aminosulfonamide (111-38); or N-(4-(4-(trifluoromethyl)-2-(4'- (trifluoromethy 1)- [ 1 , 1 '-biphenyl] -4-y 1)- lH-py rrol- 1 -y l)pheny l)aminosulfonamide (111-39).
[0042] In various embodiments of the method, the compound may be represented by Structural Formula (IV):
(IV)
Figure imgf000013_0001
wherein: R1 may be C1-C4 alkyl or C1-C4 haloalkyl; Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, naphthyl, pyridyl, or pyrrolyl, and Ar may be optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, nitrile, or SO2-C1-C4 alkyl; R2 may be H and R3 may be S02NH2, C(=0)CH2NH2, C(=0)CH2N(CH3)2, C(=0)C(cyclopropyl)NH2, C(=0)C(CH3)2NH2,, C(=0)C≡CH, C(=0)CH2NH(CH3), C(=0)CH(NH2)CH(CH3)2, C(=0)CH(NH2)CH2CH(CH3)2, C(=0)CH(CH2Ph)NH2, C(=0)CH(CH3)NH(CH3),
C(=0)CH[CH2CH(CH3)2]NH(CH3), C(=0)CH(CH2Ph)NH(CH3), C(=0)CH(CH2Ph)N(CH3)2; or, R2, R3, and the aniline nitrogen of Structural Formula (IV) together form:
Figure imgf000014_0001
wherein R4 and R5 may optionally be H or C1-C4 alkyl. For example, the compound may be represented by Structural Formula (V):
(V)
Figure imgf000014_0002
wherein: R1 may be C1-C4 alkyl or C1-C4 haloalkyl; Ar may be l-(4-CF3)-phenyl, l-(4-CN)- phenyl, 1 -(4-Me)-phenyl, 5-(2-CF3)-pyridyl, l-(4-S02Me)-phenyl, 9-anthracenyl, l-(4-OMe)- phenyl, 1 -(4-F)-phenyl, 1 -(4-^Bu)-phenyl, l-(4-Et)-phenyl, l-(4-zPr)-phenyl, or N-Me-3-pyrrolyl; R2 may be H and R3 may be C(=0)CH2NH2, S02NH2, C(=0)C(CH3)2NH2, C(=0)C(cyclopropyl)NH2, C(=0)(CH2)2NH2, C(=0)CH(NH2)(4-imidazole), S02N(CH3)2, C(=0)CH2NH(CH3); or, R2, R3, and the nitrogen of Structural Formula (V) may together form:
Figure imgf000014_0003
[0043] For example, the compound of the method may be one of compounds V-l to V-22 (FIG. 2A, 2B, and 2C): 2-amino-N-(4-(3-isopropyl-6-(4-(trifluoromethyl)phenyl)-lH-indol-l- yl)phenyl)acetamide (V-l); 2-amino-N-(4-(3-isopropyl-6-(4-(methylsulfonyl)phenyl)-lH-indol- 1 -yl)phenyl)acetamide (V-2); 3-(l -(4-(2-aminoacetamido)phenyl)-6-(4-(trifluoromethyl)phenyl)- lH-indol-3-yl)-N-methylpropanamide (V-3); N-(4-(3-isopropyl-6-(4-(trifluoromethyl)phenyl)- lH-indol-l-yl)phenyl)-2-(methylamino)acetamide (V-4); (5 -2-amino-2-(lH-imidazol-4-yl)-N- (4-(3-isopropyl-6-(4-(trifluoromethyl)phenyl)-lH-indol-l-yl)phenyl)acetamide (V-5); 2-amino- N-(4-(3-isopropyl-6-(4-(trifluoromethyl)phenyl)-lH-indol-l-yl)phenyl)-2-methylpropananiide (V-6); l-amino-N-(4-(3-isopropyl-6-(4-(trifluoromethyl)phenyl)-lH-indol-l- yl)phenyl)cyclopropane-l-carboxamide (V-7); 3-amino-N-(4-(3-isopropyl-6-(4-
(trifluoromethy l)pheny 1)- lH-indol- 1 -y l)pheny l)propanamide (V-8); 1 -( 1 -(4-(3 -isopropy l-6-(4- (trifluoromethyl)phenyl)- lH-indol- 1 -yl)phenyl)- lH-1 ,2,3-triazol-4-yl)-NN- dimethylmethanamine (V-9); N-(4-(3 -isopropy l-6-(4-(trifluoromethyl)phenyl)-lH-indol-l- yl)phenyl)aminosulfonamide (V-10); N-(4-(6-(4-cyanophenyl)-3-isopropyl-lH-indol-l- yl)phenyl)aminosulfonamide (V-ll); N-(4-(3-isopropyl-6-(p-tolyl)-lH-indol-l- yl)phenyl)aminosulfonamide (V-12); N-(4-(3-isopropyl-6-(p-tolyl)-lH-indol-l- yl)phenyl)dimethylaminosulfonamide (V-13); N-(4-(6-(4-(tert-butyl)phenyl)-3-isopropyl-lH- indol-l-yl)phenyl)aminosulfonamide (V-14); N-(4-(6-(4-ethylphenyl)-3-isopropyl-lH-indol-l- yl)phenyl)aminosulfonamide (V-15); N-(4-(3-isopropyl-6-(4-isopropylphenyl)-lH-indol-l- yl)phenyl)aminosulfonamide (V-16); N-(4-(3-isopropyl-6-(4-methoxyphenyl)-lH-indol-l- yl)phenyl)aminosulfonamide (V-17); N-(4-(6-(4-fluorophenyl)-3-isopropyl-lH-indol-l- yl)phenyl)aminosulfonamide (V-18); N-(4-(3-isopropyl-6-(4-(methylsulfonyl)phenyl)-lH-indol- l-yl)phenyl)aminosulfonamide (V-19); N-(4-(6-(anthracen-9-yl)-3-isopropyl-lH-indol-l- yl)phenyl)aminosulfonamide (V-20); N-(4-(3-isopropyl-6-(6-(trifluoromethyl)pyridin-3-yl)-lH- indol-l-yl)phenyl)aminosulfonamide (V-21); and N-(4-(3-isopropyl-6-(l-methyl-lH-pyrrol-3- yl)-lH-indol-l-yl)phenyl)aminosulfonamide (V-22).
[0044] In various embodiments of the method, the compound may be represented by Structural Formula (VI):
(V)
Figure imgf000015_0001
wherein: R1 may be C1-C4 alkyl, C2-C6 cycloalkyl, or C1-C4 haloalkyl; Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl, and Ar may be optionally substituted with haloalkyl; R2 may be Η and R3 may be S02NH2, C(=0)CH2NH2, C(=0)CH2N(CH3)2, C(=0)C(cyclopropyl)NH2, C(=0)C(CH3)2NH2i, C(=0)C≡CH, C(=0)CH2NH(CH3), C(=0)CH(NH2)CH(CH3)2, C(=0)CH(NH2)CH2CH(CH3)2, C(=0)CH(CH2Ph)NH2,
C(=0)CH(CH3)NH(CH3), C(=0)CH[CH2CH(CH3)2]NH(CH3), C(=0)CH(CH2Ph)NH(CH3), C(=0)CH(CH2Ph)N(CH3)2; or, R2, R3, and the aniline nitrogen of Structural Formula (V) may together form:
Figure imgf000016_0001
wherein R4 and R5 may be optionally H or C1-C4 alkyl. For example, the compound may be represented by Structural Formula (VII):
(VII)
Figure imgf000016_0002
wherein: R1 may be CF3 or cyclopropyl; Ar may be CF3-phenyl; and R2 may be H and R3 may be C(=0)CH2NH2 or S02NH2.
[0045] For example, the compound may be one of compounds VII-1 to VII-4 (FIG. 3): 2- amino-N-(4-(3 -(trifluoromethy l)-6-(4-(trifluoromethy l)pheny 1)- lH-indazol- 1 - yl)phenyl)acetamide (VII-1); 2-amino-N-(4-(3-cyclopropyl-6-(4-(trifluoromethyl)phenyl)-lH- indazol-l-yl)phenyl)acetamide (VII-2); N-(4-(3-cyclopropyl-6-(4-(trifluoromethyl)phenyl)-lH- indazol-l-yl)phenyl)aminosulfonamide (VII-3); or N-(4-(3 -(trifluoromethy l)-6-(4- (trifluoromethyl)phenyl)- lH-indazol- 1 -yl)phenyl)aminosulfonamide (VII-4).
[0046] In various embodiments of the method, the compound may be represented by Structural Formula (VIII):
(VIII)
Figure imgf000016_0003
,
wherein: R1 may be C1-C4 alkyl, C2-C6 cycloalkyl, or C1-C4 haloalkyl; Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl, and Ar may be optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 haloalkyl; R2 may be Η and R3 may be S02NH2, C(=0)CH2NH2, C(=0)CH2N(CH3)2, C(=0)C(cyclopropyl)NH2, C(=0)C(CH3)2NH2, C(=0)C≡CH, C(=0)CH2NH(CH3), C(=0)CH(NH2)CH(CH3)2, C(=0)CH(NH2)CH2CH(CH3)2, C(=0)CH(CH2Ph)NH2, C(=0)CH(CH3)NH(CH3), C(=0)CH[CH2CH(CH3)2]NH(CH3), C(=0)CH(CH2Ph)NH(CH3), C(=0)CH(CH2Ph)N(CH3)2; or, R2, R3, and the aniline nitrogen of Structural Formula (VIII) together form:
Figure imgf000017_0001
wherein R4 and R5 may be optionally H or C1-C4 alkyl. For example, the compound may be represented by Structural Formula (IX):
(IX)
Figure imgf000017_0002
wherein: R1 may be CF3; Ar may be phenanthryl; and R2 may be H and R3 may be
C(=0)CH2NH2 or S02NH2. For example, the compound may be (FIG. 3) 2-amino-N-(4-(6- (phenanthren-2-yl)-4-(trifluoromethyl)pyridin-2-yl)phenyl)acetamide (IX- 1) or N-(4-(6- (phenanthren-2-yl)-4-(trifluoromethyl)pyridin-2-yl)phenyl)aminosulfonamide (IX-2).
[0047] In various embodiments of the method, the compound may be represented by Structural Formula (X):
(X)
Figure imgf000017_0003
,
wherein: R1 may be C1-C4 alkyl, C2-C6 cycloalkyl, or C1-C4 haloalkyl; Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl, and Ar may be optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 haloalkyl; and R2 may be H and R3 may be S02NH2, C(=0)CH2NH2, C(=0)CH2N(CH3)2, C(=0)C(cyclopropyl)NH2, C(=0)C(CH3)2NH2, C(=0)C≡CH, C(=0)CH2NH(CH3), C(=0)CH(NH2)CH(CH3)2, C(=0)CH(NH2)CH2CH(CH3)2, C(=0)CH(CH2Ph)NH2, C(=0)CH(CH3)NH(CH3), C(=0)CH[CH2CH(CH3)2]NH(CH3), CC((==00))CCHH((CCHH22PPhh))NNHH((CCHH33)),, CC((==00))CCHH((CCFH2Ph)N(CH3)2; or, R2, R3, and the aniline nitrogen of Structural Formula (X) may together form:
Figure imgf000018_0001
wherein R4 and R5 may be optionally H or C1-C4 alkyl. For example, the compound may be represented by Structural Formula (XI):
(XI)
Figure imgf000018_0002
,
wherein: R1 may be CF3; Ar may be anthracenyl, phenanthryl, CF3-biphenyl, CF3-phenyl, or Br- phenyl; R2 may be H and R3 may be S02NH2, C(=0)CH2NH2, C(=0)CH2NH(CH3),
C(=0)CH2N(CH3)2, C(=0)CH[CH2CH(CH3)2]NH(CH3), C(=0)CH[CH(CH3)2]NH(CH3); or, or, R2, R3, and the aniline nitrogen of Struct (XI) may together form:
Figure imgf000018_0003
[0048] For example, the compound of the method may be one of compounds XI- 1 to XI-
21 (FIG. 4A, 4B, 4C, and 2C): 2-amino-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH- imidazol-l-yl)phenyl)acetamide (XI- 1); 2-amino-N-(4-(4-(trifluoromethyl)-2-(4'-
(trifluoromethyl)-[l, -biphenyl]-4-yl)-lH-imidazol-l-yl)phenyl)acetamide (XI-2); 2-amino-N- (4-(2-(4-bromophenyl)-4-(trifluoromethyl)- lH-imidazol- 1 -yl)phenyl)acetamide (XI-3); 2-amino- N-(4-(4-(trifluoromethy l)-2-(4-(trifluoromethy l)pheny 1)- lH-imidazol- 1 -y l)pheny l)acetamide (XI-4); 2 dimethylamino)-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-imidazol-l- yl)phenyl)acetamide (XI-5); 2-(methylamino)-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)- lH-imidazol- 1 -yl)phenyl)acetamide (XI-6); (5 -4-methyl-2-(methylamino)-N-(4-(2- (phenanthren-2-y l)-4-(trifluoromethy 1)- lH-imidazol- 1 -y l)pheny l)pentanamide (XI- 7); (i?)-3 - methyl-2-(methylamino)-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-imidazol-l- yl)phenyl)butanamide (XI-8); NN-dimethyl-l-(l-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)- lH-imidazol-l-yl)phenyl)-lH-l,2,3-triazol-4-yl)methanamine (XI-9); N-(4-(2-(anthracen-9-yl)- 4-(trifluoromethyl)-lH-imidazol-l-yl)phenyl)aminosulfonamide (XI- 10); N-(4-(2-(phenanthren- 2-yl)-4-(trifluoromethyl)-lH-imidazol-l-yl)phenyl)aminosulfonamide (XI-11); N-(4-(4- (trifluoromethyl)-2-(4-(trifluoromethyl)phenyl)-lH-imidazol-l-yl)phenyl)am
(XI- 12); or N-(4-(4-(trifluoromethy l)-2-(4'-(trifluoromethy 1)- [ 1 , Γ-bipheny 1] -4-y 1)- lH-imidazol- 1 -yl)phenyl)aminosulfonamide (XI- 13); (<S)-2-amino-N-(4-(2-(phenanthren-2-yl)-4-
(trifluoromethyl)-lH-imidazol-l-yl)phenyl)-3-phenylpropanamide (XI-14); N-(4-(2- (phenanthren-2-yl)-4-(trifluoromethyl)-lH-imidazol-l-yl)phenyl)propiolamide (XI-15); 2- amino-N-(4-(2-(3 5'-dimethyl-[lJ'-biphenyl]-4-yl)-4-(trifluoromethyl)-lH-imidazol-l- yl)phenyl)acetamide (XI-16); 2-amino-N-(4-(2-(3',5'-dimethoxy-[l,r-biphenyl]-4-yl)-4- (trifluoromethyl)-lH-imidazol-l-yl)phenyl)acetamide (XI-17); 2-amino-N-(4-(2-(naphthalen-2- y l)-4-(trifluoromethy 1)- lH-imidazol- 1 -y l)pheny l)acetamide (XI- 18); 2-amino-N-(4-(2- (naphthalen-l-yl)-4-(trifluoromethyl)-lH-imidazol-l-yl)phenyl)acetamide (XI-19); 2-amino-N- (4-(2-(3 5'-bis(trifluoromethyl)-[lJ'-biphenyl]-4-yl)-4-(trifluoromethyl)-lH-imidazol-l- yl)phenyl)acetamide (XI-20); or N-(4-(2-(3',5'-bis(trifluoromethyl)-[l,r-biphenyl]-4-yl)-4- (trifluoromethyl)- lH-imidazol- 1 -yl)phenyl)-2-(methylamino)acetamide (XI-21).
[0049] In various embodiments of the method, the compound may be represented by Structural Formula (XII):
Figure imgf000019_0001
(XII)
wherein R1 may be C1-C4 alkyl, C2-C6 cycloalkyl, C1-C4 haloalkyl, or an optionally alkylated alkyl amide; Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl, and Ar may be optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 haloalkyl; and R2 may be H and R3 R2' may be H, and R ' may be sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl other than glycine, a β-amino carbonyl, a γ-amino carbonyl, or an α-β-unsaturated carbonyl; or, R2, R3, and the aniline nitrogen of Structural Formula (XII) may together form:
Figure imgf000020_0001
wherein R4 and R5 may be optionally H or C1-C4 alkyl. For example, the compound may be represented by Structural Formula (XIII):
(XIII)
Figure imgf000020_0002
wherein: R1 may be CH2CH2C(=0)NHCH3; Ar may be biphenyl optionally substituted with halogen or C1-C4 haloalkyl; and R2 may be H and R3 may be S02NH2, C(=0)CH2NH2,
C(=0)CH2NH(CH3), C(=0)CH2N(CH3)2, C(=0)CH[CH2CH(CH3)2]NH(CH3), or
C(=0)CH[CH(CH3)2]NH(CH3). For example, the compound may be 3-(l-(4-(2- aminoacetamido)phenyl)-5-(4'-(trifluoromethyl)-[l, -biphenyl]-4-yl)-lH-pyrazol-3-yl)-N- methylpropanamide:
Figure imgf000020_0003
XIII- 1
[0050] In various embodiments of the method, Het may be one of: pyrrole, imidazole, triazole, tetrazole, oxazole, thiazole, indole, indazole, benzimidazole, benzoxazole, benzothiazole, carbazole, quinoline, isoquinoline, quinoxaline, quinazoline, pyridine, pyrazine, pyrimidine, and triazine.
[0051] In some embodiments of the method, R1 may be Η, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C3-C6 halocycloalkyl, halogen, nitrile, alkyl amide, or nitro. For example, R1 may be CF3, isopropyl, cyclopropyl, or -(CH2)2C(0)NH(CH3). [0052] In several embodiments of the method, R2 may be H. R3 may be, for example, S02NH2, S02NH(CH3), S02N(CH3)2, S(=0)-C1-C4 alk l amine, S02-Ci-C4 alkyl amine, C(=0)CH2NH2, C(=0)CH2N(CH3)2, C(=0)CH2NH(CH3), C(=0)(CH2)2NH2, C(=0)(CH2)3NH2, C(=0)C(CH3)2NH2, C(=0)CH(NH2)(4-imidazole), C(=0)CH(NH2)CH(CH3)2,
C(=0)CH(NH2)CH2CH(CH3)2, C(=0)CH[CH2CH(CH3)2]NH(CH3), C(=0)CH(CH2Ph)NH2, C(=0)CH(CH2Ph)NH(CH3), C(=0)CH(CH2Ph)N(CH3)2, C(=0)CH(CH3)NH(CH3),
C(=0)C(cyclopropyl)NH2, C(=0)C≡CH, or C(=0)CHCH2. Additionally or alternatively, R3, together with the aniline nitrogen of Structural Formula (I) to which R3 may be bonded, may represent an amide-bonded: glycine, alanine, serine, threonine, cysteine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tyrosine, tryptophan, aspartic acid, glutamic acid, asparagine, glutamine, histidine, lysine, or arginine.
[0053] In various embodiments of the method, the compound may be represented by Structural Formula (XIV):
Figure imgf000021_0001
wherein: R4 and R5 may each be independently: H, C1-C6 alkyl, C3-C6 cycloalkyl, or Ci- Ce haloalkyl; and n may be an integer from 1-6.
[0054] In several embodiments of the method, R2, R3, and the aniline nitrogen of Structural Formula (I) together may form an optionally substituted triazole or tetrazole. The triazole may be substituted with an alkylamino group.
[0055] In some embodiments of the method, Ar may be an optionally substituted: phenyl, pyridinyl, pyrazinyl, pyrimidinyl, naphthalenyl, quinolinyl, isoquinolinyl, quinoxalyl, quinazolinyl, biphenyl, bipyridinyl, phenanthrenyl, phenanthrolinyl, anthracenyl, tetracenyl, phenalenyl, pyrenyl, chrysenyl, acridinyl, phenazinyl, carbazolyl, fluorenyl, dibenzofuran, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, indenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, or tetrazolyl. Ar may be optionally substituted, for example, with one or more of: C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 halocycloalkyl, nitrile, C1-C6 alkylsulfone, alkyl sulfoxide, Ci-C6 O-alkyl, O-phenyl, Ci-C6 NH-alkyl, C2-Ci2 N-alkyl2, hydroxyl, NH2, halogen, dioxole, dioxolane, N02, aldehyde, C2-C7 alkyl or aryl ketone, C2-C7 alkyl or aryl ester, C2-C7 alkyl or aryl amide, guanidine, amidine, N-OH amidine, urea, imide, oxime, hydrazone, and hydrazide. Ar may be optionally substituted with one or more of: methyl, ethyl, isopropyl, tertbutyl, CF3, CN, methoxy, S(0)2-Ci-C4 alkyl, Br, and F.
[0056] In various embodiments of the method, when the compound is represented by Structural Formula (Γ):
Figure imgf000022_0001
wherein R1' may be trifluoromethyl; Ar' may be 2-phenanthrenyl; R2' may be H, and R3' may be one of: CONH2, C(=NH)NH2, C(=0)CH2NH2, CH2C(=0)NH2, C(=0)-(para-phenylene)- S02NH2, C(=0)CH2NHC(=NH)NH2, and C(=0)CH2NHCO-phenyl, the fungus is not one of:
Candida albicans, Cryptococcus neoformans, Cryptococcus gattii, Candida tropicalis, Candida krusei, Candida glabrata, Candida dubliniesis, and Candida parapsilosis.
[0057] In some embodiments of the method, when the fungus is one of: Candida albicans, Cryptococcus neoformans, Cryptococcus gattii, Candida tropicalis, Candida krusei, Candida glabrata, Candida dubliniesis, and Candida parapsilosis, the compound may be represented by Structural Formula (Γ):
Figure imgf000022_0002
wherein: R1' may be H, cycloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro; Ar' may be optionally substituted and may be one of: tetracene, phenalenyl, pyrenyl, chrysenyl, phenanthrolinyl, acridinyl, phenazinyl, carbazolyl, dibenzofuranyl, quinolinyl, isoquinolinyl, quinoxalyl, quinazolinyl, bipyridyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, and indenyl; R2' may be H, and R3' may be sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl other than glycine, a β-amino carbonyl, a γ-amino carbonyl, or an α-β-unsaturated carbonyl; or, R2', R3', and the aniline nitrogen of Structural Formula (Γ) together form an optionally substituted heterocyclic group.
[0058] In some embodiments of the method, when the compound may be represented by Structural Formula (Γ):
Figure imgf000023_0001
the fungus is not one of: Candida albicans, Cryptococcus neoformans, Cryptococcus gattii, Candida tropicalis, Candida krusei, Candida glabrata, Candida dubliniesis, and Candida parapsilosis. For example, R1' may be trifluoromethyl; Ar' may be 2-phenanthrenyl; R2' may be H, and R3' may be one of: CONH2, C(=NH)NH2, C(=0)CH2NH2, C(=0)-(para-phenylene)- S02NH2, C(=0)CH2NHC(=NH)NH2, CH2C(=0)NH2, and C(=0)CH2NHCO-phenyl. Additionally or altematively, R1' may be trihalomethyl; Ar' may be 2-phenanthrenyl; R2' may be H, and R3' may be one of: CONH2, C(=NH)NH2, C(=0)CH2NH2, C(=0)-(para-phenylene)- S02NH2, C(=0)CH2NHC(=NH)NH2, CH2C(=0)NH2, and C(=0)CH2NHCO-phenyl. Additionally or alternatively, R1' may be trihalomethyl, H, methyl, ethyl, or halo; Ar' may be 2- phenanthrenyl; R2' may be H, and R3' may be one of: CONH2, C(=NH)NH2, C(=0)CH2NH2, C(=0)-(para-phenylene)-S02NH2, C(=0)CH2NHC(=NH)NH2, CH2C(=0)NH2, and C(=0)CH2NHCO-phenyl. Additionally or altematively, R1' may be trifluoromethyl; Ar' may be phenanthrenyl; R2' may be H, and R3' may be one of: CONH2, C(=NH)NH2, C(=0)CH2NH2, C(=0)-(para-phenylene)-S02NH2, C(=0)CH2NHC(=NH)NH2, CH2C(=0)NH2, and C(=0)CH2NHCO-phenyl. Additionally or altematively, R1' may be trifluoromethyl; Ar' may be phenyl, biphenyl, naphthyl, anthracenyl, phenanthryl, or fluorenyl; R2' may be H, and R3' may be one of: CONH2, C(=NH)NH2, C(=0)CH2NH2, C(=0)-(para-phenylene)-S02NH2, C(=0)CH2NHC(=NH)NH2, CH2C(=0)NH2, and C(=0)CH2NHCO-phenyl. Additionally or alternatively, R1' may be trifluoromethyl; Ar' may be 2-phenanthrenyl; R2' may be H, methyl, or ethyl, and R3' may be one of: CONH2, C(=NH)NH2, C(=0)CH2NH2, C(=0)-(para-phenylene)- S02NH2, C(=0)CH2NHC(=NH)NH2, CH2C(=0)NH2, and C(=0)CH2NHCO-phenyl. Additionally or alternatively, R1' may be trifluoromethyl; Ar' may be 2-phenanthrenyl; R2' may be H, and R3' may be one of: CONH2, C(=NH)NH2, C(=0)CH2NH2, C(=0)-(para-phenylene)- S02NH2, C(=0)CH2NHC(=NH)NH2, CH2C(=0)NH2, and C(=0)CH2NHCO-phenyl; wherein each H position in R3' may be optionally substituted by methyl or ethyl. Additionally or alternatively, R1' may be one of alkyl and haloalkyl; Ar may be one of: phenyl, biphenyl, naphthyl, anthracenyl, phenanthryl, and fluorenyl; wherein Ar may be optionally substituted with one or more of: halo, C1-C4 alkyl, C1-C4 haloalkyl, azido, C1-C4 azidoalkyl, aryl, alkylaryl, haloaryl, haloalkylaryl, and combinations thereof; R2' may be H; and R3' may be one of N- carboxamide, N-amidine, N-acetamidine, N-aminoacetamide, N-guanidine, and N-urea. In some embodiments, R2' may be H, methyl, or ethyl, and each H bonded to a nitrogen in R3' may optionally be methyl or ethyl.
[0059] In some embodiments of the method, the compound may be represented by Structural Formula (Γ). R1' may be H, cycloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro. Ar' may be optionally substituted and may be one of: tetracene, phenalenyl, pyrenyl, chrysenyl, phenanthrolinyl, acridinyl, phenazinyl, carbazolyl, dibenzofuranyl, quinolinyl, isoquinolinyl, quinoxalyl, quinazolinyl, bipyridyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, and indenyl. R2" may be H and R3' may be sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl other than glycine, a β-amino carbonyl, a γ-amino carbonyl, or an α-β-unsaturated carbonyl. Alternatively, R2', R3', and the aniline nitrogen of Structural Formula (Γ) together may form an optionally substituted heterocyclic group. The fungus may be any fungus described herein. In some embodiments, the fungus may be one of: Candida albicans, Cryptococcus neoformans, Cryptococcus gattii, Candida tropicalis, Candida krusei, Candida glabrata, Candida dubliniesis, and Candida parapsilosis .
[0060] In various embodiments, a compound is provided. The compound may be represented by Structural Formula (I):
Figure imgf000024_0001
and pharmaceutically acceptable salts thereof. R1 may be H, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro. R2 may be H and R3 may be: sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl, a β- amino carbonyl, a γ-amino carbonyl, an α-β-unsaturated carbonyl, guanidine, or urea; or, the aniline nitrogen of Structural Formula (I), R2, and R3 may together form an optionally substituted heterocyclic group; Ar may be an optionally substituted aryl or heteroaryl group consisting of 1, 2, 3, or 4 rings that may be one or more of linked and fused; Het may be a heteroaryl group including a first ring that may be a nitrogen-containing, five or six-membered heteroaryl group, the first ring being optionally fused to one or more of a second ring and a third ring to form a bicyclic or tricyclic heteroaryl group consisting of 8, 9, 10, 11, 12, or 13 ring atoms, wherein R1 and phenyl ring A may be bonded to the first ring, and Ar may be bonded to the first ring, the second ring, or the third ring.
[0061] In several embodiments, when the compound is represented by:
Figure imgf000025_0001
one or more of: R1 ' may be H, cycloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro; Ar' may be optionally substituted and may be one of: tetracene, phenalenyl, pyrenyl, chrysenyl, phenanthrolinyl, acridinyl, phenazinyl, carbazolyl, dibenzofuranyl, quinolinyl, isoquinolinyl, quinoxalyl, quinazolinyl, bipyridyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, and indenyl; R2' may be H, and R3' may be sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl other than glycine, a β-amino carbonyl, a γ-amino carbonyl, or an α-β-unsaturated carbonyl; or, R2, R3, and the aniline nitrogen of Structural Formula (Γ) may together form an optionally substituted heterocyclic group.
[0062] In various embodiments, the compound may include any aspect of the compound as described in the method herein. For example, the compound may be represented by Structural Formula (II), wherein: R1 may be C1-C4 alkyl or C1-C4 haloalkyl; Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl, and Ar may be optionally substituted with one or more of: halogen, C1-C4 haloalkyl, C1-C4 alkyl, C1-C4 alkoxy, nitrile, and nitro; R2 may be H and R3 may be S02NH2, C(=0)CH2NH2, C(=0)CH2N(CH3)2, C(=0)C(cyclopropyl)NH2, C(=0)C(CH3)2NH2i, C(=0)C≡CH, C(=0)CH2NH(CH3), C(=0)CH(NH2)CH(CH3)2, C(=0)CH(NH2)CH2CH(CH3)2, C(=0)CH(CH2Ph)NH2, C(=0)CH(CH3)NH(CH3),
C(=0)CH[CH2CH(CH3)2]NH(CH3), C(=0)CH(CH2Ph)NH(CH3), C(=0)CH(CH2Ph)N(CH3)2; or, R2, R3, and the aniline nitrogen of Structural Formula (II) may together form:
Figure imgf000026_0001
wherein R4 and R5 may each independently be: H, C1-C6 alkyl, C3-C6 cycloalkyl, or Ci-Ce haloalkyl; and n may be an integer from 1-6.
[0063] In some embodiments, the compound may be represented by Structural Formula (III), wherein: R1 may be CF3; Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl; and Ar may be optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, or Ci- C4 haloalkyl; Ar may be 2-phenanthryl, 3 -phenanthryl, 9-anthracenyl, 4-biphenyl, 4-(4'-CF3)- biphenyl, 4-(3',5'-dimethyl)-biphenyl, 4-(3',5'-dimethoxy)-biphenyl, phenyl, l-(4-CF3)-phenyl, 1 - naphthyl, or 2-naphthyl; and R2 may be H and R3 may be S02NH2, C(=0)CH2NH2, C(=0)CH2N(CH3)2, C(=0)C(cyclopropyl)NH2, C(=0)C(CH3)2NH2, C(=0)C≡CH, C(=0)CH2NH(CH3), C(=0)CH(NH2)CH(CH3)2, C(=0)CH(NH2)CH2CH(CH3)2,
C(=0)CH(CH2Ph)NH2, C(=0)CH(CH3)NH(CH3), C(=0)CH[CH2CH(CH3)2]NH(CH3), C(=0)CH(CH2Ph)NH(CH3), C(=0)CH(CH2Ph)N(CH3)2; or, R2, R3, and the aniline nitrogen of Structural Formula (III) may together form:
Figure imgf000026_0002
For example, the compound may be one of compounds III-l to 111-39 (FIG. 1A, IB,
[0065] In various embodiments, the compound may be represented by Structural Formula
(IV), wherein: R1 may be C1-C4 alkyl or C1-C4 haloalkyl; Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, naphthyl, pyridyl, or pyrrolyl, and Ar may be optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, nitrile, or S02-Ci-C4 alkyl; R2 may be H and R3 may be S02NH2, C(=0)CH2NH2, C(=0)CH2N(CH3)2, C(=0)C(cyclopropyl)NH2, C(=0)C(CH3)2NH2i, C(=0)C≡CH, C(=0)CH2NH(CH3), C(=0)CH(NH2)CH(CH3)2, C(=0)CH(NH2)CH2CH(CH3)2, C(=0)CH(CH2Ph)NH2, C(=0)CH(CH3)NH(CH3),
C(=0)CH[CH2CH(CH3)2]NH(CH3), C(=0)CH(CH2Ph)NH(CH3), C(=0)CH(CH2Ph)N(CH3)2; or, R2, R3, and the aniline nitrogen of Structural Formula (IV) together form:
Figure imgf000026_0003
wherein R4 and R5 may optionally be H or C1-C4 alkyl. For example, the compound may be represented by Structural Formula (V), wherein: R1 may be C1-C4 alkyl or C1-C4 haloalkyl; Ar may be l-(4-CF3)-phenyl, l-(4-CN)-phenyl, 1 -(4-Me)-phenyl, 5-(2-CF3)-pyridyl, l-(4-S02Me)- phenyl, 9-anthracenyl, 1 -(4-OMe)-phenyl, 1 -(4-F)-phenyl, l-(4-iBu)-phenyl, 1 -(4-Et)-phenyl, 1- (4-zPr)-phenyl, or N-Me-3-pyrrolyl; R2 may be H and R3 may be C(=0)CH2NH2, S02NH2, C(=0)C(CH3)2NH2, C(=0)C(cyclopropyl)NH2, C(=0)(CH2)2NH2, C(=0)CH(NH2)(4- imidazole), S02N(CH3)2, C(=0)CH2NH(CH3); or, R2, R3, and the nitrogen of Structural Formula
(V) may together form:
Figure imgf000027_0001
[0066] For example, the compound may be one of compounds V-l to V-22 (FIG. 2A, 2B, and 2C).
[0067] In various embodiments, the compound may be represented by Structural Formula
(VI) , wherein: R1 may be C1-C4 alkyl, C2-C6 cycloalkyl, or C1-C4 haloalkyl; Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl, and Ar may be optionally substituted with haloalkyl; R2 may be H and R3 may be S02NH2, C(=0)CH2NH2, C(=0)CH2N(CH3)2, C(=0)C(cyclopropyl)NH2, C(=0)C(CH3)2NH2, C(=0)C≡CH, C(=0)CH2NH(CH3), C(=0)CH(NH2)CH(CH3)2, C(=0)CH(NH2)CH2CH(CH3)2, C(=0)CH(CH2Ph)NH2, C(=0)CH(CH3)NH(CH3), C(=0)CH[CH2CH(CH3)2]NH(CH3), C(=0)CH(CH2Ph)NH(CH3), C(=0)CH(CH2Ph)N(CH3)2; or, R2, R3, and the aniline nitrogen of Structural Formula (V) may together form:
Figure imgf000027_0002
wherein R4 and R5 may be optionally H or C1-C4 alkyl. For example, the compound may be represented by Structural Formula (VII), wherein: R1 may be CF3 or cyclopropyl; Ar may be CF3-phenyl; and R2 may be H and R3 may be C(=0)CH2NH2 or S02NH2. For example, the compound may be one of compounds VII- 1 to VII-4 (FIG. 3).
[0068] In various embodiments, the compound may be represented by Structural Formula (VIII), wherein: R1 may be C1-C4 alkyl, C2-C6 cycloalkyl, or C1-C4 haloalkyl; Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl, and Ar may be optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 haloalkyl; R2 may be H and R3 may be S02NH2, C(=0)CH2NH2, C(=0)CH2N(CH3)2, C(=0)C(cyclopropyl)NH2, C(=0)C(CH3)2NH2, C(=0)C≡CH, C(=0)CH2NH(CH3), C(=0)CH(NH2)CH(CH3)2, C(=0)CH(NH2)CH2CH(CH3)2, C(=0)CH(CH2Ph)NH2, C(=0)CH(CH3)NH(CH3), C(=0)CH[CH2CH(CH3)2]NH(CH3), C(=0)CH(CH2Ph)NH(CH3), C(=0)CH(CH2Ph)N(CH3)2; or, R2, R3, and the aniline nitrogen of Structural Formula (VIII) together form:
Figure imgf000028_0001
wherein R4 and R5 may be optionally H or C1-C4 alkyl. For example, the compound may be represented by Structural Formula (IX), wherein: R1 may be CF3; Ar may be phenanthryl; and R2 may be H and R3 may be C(=0)CH2NH2 or S02NH2. For example, the compound may be (FIG. 3) 2-amino-N-(4-(6-(phenanthren-2-yl)-4-(trifluoromethyl)pyridin-2-yl)phenyl)acetamide (IX- 1) or N-(4-(6-(phenanthren-2-yl)-4-(trifluoromethyl)pyridin-2-yl)phenyl)aminosulfonamide (IX-2).
[0069] In various embodiments, the compound may be represented by Structural Formula
(X) , wherein: R1 may be C1-C4 alkyl, C2-C6 cycloalkyl, or C1-C4 haloalkyl; Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl, and Ar may be optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 haloalkyl; and R2 may be H and R3 may be S02NH2, C(=0)CH2NH2, C(=0)CH2N(CH3)2, C(=0)C(cyclopropyl)NH2, C(=0)C(CH3)2NH2, C(=0)C≡CH, C(=0)CH2NH(CH3), C(=0)CH(NH2)CH(CH3)2, C(=0)CH(NH2)CH2CH(CH3)2, C(=0)CH(CH2Ph)NH2, C(=0)CH(CH3)NH(CH3), C(=0)CH[CH2CH(CH3)2]NH(CH3), C(=0)CH(CH2Ph)NH(CH3), C(=0)CH(CH2Ph)N(CH3)2; or, R2, R3, and the aniline nitrogen of Structural Formula (X) may together form:
Figure imgf000028_0002
wherein R4 and R5 may be optionally H or C1-C4 alkyl. For example, the compound may be represented by Structural Formula (XI), wherein: R1 may be CF3; Ar may be anthracenyl, phenanthryl, CF3-biphenyl, CF3-phenyl, or Br-phenyl; R2 may be H and R3 may be S02NH2, C(=0)CH2NH2, C(=0)CH2NH(CH3), C(=0)CH2N(CH3)2, C(=0)CH[CH2CH(CH3)2]NH(CH3), C(=0)CH[CH(CH3)2]NH(CH3); or, or, R2, R3, and the aniline nitrogen of Structural Formula
(XI) may together form:
Figure imgf000029_0001
[0070] For example, the compound may be one of compounds XI-1 to XI-21 (FIG. 4A, 4B, 4C, and 2C).
[0071] In various embodiments, the compound may be represented by Structural Formula (XII), wherein R1 may be C1-C4 alkyl, C2-C6 cycloalkyl, C1-C4 haloalkyl, or an optionally alkylated alkyl amide; Ar may be phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl, and Ar may be optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 haloalkyl; and R may be H and R3 R2' may be H, and R ' may be sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl other than glycine, a β-amino carbonyl, a γ- amino carbonyl, or an α-β-unsaturated carbonyl; or, R2, R3, and the aniline nitrogen of Structural Formula (XII) may together form:
Figure imgf000029_0002
wherein R4 and R5 may be optionally H or C1-C4 alkyl. For example, the compound may be represented by Structural Formula (XIII), wherein: R1 may be
Figure imgf000029_0003
Ar may be biphenyl optionally substituted with halogen or C1-C4 haloalkyl; and R2 may be H and R3 may be S02NH2, C(=0)CH2NH2, C(=0)CH2NH(CH3), C(=0)CH2N(CH3)2,
C(=0)CH[CH2CH(CH3)2]NH(CH3), or C(=0)CH[CH(CH3)2]NH(CH3). For example, the compound may be 3-(l-(4-(2-aminoacetamido)phenyl)-5-(4'-(trifluoromethyl)-[l, -biphenyl]-4- yl)-lH-pyrazol-3-yl)-N-methylpropanamide (compound XIII- 1).
[0072] In various embodiments of the compound, Het may be one of: pyrrole, imidazole, triazole, tetrazole, oxazole, thiazole, indole, indazole, benzimidazole, benzoxazole, benzothiazole, carbazole, quinoline, isoquinoline, quinoxaline, quinazoline, pyridine, pyrazine, pyrimidine, and triazine.
[0073] In some embodiments of the compound, R1 may be H, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C3-C6 halocycloalkyl, halogen, nitrile, alkyl amide, or nitro. For example, R1 may be CF3, isopropyl, cyclopropyl, or -(CH2)2C(0)NH(CH3).
[0074] In several embodiments of the compound, R2 may be H. R3 may be, for example, S02NH2, S02NH(CH3), S02N(CH3)2, S(=0)-Ci-C4 alkyl amine, S02-Ci-C4 alkyl amine, C(=0)CH2NH2, C(=0)CH2N(CH3)2, C(=0)CH2NH(CH3), C(=0)(CH2)2NH2, C(=0)(CH2)3NH2, C(=0)C(CH3)2NH2, C(=0)CH(NH2)(4-imidazole), C(=0)CH(NH2)CH(CH3)2,
C(=0)CH(NH2)CH2CH(CH3)2, C(=0)CH[CH2CH(CH3)2]NH(CH3), C(=0)CH(CH2Ph)NH2, C(=0)CH(CH2Ph)NH(CH3), C(=0)CH(CH2Ph)N(CH3)2, C(=0)CH(CH3)NH(CH3),
C(=0)C(cyclopropyl)NH2, C(=0)C≡CH, or C(=0)CHCH2. Additionally or alternatively, R3, together with the aniline nitrogen of Structural Formula (I) to which R3 may be bonded, may represent an amide-bonded: glycine, alanine, serine, threonine, cysteine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tyrosine, tryptophan, aspartic acid, glutamic acid, asparagine, glutamine, histidine, lysine, or arginine.
[0075] In various embodiments, the compound may be represented by Structural Formula (XIV), wherein: R4 and R5 may each be independently: H, C1-C6 alkyl, C3-C6 cycloalkyl, or Ci- Ce haloalkyl; and n may be an integer from 1-6.
[0076] In several embodiments of the compound, R2, R3, and the aniline nitrogen of Structural Formula (I) together may form an optionally substituted triazole or tetrazole. The triazole may be substituted with an alkylamino group.
[0077] In some embodiments of the compound, Ar may be an optionally substituted: phenyl, pyridinyl, pyrazinyl, pyrimidinyl, naphthalenyl, quinolinyl, isoquinolinyl, quinoxalyl, quinazolinyl, biphenyl, bipyridinyl, phenanthrenyl, phenanthrolinyl, anthracenyl, tetracenyl, phenalenyl, pyrenyl, chrysenyl, acridinyl, phenazinyl, carbazolyl, fluorenyl, dibenzofuran, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, indenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, or tetrazolyl. Ar may be optionally substituted, for example, with one or more of: Ci-C6 alkyl, C3-C6 cycloalkyl, Ci-C6 haloalkyl, C3-C6 halocycloalkyl, nitrile, Ci-C6 alkylsulfone, alkyl sulfoxide, Ci-C6 O-alkyl, O-phenyl, Ci-C6 NH-alkyl, C2-Ci2 N-alkyl2, hydroxyl, NH2, halogen, dioxole, dioxolane, N02, aldehyde, C2-C7 alkyl or aryl ketone, C2-C7 alkyl or aryl ester, C2-C7 alkyl or aryl amide, guanidine, amidine, N-OH amidine, urea, imide, oxime, hydrazone, and hydrazide. Ar may be optionally substituted with one or more of: methyl, ethyl, isopropyl, fertbutyl, CF3, CN, methoxy, S(0)2-Ci-C4 alkyl, Br, and F.
[0078] In various embodiments, a pharmaceutical composition is provided. The pharmaceutical composition may include a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition may include a compound represented by Structural Formula (I):
Figure imgf000030_0001
and pharmaceutically acceptable salts thereof. R1 may be H, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro. R2 may be H and R3 may be: sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl, a β- amino carbonyl, a γ-amino carbonyl, an α-β-unsaturated carbonyl, guanidine, or urea; or, R2, R3, and the aniline nitrogen of Structural Formula (I) may together form an optionally substituted heterocyclic group. Ar may be an optionally substituted aryl or heteroaryl group consisting of 1, 2, 3, or 4 rings that may be one or more of linked and fused. Het may be a heteroaryl group including a first ring that may be a nitrogen-containing, five or six-membered heteroaryl group. The first ring may be optionally fused to one or more of a second ring and a third ring to form a bicyclic or tricyclic heteroaryl group characterized by 8, 9, 10, 1 1, 12, or 13 ring atoms. R1 and phenyl ring A may be bonded to the first ring, and Ar may be bonded to the first ring, the second ring, or the third ring.
[0079] In some embodiments, the com ound may be represented by Structural Formula (Γ):
Figure imgf000031_0001
one or more of the following may be present. R1 ' may be H, cycloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro. Ar' may be optionally substituted and may be one of: tetracene, phenalenyl, pyrenyl, chrysenyl, phenanthrolinyl, acridinyl, phenazinyl, carbazolyl, dibenzofuranyl, quinolinyl, isoquinolinyl, quinoxalyl, quinazolinyl, bipyridyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, and indenyl. R2' may be H, and R3' may be sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl other than glycine, a β-amino carbonyl, a γ-amino carbonyl, or an α-β-unsaturated carbonyl. Altematively, the aniline nitrogen of Structural Formula (Γ), R2, and R3 may together form an optionally substituted heterocyclic group.
[0080] In several embodiments, the pharmaceutical composition may further include an antifungal, e.g., the antifungal drugs (other than the compound) described herein for the method.
[0081] In some embodiments of the pharmaceutical composition, the compound may include any aspect of the compound or compound of the method as described herein. For example, the compound of the pharmaceutical composition may be one of compounds III-l to III-39 (FIG. 1A, IB, 1C, and ID), V-l to V-22 (FIG. 2A, 2B, and 2C), VII-1 to VII-4 (FIG. 3), IX-1 and IX-2 (FIG. 3), XI-1 to XI-21 (FIG. 4A, 4B, 4C, and 2C), or XIII-1
[0082] In various embodiments, a kit is provided. The kit may include a compound and instructions. The instructions may direct a user to provide a subject that may have a fungal infection or may be at risk of the fungal infection. The instructions may direct the user to administer the compound to the subject in an amount effective to mitigate the fungal infection. The compound may be represented by Structural Formula (I):
Figure imgf000032_0001
and pharmaceutically acceptable salts thereof. R1 may be H, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro. R2 may be H and R3 may be: sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl, a β- amino carbonyl, a γ-amino carbonyl, an α-β-unsaturated carbonyl, guanidine, or urea; or, R2, R3, and the aniline nitrogen of Structural Formula (I) may together form an optionally substituted heterocyclic group. Ar may be an optionally substituted aryl or heteroaryl group consisting of 1, 2, 3, or 4 rings that may be one or more of linked and fused. Het may be a heteroaryl group including a first ring that may be a nitrogen-containing, five or six-membered heteroaryl group. The first ring may be optionally fused to one or more of a second ring and a third ring to form a bicyclic or tricyclic heteroaryl group characterized by 8, 9, 10, 11, 12, or 13 ring atoms. R1 and phenyl ring A may be bonded to the first ring, and Ar may be bonded to the first ring, the second ring, or the third ring. When the compound is re resented by Structural Formula (I'):
Figure imgf000032_0002
one or more of the following may be present. R1' may be H, cycloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro. Ar' may be optionally substituted and may be one of: tetracene, phenalenyl, pyrenyl, chrysenyl, phenanthrolinyl, acridinyl, phenazinyl, carbazolyl, dibenzofuranyl, quinolinyl, isoquinolinyl, quinoxalyl, quinazolinyl, bipyridyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, and indenyl. R2' may be H, and R3' may be sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl other than glycine, a β-amino carbonyl, a γ-amino carbonyl, or an α-β-unsaturated carbonyl. Alternatively, the aniline nitrogen of Structural Formula (Γ), R2, and R3 may together form an optionally substituted heterocyclic group.
[0083] In several embodiments, the kit may further include an antifungal, e.g., the antifungal drugs described herein for the method.
[0084] In various embodiments of the kit, the compound may include any aspect of the compound, the compound of the method, or the compound of the pharmaceutical composition as described herein. For example, the compound of the pharmaceutical composition may be one of compounds III-l to 111-39 (FIG. 1A, IB, 1C, and ID), V-l to V-22 (FIG. 2A, 2B, and 2C), VII-1 to VII-4 (FIG. 3), IX-1 and IX-2 (FIG. 3), XI-1 to XI-21 (FIG. 4A, 4B, 4C, 2C), or XIII-1. Alternatively, the compound in the kit may be provided in the form of the pharmaceutical composition. The instructions in the kit may direct the user to carry out any aspect of the method as described herein.
EXAMPLES
[0085] The following examples and results are illustrated in FIGS. 5A-8B. All commercially available reagents were used without further purification unless otherwise stated. Anhydrous tetrahydrofuran (THF) was obtained by distilling commercial reagent over CaH2 and anhydrous dimethylformamide (DMF) was obtained by distillation over P2O5 under reduced pressure. Silica gel for column chromatography 230 - 400 mesh, was purchased from Fisher Scientific, Pittsburg, PA. Routine XH and 1 C nuclear magnetic resonance spectra were recorded on the DPX 300 or Ascend 400 (Bruker, Billerica, MA). Samples were dissolved in deuterated chloroform (CDCI3) or dimethyl sulfoxide (DMSOde) and tetramethylsilane (TMS) was used as a reference. Electrospray ionization mass spectrometry analyses were performed with a maXis 4G mass spectrometer (Bruker, Billerica, MA). All compounds for bioassay were identified with XH NMR, 1 C NMR and FIRMS, and purities confirmed to be higher than 95%. The purities of all tested compounds were determined by a Hitachi Elite LaChrom HPLC system, including a Versa Grad Prep 36 pump, an L-2400 UV detector, an L-2200 auto sampler and a 250 χ 4.6 mm Phenomenex Luna 5μ C18 column (Hitachi High-Technologies Science America, Inc., Northridge, CA).
EXAMPLE 1: 2-amino-A^-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)- 1H- pyrrol- 1- yl)phenyl)acetamide (III-l) [0086] The synthetic sequence described below is illustrated in FIG. 5A. Derivatives of compound III-l were prepared from precursor (lg) by various "step h" methods (A-E). Method A, as depicted in FIG. 5A, prepared compounds such as III-l, III-2, and III- 10. Method B, as described below, prepared compounds such as III- 16. Method C, as described below, prepared compounds such as 111-36. Method D, as described below, prepared compounds such as 111-33. Method E, as described below, prepared compounds such as 111-28, 111-26, 111-22, III- 18, III- 27, 111-24, 111-30, and 111-20
2-f 1, l-diethoxyethvQphenanthrene ( la)
Figure imgf000034_0001
[0087] See FIG. 5A, step a. N-bromosuccinimide (0.121 g, 0.68mmol) was added to a solution of 2-acetylphenanthrene (5.0 g, 22.69 mmol), triethyl orthoformate (6.72 g, 45.39 mmol), and absolute EtOH (50 mL). The resulting solution was stirred at room temperature for 5 to 6 h. The reaction was monitored by TLC. Upon completion, a cold aqueous solution of NaOH (10%, 15 mL) was added and the mixture was extracted with EtjO (3 χ 50 mL). The organic extracts were washed with water (3 χ 25 mL) and dried over anhydrous Na2SC>4. The solvent was removed under reduced pressure. The crude product was purified by TEA-coated silica flash chromatography to afford 2-(l,l-diethoxyethyl)phenanthrene (la) (5.4 g) in 82% yield.
4-ethoxy-l, 1, l-trifluoro-4-(phenanthren-2-yl)but-3-en-2-one (lb)
Figure imgf000034_0002
[0088] See FIG. 5A, step b. To a solution of 2-(l,l-diethoxyethyl)phenanthrene (la) (7.0 g, 23.77 mmol) in chloroform (50 mL) was added pyridine (3.76 g, 47.55 mmol) and the resulting solution was stirred at 0 °C for 5 min. A solution of trifluoroacetic anhydride (9.98 g, 47.55 mmol) in 20 mL of chloroform was added dropwise over 15 min. The resulting solution was stirred at room temperature for 5 to 6 h. The reaction was monitored by TLC. Upon completion of the reaction, ice cold water was added and the mixture was extracted with DCM. The organic layer was washed with 2 N HCl solution, washed with a 10% aq. Na2CC>3 solution, and dried over anhydrous Na2SC>4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography to afford (Z)-4-ethoxy- 1,1,1 -trifluoro-4-(phenanthren-2- yl)but-3-en-2-one (lb) (6.95 g) in 85% yield. 4-ethoxy-4-(phenanthren-2-yl)-2-(trifluoromethyl)-2-((trimeth^ (lc)
Figure imgf000035_0001
[0089] See FIG. 5A, step c. To a solution of trimethylsilyl cyanide (5.0 g, 14.5 mmol) and triethylamine (0.073 g, 0.726 mmol) in acetonitrile (20 mL) was added (Z)-4-ethoxy- 1,1,1 - trifluoro-4-(phenanthren-2-yl)but-3-en-2-one (lb) as a solution in acetonitrile (20 mL) at 0°C. The resulting solution was stirred for 16 h and then concentrated under reduced pressure. The crude product was purified by flash chromatography to afford (Z)-4-ethoxy-4-(phenanthren-2- yl)-2-(trifluoromethyl)-2-((trimethylsilyl)oxy)but-3-enenitrile (lc) (4.89 g) in 76 % yield.
2-(aminomethyl)-4-ethoxy-l , 1, l-trifluoro-4-(phenanthren-2-yl)but-3-en-2-ol (Id)
Figure imgf000035_0002
[0090] See FIG. 5A, step d. L1AIH4 (0.753 g, 19.0 mmol) was suspended in dry ether (50 mL) under an inert atmosphere and cooled to 0-5 °C. A solution of (Z)-4-ethoxy-4- (phenanthren-2-yl)-2-(trifluoromethyl)-2-((trimethylsilyl)oxy)but-3-enenitrile (lc) (8.0 g, 18.0 mmol) in dry ether (30 mL) was added dropwise over 30 min at 0-5 °C. The mixture was allowed to come to room temperature and stirred overnight. The mixture was cooled to 0-5 °C and a cooled 30% aq. NaOH (10 mL) solution was added to quench the excess L1AIH4. The mixture was filtered and the solids were washed with EtOAc (3 x 50 mL). The filtrate was dried over Na2SC>4 and concentrated under reduced pressure to give (Z)-2-(aminomethyl)-4-ethoxy- l,l,l-trifluoro-4-(phenanthren-2-yl)but-3-en-2-ol (Id) (5.28 g) in 78% yield.
2-(phenanthren-2-yl)- -( trifluoromethvl)-lH-pvrrole fie)
Figure imgf000035_0003
[0091] See FIG. 5A, step e. To a solution of (Z)-2-(aminomethyl)-4-ethoxy- 1,1,1 -trifluoro- 4-(phenanthren-2-yl)but-3-en-2-ol (Id) (3.0 g, 7.99 mmol). acetonitrile (20 mL), and water (1.5 mL) was added 5% aq. HCl (1.15 mL, 32.0 mmol). The resulting solution was stirred at 80 °C for 12 h and monitored by TLC. Upon completion, water and 3% NaHCC (20 mL) were added. The solution was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over anhydrous Na2SC>4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (Hex:EtOAc 6:2) to give 2-(phenanthren-2-yl)-4- (trifluoromethyl)-lH-pyrrole (le) as an off-white solid (2.13 g) in 86% yield.
Figure imgf000036_0001
[0092] See FIG. 5A, step f. To a solution of 2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH- pyrrole (le) (2.0 g, 6.42 mmol) in DMF (20 mL), was added 4-fluoronitrobenzene (1.35 g, 9.63 mmol) and K2CO3 (1.77g, 12.8mmol). The resulting mixture was stirred at 120 °C for 12 h. The reaction was monitored by TLC. Upon completion, ice cold water was added and the solution was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SC>4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (Hex:EtOAc 7:3) to give l-(4-nitrophenyl)-2-(phenanthren-2-yl)-4- (trifluoromethyl)-lH-pyrrole (If) as a light yellow solid (1.80 g) in 65% yield.
4-(2-(phenanthren-2- -4-(trifluoromethyl)-lH^yrrol-l-yl)aniline fig)
Figure imgf000036_0002
[0093] See FIG. 5A, step g. To a solution of l-(4-nitrophenyl)-2-(phenanthren-2-yl)-4- (trifluoromethyl)-lH-pyrrole (If) (1.0 g, 2.31 mmol) in EtOAc (20 ml) and MeOH (10 mL) was added 10 % Pd/C (122 mg, 1.15 mmol). 70 PSI of H2 gas was applied to the mixture using a Parr apparatus for 3h. The reaction mixture was filtered through celite to remove the catalyst, and the filtrate was concentrated under reduced pressure to give pure 4-(2-(phenanthren-2-yl)-4- (trifluoromethyl)-lH-pyrrol-l-yl)aniline (lg) (725 mg) in 78 % yield.
Method (A); Representative Amino Acid Derivatives Using Peptide Coupling Agents
(2-amino-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l-yl) phenyl) acetamide) u i
Figure imgf000036_0003
III-l [0094] Method (A). See FIG. 5A, step h. To a solution of i-butyloxycarbonyl (YBOC)- glycine (0.143 g, 0.82 mmol) and 4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l- yl)aniline (lg) (0.300 g, 0.75 mmol) in dry tetrahydrofuran (20 mL) was added l-[3- (dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (0.162 g, 0.81 mmol). The resulting solution was stirred at 25 °C for 12 h, and then concentrated under reduced pressure. The resulting residue was suspended in water, and extracted with EtOAc. The organic layer was dried over anhydrous Na2SC>4, and the solvent was removed under reduced pressure to give the Boc-protected intermediate, This crude boc-protected intermediate (0.410 g, 0.73 mmol) was dissolved in EtOAc (9 mL) containing concentrated HC1 (1 mL). The resulting solution was stirred at room temperature for 2 h, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (DCM:MeOH:NH4OH 96:2:2) to afford compound III-l as a white powder (308 mg) in 90 % yield.
2-amino-N-(4-(2-(phenanthren-3-yl)-4-(trifluoromethyl)-lH-pyrrol-l-yl) phenvQacetamide fill-
Figure imgf000037_0001
(phenanthren-3-yl derivative of 1g)
[0095] Compound III-2 was prepared from a phenanthren-3-yl derivative of (lg) according to Method (A). The phenanthren-3-yl derivative was prepared according to the scheme in FIG. 5A, beginning with l-(phenanthren-3-yl)ethan-l-one.
2-(methylamino)-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl) -lH-pyrrol-l-yl) phenyl) acetamide (III-10)
Figure imgf000037_0002
10
[0096] Compound III-10 was prepared from lg according to Method A using N-Boc, N- methyl glycine.
Method (B); Representative Amino Acid Derivatives
2-{άί βώνΙα ίηο)-Ν-{4-{2- ΗβηαηώΓβη-2-νΙ)-4-{ίηΑηοΓθ βώνΙ)-1Η-ρνΓΓθΙ-1 -yl) phenyl) acetamide (111-16)
Figure imgf000038_0001
111-16
[0097] Method (B). Alternative Step h. Dimethylglycine (76 mg, 0.74 mmol) was suspended in DCM (3 mL) at 0 °C and treated with oxalyl chloride (0.094g, 0.74 mmol) and 2 drops of DMF. After 1 h the solution was warmed to room temperature and stirred for 1 h, A THF solution of compound (lg) (100 mg, 024 mmol) and triethylamine (0.150g, 1.48 mmol) was added and the resulting suspension was stirred overnight. The solution was diluted with water and extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SC>4, filtered and concentrated. The residue was purified by flash column chromatography (DCM:MeOH 8:2) to afford compound 111-16 (99 mg) in 82% yield.
Method (C) Representative Sulfuric Diamide Derivatives
2-amino-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l-yl) phenyl) sulfonamide qiI-36)
Figure imgf000038_0002
111-36
[0098] Method (C). Alternative Step h. Chlorosulfonyl isocyanate (1.1 mmol) was added dropwise to a solution of /-BuOH (1.2 mmol) in dry THF at 0 °C and the resulting solution was warmed to 25 °C and stirred for 30 min. A solution of 4-(2-(phenanthren-2-yl)-4- (trifluoromethyl)-lH-pyrrol-l-yl)aniline (lg) (1.0 mmol) and pyridine (2.0 mmol) in THF was then added. The solution was stirred at 25 °C for 4h, and then concentrated under reduced pressure. The resulting residue was treated with 20% trifiuoroacetic acid in DCM at room temperature for 3 h, and then washed with 10% NaHCC , dried over Na2SC>4, and concentrated under reduced pressure. The residue was purified by flash chromatography to give compound 111-36 (83 mg) in 70% yield.
Method (D); Representative Triazole Derivatives
2-amino-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-pyrrole-l-yl)phenyl) acetamide qiI-33) F3
Figure imgf000039_0001
(Step h) 111-33
[0099] Method (D). Alternative Step h. A mixture of 4-(2-(phenanthren-2-yl)-4- (trifluoromethyl)-lH-pyrrole-l-yl) aniline (lg) (70 mg, 0.17 mmol), tert-bu yl nitrite (26 mg, 0.26 mmol), and trimethylsilyl azide (24 mg, 0.20 mmol) in dry acetonitrile (10 mL) was stirred at 0 °C for 2 h, and then concentrated under reduced pressure. The crude azide residue (70 mg, 0.16 mmol) and N,N-dimethylprop-2-yn-l -amine (27 mg, 0.32 mmol) were suspended in THF (2 mL) and /-BuOH (1.0 mL), and a solution of sodium ascorbate (19 mg, 0.096 mmol) in water (1 mL) and CuS04.5H20 (12 mg, 0.048 mmol) were added. The resulting mixture was stirred overnight. The mixture was diluted with water and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over anhydrous Na2SC>4, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (DCM:MeOH 98:2) to afford compound 111-33 as off-white powder (64.0 mg) in 72 % yield.
Method (E); Representative Amino Acid Derivatives Using Peptide Coupling Agent PvBOP
Figure imgf000039_0002
[00100] Method (F). Alternative Step h. To a solution of a Boc-protected amino acid (3.0 equiv) and triethylamine (3.0 equiv) in anhydrous DMF, was added PyBOP (3.2 eq.) at 0 °C. The reaction was allowed to warm to room temperature and stirred for 1 h. The mixture was cooled to 0 °C and amine (lg) (1.0 eq.) and triethylamine (3.0 equiv) were added. The resulting mixture was stirred for 48h at 25 °C. The reaction was monitored by TLC. The mixture was poured into ice-cold water and then extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM:MeOH) to afford the corresponding Boc-protected amide in 70-79% yield. The Boc-protected amide (0.200 g) was dissolved in EtOAc (10 mL) and concentrated HC1 (2.0 mL) was added. The resulting solution was stirred at room temperature for 2 h, and then concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (DCM:Methanol:NH4OH, 96:2:2) to afford the corresponding compounds 111-18, 111-20, 111-22, 111-24, 111-26, 111-27, 111-28, and 111-30 in 54- 83% yields.
EXAMPLE 2: N-(4-(4-(trifluoromethyl)-2-(4'-(trifluoromethyl)- [ 1,1 '-biphenyl] -4-yl)- 1H- pyrrol-l-yl)phenyl) propiolamide fIII-32)
[00101] The synthetic sequence described below is illustrated in FIG. 5B and was used to prepare compounds such as III-6, III-7, III-8, III-9, 111-13, 111-14, 111-15, 111-31, 111-32, III- 35, and 111-39
l-(4'-(trifluoromethyl)-[ 1, 1 '-biphenyl J-4-yl)ethanone
[00102] See FIG. 5B, step a. A mixture of 4-bromoacetophenone (11.8 g, 59 mmol), 4- trifluoromethyl phenyl boronic acid (11.4 g, 60 mmol), palladium (II) acetate (250 mg, 2 mol %), potassium carbonate (20.3 g, 147 mmol), and tetrabutyl ammonium bromide (20.1 g, 62 mmol), was flushed with argon. Water (500 mL) was introduced using a syringe. The resulting suspension was stirred and heated to 60°C for 2 h, then cooled to room temperature, diluted with water, extracted with ethyl acetate, filtered through celite, dried over Na2SC>4, and concentrated to dryness under vacuum to afford l-(4'-(trifluoromethyl)-[l, -bi phenyl] -4-yl)ethanone (15.2 g) in 97 % yield. The product was used without further purification in step b.
4-(l, l-diethoxyethyl)-4'-(trifluoromethyl)-l '-biphenyl
[00103] See FIG. 5B, step b. N-bromosuccinimide (0.094 g, 0.52 mmol) was added to a solution of l-(4'-(trifluoromethyl)-[l, -biphenyl]-4-yl)ethanone (7.0 g, 26.44 mmol), triethyl orthoformate (7.70 g, 52.88 mmol), and absolute EtOH (70 mL). The resulting solution was stirred at room temperature for 6 h. The reaction was monitored by TLC. Upon completion, a cold aqueous solution of NaOH (10%, 15 mL) was added and the mixture was extracted with Et^O (3 x 50 mL). The organic extracts were washed with water (3 χ 25 mL) and dried over anhydrous Na2SC>4. The solvent was removed under reduced pressure. The crude product was purified by TEA-coated silica flash chromatography to afford 4-(l,l-diethoxyethyl)-4'- (trifluoromethyl)- 1,1 '-biphenyl (7.33 g) in 82% yield.
fZ)-4-ethoxy-l , 1, l-trifluoro-4-(4'-(trifluoromethyl)-[ 1, 1 '-biphenyl! -4-yl)but-3-en-2-one
[00104] See FIG. 5B, step c. To a solution of 4-(l,l-diethoxyethyl)-4'-(trifluoromethyl)-l,l'- biphenyl (9.36 g, 27.66 mmol) in chloroform (50 mL) was added pyridine (4.35 g, 55.32 mmol), and the resulting solution was stirred at 0 °C for 5 min. A solution of trifluoroacetic anhydride (11.63 g, 55.32 mmol) in 30 mL of chloroform was added dropwise over 15 min. The resulting solution was stirred at room temperature for 5 to 6 h. The reaction was monitored by TLC. Upon completion of the reaction, ice cold water (50 mL) was added and the mixture was extracted with DCM (3 χ 60 mL). The organic layer was washed with 2 N HC1 solution, washed with a 10% aq. Na2CC>3 solution, and dried over anhydrous Na2S04. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography to afford (Z)- 4-ethoxy-l,l,l-trifluoro-4-(4'-(trifluoromethyl)-[l,r-biphenyl]-4-yl)but-3-en-2-one (9.12 g) in 85% yield.
(Z)-4-ethoxy-2-(trifluoromethyl)-4-(4'-(trifluoromethyl)-[ 1, 1 '-biphenyl]-4-yl)-2- ((trimethylsilyl)oxy) but-3-enenitrile
[00105] See FIG. 5B, step d. To a solution of trimethylsilyl cyanide (2.49 g, 25.10 mmol) and triethylamine (0.095 g, 0.965 mmol) in acetonitrile (20 mL) was added (Z)-4-ethoxy- 1,1,1- trifluoro-4-(4'-(trifluoromethyl)-[l, -biphenyl]-4-yl)but-3-en-2-one (7.50 g, 19.31 mmol) as a solution in acetonitrile (20 mL) at 0°C. The resulting solution was stirred for 16 h and then concentrated under reduced pressure to afford (Z)-4-ethoxy-2-(trifluoromethyl)-4-(4'- (trifluoromethyl) 1,r-biphenyl]-4-yl)-2-((trimethylsilyl)oxy)but-3-enenitrile (7.90 g) in 84 % yield. The product was used without further purification in step 5.
(Z)-2-(aminomethyl)-4-ethoxy-l, 1, l-trifluoro-4-(4'-(trifluoromethyl)-[ 1, 1 '-biphenyl]-4-yl)but-3- en-2-ol
[00106] See FIG. 5B, step e. LiAlH4 (0.857 g, 22.56 mmol) was suspended in dry ether (40 mL) under an inert atmosphere and cooled to 0-5 °C. A solution of (Z)-4-ethoxy-2- (trifluoromethyl)-4-(4'-(trifluoromethyl)-[l, -biphenyl]-4-yl)-2-((trimethylsilyl)oxy)but-3- enenitrile (10.0 g, 20.51 mmol) in dry ether (60 mL) was added dropwise over 30 min at 0-5 °C. The mixture was allowed to come to room temperature and was stirred ovemight. The mixture was cooled to 0-5 °C and cooled 30% aq. NaOH (10 mL) \ was added to quench the excess LiAlH4. The mixture was filtered and the solids were washed with EtOAc (3 x 50 mL). The filtrate was dried over Na2S04 and concentrated under reduced pressure to give (Z)-2- (aminomethyl)-4-ethoxy- 1 ,1,1 -trifluoro-4-(4'-(trifluoromethyl)-[ 1 , 1 '-biphenyl] -4-yl)but-3-en-2- ol (6.70 g) in 78 % yield.
4-( trifJuoromethyl)-2-f 4 '-( trifluoromethyl)-[ 1, 1 '-biphenyll -4-yl)-lH-pyrrole
[00107] See FIG. 5B, step f. To a solution of (Z)-2-(aminomethyl)-4-ethoxy- 1,1,1 -trifluoro- 4-(4'-(trifluoromethyl)-[l,r-biphenyl]-4-yl)but-3-en-2-ol (3.0 g, 7.15 mmol) acetonitrile (20 mL), and water (1.5 mL) was added HC1 (1.3 mL, 35.76 mmol). The resulting solution was stirred at 80 °C for 12 h and monitored by TLC. Upon completion, water and saturated NaHCCb (20 mL) were added. The solution was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over anhydrous Na2SC>4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (Hex:EtOAc 6:2) to afford 4-(trifluoromethyl)-2-(4'-(trifluoromethyl)-[l,r-biphenyl]-4-yl)-lH-pyrrole as an off-white solid (2.18 g) in 86% yield).
l-(4-nitrophenyl)-4-(trifluoromethyl)-2-(4'-(trifluoromethyl)-[l '-bwhenv
[00108] See FIG. 5B, step g. To a solution of 4-(trifluoromethyl)-2-(4'-(trifluoromethyl)- [l,l'-biphenyl]-4-yl)-lH-pyrrole (2.0 g, 5.62 mmol) in DMF (20 mL) was added 4- fluoronitrobenzene (1.19 g, 8.44 mmol) and K2CO3 (1.55g, 11.25 mmol). The resulting mixture was stirred at 120 °C for 12 h. Upon completion, ice cold water was added and the solution was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SC>4. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (Hex:EtOAc 7:3) to afford l-(4-nitrophenyl)-4-(trifluoromethyl)-2-(4'- (trifluoromethyl)-[l,r-biphenyl]-4-yl)-lH-pyrrole as a light yellow solid (1.74 g) in 65% yield. 4-( 4-( trifluoromethyl)-2-(4'-( trifluoromethyl)-[ 1, 1 '-biphenyll-4-yl)-lH-pyrrol-l-yl)aniline
[00109] See FIG. 5B, step h. To a solution of l-(4-nitrophenyl)-4-(trifluoromethyl)-2-(4'- (trifluoromethyl)-[l,r-biphenyl]-4-yl)-lH-pyrrole (1.0 g, 2.1 mmol) in EtOAc (20 ml) and MeOH (10 mL) was added 10 % Pd/C (111 mg, 1.04 mmol). 70 PSI of H2 gas was applied to the mixture using a Parr apparatus for 3h. The reaction mixture was filtered through celite to remove the catalyst, and the filtrate was concentrated under reduced pressure to give pure 4-(4- (trifluoromethyl)-2-(4'-(trifluoromethyl)-[l,r-biphenyl]-4-yl)-lH-pyrrol-l-yl)aniline (0.730 g) in 78 % yield
[00110] Representative Michael-Acceptor Derivatives Using Peptide Coupling Agent TBTU; N-(4-(4-(trifluoromethvl)-2-(4'-(trifluoromethvl)-[l,l'-biphenvll-4-vl)-lH-pvrrol-l- yl)phenyl) propiolamide fIII-32)
[00111] See FIG. 5B, step i. A mixture of 4-(4-(trifluoromethyl)-2-(4'-(trifluoromethyl)-[l,r- biphenyl]-4-yl)-lH-pyrrol-l-yl)aniline (1.0 equiv), propiolic acid (1.2 equiv) and 2-(li- benotriazole-l-yl)-l,l,3,3-tetramethyluronium tetrafluoroborate (TBTU) (1.5 equiv) in DCM was stirred at room temperature for 48 h (monitored by TLC; DCM:MeOH). The resulting mixture was diluted with DCM, and washed with water and brine. The organic phase was dried over Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM:MeOH) to afford compound 111-32 (82 mg) in 74 % yield.
EXAMPLE 3 : 2-amino-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)- lH-imidazol- 1- yl)phenyl) acetamide (XI- 1)
[00112] The synthetic sequence described below is illustrated in FIG. 6. Derivatives of XI- 1 were prepared from compound 2c, as shown in FIG. 6, by various late-stage modification methods (A-F). Method A, as shown in FIG. 6, was used to prepare XI-1 and XI-6. Method B, as described above, was used to prepare XI-5. Method D, as described above, was used to prepare XI-9. Method F, as described above, was used to prepare XI-14, XI- 15, and XI-16.
2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-imidazole (2a)
Figure imgf000043_0001
[00113] 3,3-dibromo-l,l,l-trifluoropropan-2-one (2.0 g, 7.40 mmol) and sodium acetate (600 mg, 7.40 mmol) were dissolved in water (2 mL) and heated to 100 °C for 1 h. The resulting mixture was then cooled to room temperature and added to a solution of phenanthrene-2- carbaldehyde (1.52 g, 7.40 mmol) and ammonium hydroxide (15 mL) in methanol (40 mL). The resulting mixture was stirred at room temperature for 1 h, heated to reflux for 2 h, and then stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was diluted with water (25 mL) and extracted in DCM (3 x 50 mL). The combined organic extracts were dried over anhydrous Na2SC>4, filtered, and concentrated. The crude product was purified by flash chromatography (Hex:EtOAc 6:4) to give 2-(phenanthren-2- yl)-4-(trifluoromethyl)-lH-imidazole (2a) as an off-white solid (1.75 g) in 76 % yield.
l-(4-nitrophenyl)-2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-imidazole (2b)
Figure imgf000043_0002
[00114] To a solution of 2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-imidazole (2a) (1.75 g, 5.60 mmol) in DMF (20 mL), was added 4-fluoronitrobenzene (1.18 g, 8.41 mmol) and K2C03 (1.55 g, 11.2 mmol). The resulting mixture was stirred at 130 °C temperature for 12 h. The reaction was monitored by TLC. Upon completion, ice-cold water was added and the solution was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (Hex:EtOAc 7:3) to give l-(4-nitrophenyl)-2-(phenanthren-2-yl)-4- (trifluoromethyl)-lH-imidazole (2b) as a light yellow solid (1.16 g) in 67% yield.
4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH midazol-l-yl)aniline (2c)
Figure imgf000044_0001
[00115] To a solution of l-(4-nitrophenyl)-2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH- imidazole (2b) (1.0 g, 2.31 mmol) in EtOAc (20 ml) and MeOH (10 mL) was added 10% palladium on carbon (122 mg, 1.15 mmol). The resulting mixture was pressurized with H2 gas at 75 psi on a Parr apparatus for 3 h. The mixture was filtered through celite, and the filtrate was concentrated to under reduced pressure to give pure 4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)- lH-imidazol-l-yl) aniline (2c) (763 mg) in 82 % yield.
2-amino-N-f4-f2-fphenanthren-2-yl)-4-ftrifIuoromethyl)-lH-imidazol-l-yl)phenyl) acetamide
Figure imgf000044_0002
XI-
[00116] Method (A): To a solution of Boc-protected glycine (47 mg, 0.27 mmol) and 4-(2- (phenanthren-2-yl)-4-(trifluoromethyl)-lH-imidazol-l-yl) aniline (2c) (0.100 g, 0.24 mmol) in dry THF (20 mL) was added l-[3-(dimethylamino)propyl]-3-ethylcarbodiirnidehydrochloride (71 mg, 0.36 mmol). The resulting mixture was stirred at 25 °C for 12 h, and then concentrated under reduced pressure. The residue was suspended in water and then extracted with EtOAc. The organic phase was dried over anhydrous Na2S04, and concentrated under reduced pressure to give the Boc-protected intermediate. The intermediate was dissolved in EtOAc (9 mL) and cone. HCl (1 mL) was added. The resulting solution was stirred at room temperature for 2 h, and then concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (DCM:MeOH:NH4OH 96:2:2) to afford 2-amino-N-(4-(2-(phenanthren-2-yl)- 4-(trifluoromethyl)-lH-imidazol-l-yl)phenyl) acetamide (XI- 1) as a white powder (95 mg) in 90 % yield.
2-(methylamino)-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-imidazol-l- vDphenyl) acetamide (XI-6)
Figure imgf000045_0001
XI-6
[00117] Compound XI-6 was prepared according to Method A, as described above, using N- Boc, N-methyl glycine.
2-fdimethylamino)-N-f4-f2-fphenanthren-2-yl)-4-ftrifluoromethyl)-lH-imidazol-l-yl) phenyl) acetamide (XI-5)
Figure imgf000045_0002
XI-5
[00118] Compound XI-5 was prepared according to Method B, as described above.
N -dimethyl-l-(l-(4-(2-(phenanthren-2-yl)-4-(trifluoromethy
l,2, 3-triazol-4-yl) methanamine (XI-9)
Figure imgf000045_0003
Compound XI-9 was prepared according to Method D, as described above.
Compounds XI-14, XI-15, and XI-16
Figure imgf000045_0004
[00119] Compounds XI-14, XI-15, and XI-16 were prepared according to Method F, as described above. EXAMPLE 4: 2-amino-A^-(4-(6-(phenanthren-2-yl)-4-(trifluoromethyl) pyridin-2- yl)phenyl)acetamide (IX- 1)
[00120] The synthetic sequence described below is illustrated in FIG. 7A. Derivatives of IX- 1 were prepared from compound 3d, as shown in FIG. 7A, by various late-stage modification methods (A-F).
Figure imgf000046_0001
(3a)
[00121] NaH (871 mg, 36.3 mmol) was suspended in dry THF (20 mL) and ethyl trifluoroacetate (5.16 g, 14.0 mmol) was added at 0 °C under an inert atmosphere. The resulting mixture was stirred at room temperature for 10 min. To this mixture was added a solution of 4- nitroacetophenone (5.0 g, 12.0 mmol) in THF (10 mL) dropwise at 0 °C, and the resulting mixture was allowed to stir at room temperature for 4 h. The mixture was then cooled to 0 °C and quenched with 1 N HC1 (0.5 mL). The solution was allowed to stir for 15 min before a saturated NaHCCb solution was added. The resulting solution was extracted with EtO Ac. The organic layer was dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to afford 4,4,4- trifluoro-l-(4-nitrophenyl)butane-l, 3-dione (3a) (5.51 g) in 95% yield.
3-hvdroxy-l-(4-nitrophenyl)-5-(phenanthren-2-yl)-3-(trifluo (3b)
i. n-BuLi, THF, -78 °C
Figure imgf000046_0002
(3a) (3b)
[00122] To a solution of 2-ethynylphenanthrene (935 mg, 4.6 mmol) in dry THF (7 mL) was added «-BuLi (0.294 g 4.6 mmol) dropwise at -78 °C. The cooling bath was removed after «-BuLi addition, and the solution was allowed to warm up to room temperature and stir for 1.5 h. The solution was re-cooled to -78 °C and 4,4,4-trifluoro-l-(4-nitrophenyl)butane-l, 3-dione (3a) (500 mg, 2.3 mmol), was added dropwise as a solution in dry THF (3 mL). After the addition of 3a, the solution was allowed to warm to room temperature and stir for 3 h. A sat. aq. solution of NH4CI (5 mL) was added and the mixture was stirred 15 min. Water and EtO Ac was added and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with water and dried over NaaSOzi, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography to give 3-hydroxy-l-(4-nitrophenyl)-5- (phenanthren-2-yl)-3-(trifluoromethyl)pent-4-yn-l-one (3b) (911mg) in 85% yield.
2-( 4-nitrophenyl)-6-(phenanthren-2-yl)-4-( trifluoromethvDpyridine ( 3c)
Figure imgf000047_0001
[00123] To a solution of 3-hydroxy-l-(4-nitrophenyl)-5-(phenanthren-2-yl)-3- (trifluoromethyl)pent-4-yn-l-one (3b) (200 mg, 0.43 mmol) in toluene (4 mL) was added urea (34 mg, 0.51 mmol) and TFA (187 mg, 1.5 mmol). The resulting mixture was heated at reflux for 6 h, and the reaction was monitored by TLC. Triethylamine (0.2 mL) was added and the solution was concentrated under reduced pressure. The residue was purified by flash chromatography to give 2- (4-nitrophenyl)-6-(phenanthren-2-yl)-4-(trifluoromethyl)pyridine (3c) (149 mg) in 78 % yield. 4-( 6-(Phenanthren-2-yl)-4-( trifluoromethyl)pyridin-2-yl)aniline ( 3d)
Figure imgf000047_0002
[00124] To a solution of 2-(4-nitrophenyl)-6-(phenanthren-2-yl)-4-(trifluoromethyl)pyridine (3c) (150 mg, 0.43 mmol) in EtOAc (10 ml) and MeOH (5 mL) was added 10 % palladium on carbon (46 mg, 0.43 mmol). To the resulting mixture was added H2 gas at 75 psi using a Parr apparatus and the reaction was allowed to stir for 2 h. The mixture was filtered through celite to remove the catalyst, and concentrated under reduced pressure to give 4-(6-(phenanthren-2-yl)-4- (trifluoromethyl)pyridin-2-yl)aniline (3d) compound (115 mg) in 82 % yield.
2-amino-N-f 4-( 6-(phenanthren-2-yl)-4-( trifluoromethyl)pyridin-2-yl)phenyl)acetamide (IX-1)
Figure imgf000047_0003
[00125] Compound IX-1 was prepared according to Method A as described above. To a solution of /-butyloxycarbonyl (iBOC)-glycine (46 mg, 0.26 mmol) and 4-(6-(phenanthren-2-yl)- 4-(trifluoromethyl)pyridin-2-yl)aniline (3d) (100 mg, 0.24 mmol) in dry THF (10 mL) was added l-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride (71 mg, 0.36 mmol). The resulting mixture was stirred at 25 °C for 12 h, and then concentrated under reduced pressure. The residue was suspended in water and extracted with EtOAc. The organic phase was dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to give the Boc- protected intermediate. The intermediate (0.110 g, 0.73 mmol) was dissolved in EtOAc (10 mL) and cone. HCl (1.0 mL) was added. The resulting solution was stirred at room temperature for 2 h, and then concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (DCMiMethanoliNLLOH 96:2:2) to afford corresponding 2-amino-N-(4- (6-(phenanthren-2-yl)-4-(trifluoromethyl) pyridin-2-yl) phenyl)acetamide (IX-1) as a white powder (98.5 mg) in 87 % yield.
EXAMPLE 5: 2-amino-N-(4-(2-(naphthalen-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l- yl)phenyl)acetamide (III-3)
[00126] Compound III-3 and its derivatives were prepared as shown in FIG. 7B, such as III- 4, III-ll, 111-12, 111-17, 111-19, 111-24, 111-26, and 111-29
4-f 1 , 1 -diethoxyethyl)-4'-ftrifIuoromethyl)-l , Γ-biphenyl
[00127] See FIG. 7B, step a. N-bromosuccinimide (0.168 g, 0.94 mmol) was added to a solution of 2-acetylnaphthalene (8.0 g, 47.0 mmol), triethyl orthoformate (13.93 g, 94.00 mmol), and absolute EtOH (80 mL). The resulting solution was stirred at room temperature for 6 h. The reaction was monitored by TLC. Upon completion, a cold aqueous solution of NaOH (10%, 15 mL) was added and the mixture was extracted with Et^O (3 χ 50 mL). The organic extracts were washed with water (3 χ 25 mL) and dried over anhydrous Na2SC>4. The solvent was removed under reduced pressure. The crude product was purified by TEA-coated silica flash chromatography to afford 2-(l,l-diethoxyethyl)naphthalene (9.76 g) in 85% yield.
(Z)-4-ethoxy-l , 1 , l-trifluoro-4-(naphthalen-2-yl)but-3-en-2-one
[00128] See FIG. 7B, step b. To a solution of 2-(l,l-diethoxyethyl)naphthalene (15.0 g, 61.39 mmol) in chloroform (60 mL) was added pyridine (9.7 g, 122.7 mmol) and the resulting solution was stirred at 0 °C for 5 min. A solution of trifluoroacetic anhydride (25.8 g, 122.7 mmol) in 40 mL of chloroform was added dropwise over 15 min. The resulting solution was stirred at room temperature for 5 to 6 h. The reaction was monitored by TLC. Upon completion of the reaction, ice cold water (50 mL) was added and the mixture was extracted with DCM (3 χ 60 mL). The organic layer was washed with 2 N HCl solution, washed with a 10% aq. Na2CC>3 solution, and dried over anhydrous Na2SC>4. The solvent was removed under reduced pressure. The crude product was purified by flash chromatography to afford (Z)-4-ethoxy- 1,1,1 -trifluoro- 4-(naphthalen-2-yl)but-3-en-2-one (14.0g) in 78 % yield.
(Z)-4-ethoxy-4-(naphthalen-2-yl)-2-(trifluoromethyl)-2-((trim
[00129] See FIG. 7B, step c. To a solution of trimethylsilyl cyanide (6.13 g, 61.75 mmol) and triethylamine (0.240 g, 0.237 mmol) in acetonitrile (40 mL) was added (Z)-4-ethoxy- 1,1,1 - trifluoro-4-(naphthalen-2-yl)but-3-en-2-one (7.50 g, 19.31 mmol) as a solution in acetonitrile (20 mL) at 0°C. The resulting solution was stirred for 16 h and then concentrated under reduced pressure to afford ((Z)-4-ethoxy-4-(naphthalen-2-yl)-2-(trifluoromethyl)-2-((trimethylsilyl)oxy) but-3-enenitrile (6.96 g) in 85 % yield. The product was used without further purification the following step.
(Z)-2-(aminomethyl)-4-ethoxy-l , 1 , l-trifluoro-4-(naphthalen-2-yl)but-3-en-2-ol
[00130] See FIG. 7B, step d. LiAlH4 (2.0 g, 53.11 mmol) was suspended in dry ether (40 mL) under an inert atmosphere and cooled to 0-5 °C. A solution of ((Z)-4-ethoxy-4-(naphthalen-2- yl)-2-(trifluoromethyl)-2-((trimethylsilyl)oxy)but-3-enenitrile (19.0 g, 48.28 mmol) in dry ether (60 mL) was added dropwise over 30 min at 0-5 °C. The mixture was allowed to come to room temperature and stirred overnight. The mixture was cooled to 0-5 °C and a cooled 30% aq. NaOH (10 mL) solution was added to quench the excess LiAlH4. The mixture was filtered and the solids were washed with EtOAc (3 x 50 mL). The filtrate was dried over Na2SC>4 and concentrated under reduced pressure to give (Z)-2-(aminomethyl)-4-ethoxy- 1,1,1 -trifluoro-4- (naphthalen-2-yl)but-3-en-2-ol (12.24 g) in 78 % yield.
2-(naphthalen-2-yl)-4-(trifluoromethyl)-lH-pyrrole
[00131] See FIG. 7B, step e. To a solution of (Z)-2-(aminomethyl)-4-ethoxy- 1,1,1 -trifluoro- 4-(naphthalen-2-yl)but-3-en-2-ol (4.0 g, 12.31 mmol) acetonitrile (20 mL), and water (1.5 mL) was added con. HC1 (1.5 mL). The resulting solution was stirred at 80 °C for 12 h and monitored by TLC. Upon completion, water and saturated NaHCC (20 mL) were added. The solution was extracted with EtOAc (3 x 50 mL) and the combined organic layers were dried over anhydrous Na2S04. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (Hex: EtOAc 6:2) to afford 2-(naphthalen-2-yl)-4- (trifluoromethyl)-lH-pyrrole as an off-white solid (2.76 g) in 86% yield.
2-(naphthalen-2-yl)-l-(4-nitrophenyl)-4-(trifluoromethyl)-lH-pyrrole
[00132] See FIG. 7B, step f. To a solution of 2-(naphthalen-2-yl)-4-(trifluoromethyl)-lH- pyrrole (1.0 g, 3.82 mmol) in DMF (20 mL), was added 4-fluoronitrobenzene (0.809 g, 5.74 mmol) and K2CO3 (1.05 g, 7.52 mmol). The resulting mixture was stirred at 120 °C for 12 h. Upon completion, ice cold water was added and the solution was extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over anhydrous Na2S04. The solvent was removed under reduced pressure and the crude product was purified by flash chromatography (Hex:EtOAc 7:3) to afford 2-(naphthalen-2-yl)-l-(4-nitrophenyl)-4-(trifluoromethyl)-lH-pyrrole as a light yellow solid (1.05 g) in 72 % yield.
4-( 4-( trifluoromethyl)-2-(4'-( trifluoromethyl)-[ 1, 1 '-biphenyl]-4-yl)-lH-pyrrol-l-yl)aniline
[00133] See FIG. 7B, step g. To a solution of 2-(naphthalen-2-yl)-l-(4-nitrophenyl)-4- (trifluoromethyl)-lH-pyrrole (1.0 g, 2.84 mmol) in EtOAc (20 ml) and MeOH (10 mL) was added 10 % Pd/C (0.150 g, 1.41 mmol) 70 PSI of H2 gas was applied to the mixture using a Pan- apparatus for 3h. The reaction mixture was filtered through celite, filtrate was concentrated under reduced pressure to give pure 4-(4-(trifluoromethyl)-2-(4'-(trifluoromethyl)-[l, r- biphenyl]-4-yl)-lH-pyrrol-l-yl)aniline (0.850 g) in 92 % yield.
2- amino-N-(4-(2-(naphthalen-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l-yl)phenv
[00134] See FIG. 7B, step h. To a solution of i-butyloxycarbonyl (^BOC)-glycine (0.054 g, 0.31 mmol) and 4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l-yl)aniline (0.100 g, 0.28 mmol) in dry tetrahydrofuran (20 mL) was added l-[3-(dimethylamino)propyl]-3- ethylcarbodiimidehydrochloride (0.083 g, 0.42 mmol). The resulting solution was stirred at 25 °C for 12 h, and then concentrated under reduced pressure. The resulting residue was suspended in water, and extracted with EtOAc. The organic layer was dried over anhydrous Na2SC>4, and the solvent was removed under reduced pressure to give the Boc-protected intermediate, to this crude Boc-protected intermediate (0.140 g, 0.73 mmol) was dissolved in EtOAc (9 mL) containing concentrated HCl (1 mL). The resulting solution was stirred at room temperature for 2 h, and concentrated under reduced pressure. The crude product was purified by silica gel flash chromatography (DCM:MeOH:NH4OH 96:2:2) to afford 2-amino-N-(4-(2-(naphthalen-2-yl)-4- (trifluoromethyl)-lH-pyrrol-l-yl)phenyl)acetamide II-3 as a white powder (0.101 g) in 90 % yield. XH NMR (400 MHz, CDC13) δ: 9.52 (s, 1H), 8.76 (dd, J = 5.9, 3.3 Hz, 1H), 7.72 - 7.69 (m, 2H), 7.66 (d, J = 8.6 Hz, 1H), 7.59 (d, J = 8.70 Hz, 2H), 7.44 (dd, J = 6.18, 3.2 Hz, 2H), 7.25 (s, 1H), 7.16 ~ 7.14 (m, 3H), 6.69 (s, 1H), 3.46 (s, 2H), 1.61 (s, 2H); 1 C NMR (100 MHz, CDC13) 5: 170.8, 137.1, 135.1, 134.9, 133.1, 132.2, 129.0, 127.9, 127.7, 127.5, 127.3, 126.3(3 X CH), 126.1, 125.1, 123.0 (q, J= 4.8 Hz), 119.8, 115.5 (d, J= 37.3 Hz), 107.6 (d, J = 2.7 Hz), 44.9. EXAMPLE 6: 2-amino-N-(4-(3-isopropyl-6-(4-(trifluoromethyl)phenyl)-lH-indol-l- yl)phenyl)acetamide (V-l): Compounds represented by formula V were prepared from compound 3d, as shown in FIG. 7C, such as compounds V-l to V-17.
3- Isopropyl-6-bromo lH-indole
[00135] See FIG. 7C, step a. A mixture of triethylsilane (8.90 g, 76.53 mmol) trichloroacetic acid (6.12 g, 38.26 mmol) were dissolved in toluene (40 mL) and the resulting solution was heated to 70 °C, for 1 hour then a solution of 6-bromoindole (5.0 g, 25.51 mmol) and acetone (4.35g, 76.53 mmol) in toluene (15 mL) were added drop wise over 1 hour, the reaction mixture was stirred at 70 °C for 2 hour, after completion of the reaction the solution was quenched with 10% aqueous sodium carbonate, the organic layer was extracted in ethyl acetate (2 X 50 mL) dried over anhydrous Na2SC>4, concentrated under reduced pressure, and purified by flash column chromatography (Hex:EtOAc = 8:2) to afford 3-Isopropyl-6-bromo lH-indole (3.09 g, 68%) as a brown solid.
6-bromo-3-isopropyl-l-(4-nitrophenyl)-lH-indole
[00136] See FIG. 7C, step b. A mixture of 3-Isopropyl-6-bromo lH-indole (3.0 g, 12.0 mmol), 4-iodonitrobenzene (6.29 g, 25.0 mmol), Cu20 (858 mg, 6.0 mmol), and Cs2C03 (4.60 g, 24.0 mmol) in DMF (20 mL) the resulting mixture was stirred at 130 °C for 24 hour, then ice- cold water was added, extracted with ethyl acetate (3 X 50 mL) dried over anhydrous Na2SC>4, filtered, concentrated under reduced pressure, and purified by flash column chromatography (Hexanes:EtOAc = 7:3) to afford 6-bromo-3-isopropyl-l-(4-nitrophenyl)-lH-indole (3.0 g, 68 %) as a brown solid.
3- isopropyl-l-f 4-nitrophenyl)-6-( 4-( trifluoromethyl)phenyl)-lH-indole
[00137] See FIG. 7C, step c. A solution of 6-bromo-3-isopropyl-l-(4-nitrophenyl)-lH-indole (1.9 g, 5.2 mmol), (4-(trifluoromethyl)phenylboronic acid (1.2 g, 6.3 mmol), and 2M. Na2C03 (3 mL) in Toluene : Methanol (10:5 mL) degassed with Nitrogen then Pd(PPh3)4 (0.180 g, 0.15 mmol) was added and reaction mixture was heated at 80 °C for 24 hour, the reaction mixture was concentrated, water was added, extracted with ethyl acetate (3 X 50 mL) dried over anhydrous Na2SC>4, concentrated under reduced pressure, and purified by flash column chromatography (Hexanes:EtOAc = 7:3) to afford 3-isopropyl-l-(4-nitrophenyl)-6-(4-(trifluoromethyl)phenyl)- lH-indole (1.8 g, 80 %) as a brown solid.
4- (3 sopropyl-6-(4-(trifluoromethyl)phenyl)-lH ndol-l-yl)aniline
[00138] See FIG. 7C, step d. To a solution of 3-isopropyl-l-(4-nitrophenyl)-6-(4- (trifluoromethyl)phenyl)-lH-indole (1.8 g, 4.24 mmol) in (20 ml) of Ethyl acetate and (10 mL) of methanol was added 10 % Palladium on carbon (0.225 g, 2.12 mmol), The reaction was carried out at 70 PSI H2 gas on the Par apparatus for 3h. After completion the reaction was filtered through celite to remove the catalyst, and concentrated to dryness under vacuum to give pure 4-(3-isopropyl-6-(4-(trifluoromethyl)phenyl)-lH-indol-l-yl)aniline (1.28 g, 77 % yield). 2-amino-N-f4-f3-isopropyl-6-f4-ftrifIuoromethyl)phenyl)-lH-indol-l-yl)phenv
[00139] See FIG. 7C, step e. To a solution of i-butyloxycarbonyl (^BOC)-glycine (175 mg, 1.0 mmol) and 4-(3-isopropyl-6-(4-(trifluoromethyl)phenyl)-lH-indol-l-yl)aniline (0.360 g, 0.91 mmol) in 20 ml of dry tetrahydrofuran was added l-[3-(dimethylamino)propyl]-3- ethylcarbodiimidehydrochloride (270 mg, 1.3 mmol), stirred at 25 °C for 12 h, and concentrated to dryness under vacuum. The residue was suspended in water, and the product was extracted with ethyl acetate (2 x 50 mL), dried over anhydrous Na2SC>4, and concentrated to dryness under vacuum to give tert-butyl (2-((4-(3-isopropyl-6-(4-(trifluoromethyl)phenyl)-lH-indol-l- yl)phenyl)amino)-2-oxoethyl)carbamate almost pure compound, To this crude compound of (2- ((4-(3-isopropyl-6-(4-(trifluoromethyl)phenyl)-lH-indol-l-yl)phenyl)amino)-2- oxoethyl)carbamate (0.396 g, 0.71 mmol) was dissolved in 10 ml of ethyl acetate containing 1.0 ml of concentrated HCl solution, stirred at room temperature for 2 h, and concentrated to dryness under vacuum. The crude product was purified by silica gel column chromatography (DCM/Methanol/ NH4OH in H20= 6/2/2) to afford corresponding 2-amino-N-(4-(3-isopropyl-6- (4-(trifluoromethyl)phenyl)-lH-indol-l-yl)phenyl)acetamide as a white powder V-l (0.300 g, 93 %). lH NMR (300 MHz, CDC13) δ: 9.59 (s, 1H), 7.79 ~ 7.76 (m, 3H), 7.73 ~ 7.64 (m, 5H), 7.49 (d, J = 8.6 Hz, 2H), 7.41 (d, J = 7.7 Hz, 1H), 7.14 (s, 1H), 3.53 (s, 2H), 3.33 ~ 3.24 (m, 1H), 1.69 (s, 2H), 1.44 (d, J = 6.8 Hz, 6H); 1 C NMR (75 MHz, CDC13) 5: 170.8, 145.8, 136.8, 135.9, 135.6, 134.2, 127.9, 127.5, 125.5 (d, J = 3.7 Hz), 124.9, 124.7, 124.6, 120.5, 119.6 (d, J = 69.9 Hz), 109.2, 45.0, 25.4, 23.3.
EXAMPLE 7: 2-amino-N-(4-(3-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl) -1H- indazol-l-yl)phenyl)acetamide (VI-2)
[00140] Compounds represented by formula VI were prepared from compound 3d, as shown in FIG. 7C, such as compounds V-l to V-17.
l-( 4-Bromo-2-fluorophenyl)-2, 2, 2-trifluoroethan-l-one
[00141] See FIG. 7D, step a. To a solution of l-(4-bromo-2-fluorophenyl)-2,2,2- trifluoroethanol (1.09 g, 3.99 mmol) in ethyl acetate (30 mL) was added 2-iodoxy benzoic acid (2.28 g, 7.97 mmol). The reaction was heated to reflux overnight. The reaction was cooled to room temperature and diluted with hexanes (30 mL). The mixture was filtered through Celite and the filtrate was concentrated to give l-(4-bromo-2-fluorophenyl)-2,2,2-trifluoroethan-l-one (1.03 g, 95%) as pale yellow oil.
6-Bromo-3-(trifluoromethyl)-lH-indazole
[00142] See FIG. 7D, step b. A solution of Hydrazine hydrate (3.5 mL, 45 mmol), and l-(4- bromo-2-fluorophenyl)-2,2,2-trifluoroethanone (1.00 g, 3.69 mmol) in 1-butanol (15 mL). The reaction was heated to reflux for 6 hours, then cooled to room temperature and left stirring overnight. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organics were dried over sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (EtOAc/Hex = 6/4) gave 6- bromo-3-(trifluoromethyl)-lH-indazole as an off-white solid (0.850 g, 83%).
6-Bromo-l-(4-nitrophenyl)-3-(trifluoromethyl)-lH-indazole [00143] See FIG. 7D, step c. A solution of 6-bromo-3-(trifluoromethyl)-lH-indazole (1.0 g, 3.77 mmol), 4-fluoronitrobenzene (0.800 g, 5.66 mmol) and K2C03 (1.02 g, 7.54 mmol) in DMF (10 mL) was stirred at 120°C temperature for 12 h. The reaction was monitored by TLC and after completion of reaction, ice cold water was added, the product were extracted with ethyl acetate (3x 50 mL) dried over anhydrous Na2SC>4. After the solvent was evaporated, the crude product was purified by column chromatography (EtO Ac/Hex = 7/3) to give 6-bromo-l-(4- nitrophenyl)-3-(trifluoromethyl)-lH-indazole as a light yellow solid (0.947 g, 65% yield).
1- (4-nitrophenyl)-3-(trifluoromethyl)-6-(4-(trifluoromethv
[00144] See FIG. 7D, step d. To a mixture of 6-bromo-l-(4-nitrophenyl)-3- (trifluoromethyl)-lH-indazole (300 mg, 0.77 mmol), (4-(trifluoromethyl)phenylboronic acid (177 mg, 0.93 mmol), and 2M Na2CC>3 (2 mL) in toluene : methanol (10 mL : 5 mL) degassed with nitrogen then Pd(PPl¾)4 (26 mg, 0.023 mmol) was added and reaction mixture was heated at 80 °C for 12 hour, the reaction mixture was concentrated, water was added and extracted with ethyl acetate (3 X 50 mL) dried over sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash column chromatography (Hexanes:EtOAc = 7:3) to afford l-(4- nitrophenyl)-3-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)-lH-indazole (0.280 g, 85 %) as a brown solid.
4-( 3-f trifluoromethyl)-6-( 4-(trifluoromethyl)phenyl)-lH-indazol-l-yl)aniline
[00145] See FIG. 7D, step e. To a solution of l-(4-nitrophenyl)-3-(trifluoromethyl)-6-(4- (trifluoromethyl)phenyl)-lH-indazole compound (0.280 g, 0.62 mmol) in (10 ml) of Ethyl acetate and (5 mL) of methanol was added 10 % Palladium on carbon (0.035 g, 0.31 mmol), The reaction was carried out at 70 PSI H2 gas on the Par apparatus for 2h. After completion, the reaction was filtered through celite and concentrated to dryness under vacuum to give pure 4-(3- (trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)-lH-indazol-l-yl)aniline (0.250 g, 96 % yield).
2- amino-N-(4-(3-( trifluoromethyl)-6-( 4-( trifluoromethyl)phenyl)-lH-indazol-l- vDphenvDacetamide
[00146] See FIG. 7D, step f. To a solution of i-butyloxycarbonyl (iBOC)-glycine (0.035 g, 0.20 mmol) and 4-(3-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)-lH-indazol-l-yl)aniline (0.080 g, 0.19 mmol) in 10 ml of dry tetrahydrofuran was added l-[3-(dimethylamino)propyl]-3- ethylcarbodiimidehydrochloride (53 mg, 0.27 mmol), stirred at 25 °C for 12 h, and concentrated to dryness under rotary evaporator. The residue was suspended in water and extracted with ethyl acetate, dried over anhydrous Na2SC>4, and concentrated to dryness under vacuum to give almost pure Boc protected intermediate. To this crude Boc protected intermediate (0.110 g, 0.20 mmol) was dissolved in 9 ml of ethyl acetate containing 1.0 ml of concentrated HCl solution, stirred at room temperature for 2 h, and concentrated to dryness under vacuum. The crude product was purified by silica gel column chromatography (DCM/Methanol/ NH4OH in H20= 6/2/2) to afford 2-amino-N-(4-(3-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)-lH-indazol-l- yl)phenyl)acetamide as a white powder VII-2 (0.081 g, 90 %). l NMR (300 MHz, CDC13) δ: 9.58 (s, 1H), 7.92 (d, J= 8.4 Hz, 1H), 7.83 ~ 7.77 (m, 4H), 7.73 (s, 1H), 7.71 (s, 1H), 7.62 (d, J = 8.8 Hz, 2H), 7.47 (dd, J = 8.4, 1.3 Hz, 2H), 3.45 (s, 2H), 1.69 (s, 2H); 1 C NMR (75 MHz, CDCI3) 5: 169.8, 150.8, 144.2, 140.3, 136.0 (d, J = 32.7 Hz), 127.9, 125.7 (m, J = 3.7 Hz), 123.9, 123.4, 122.8, 121.1, 120.6, 120.3, 108.9 (d, J = 3.4 Hz), 45.0.
Example 4: Broad Spectrum Antifungal Activity Of The Disclosed Compounds
[00147] Selected compounds were tested to determine IC50 values in an assay using one of C. albicans (SC5314), C. neoformans (H99), A. fumigatus (AF293), T. Rubrum (MYA-4438), and . solani (Fungus III-6) as follows.
[00148] Clinical Laboratory Standards Institute (CLSI) M27-A3 protocol was used to determine the MICs of yeast pathogens, such as C. albicans and C. neoformans . Two-fold serial dilutions of compounds were prepared in 2 of RPMI 1640 medium, and the final concentrations of the antifungal agents ranged from 0.125 to 64 μg/mL after the addition of the inoculum. C. albicans and C. neoformans were incubated in liquid YPD medium overnight at 37°C, washed twice with ddH20, and adjusted to 0.0005 OD/mL at 600 nm wave length. 98 of the inoculum was added to the RPMI 1640 medium containing serial concentrations of the antifungal agents. The microtitration plates (Becton Dickinson #353072) were then incubated at 35°C for 24 hr (C. albicans) or 48 hr (C. neoformans). The MIC was defined as the lowest concentration of the antifungal agents that completely inhibited growth of C. albicans and C. neoformans in the microtitration wells as detected by the unaided eye and by spectrophotometer.
[00149] The CLSI M38-A2 protocol was used to measure the MICs of filamentous fungi such as A. fumigatus, T. rubrum and F. solani. Two-fold serial dilutions of compounds were prepared in 2 xL of RPMI 1640 medium in 96-well microtitration plates. The final concentrations of the agents after the addition of freshly prepared conidia solution ranged from 0.125 to 64 μg/mL. Conidia of fungal strains were collected from PDA solid agar plates, washed twice with ddH20, and adjusted to 0.5 x 104 conidia/mL with RPMI 1640 medium. 98 μί of each conidia solution was added to the RPMI 1640 medium containing serial concentrations of the antifungal agents. After the addition of the inoculum to the RPMI media containing the antifungal agents, all microtitration plates were incubated at 35°C for 48 hr A. fumigatus and . solani), or 4 to 7 days (T. rubrum) due to its lower growth rate. The MIC values were determined as the lowest drug concentration showing no visible growth. [00150] The table in FIGS. 8A and 8B reports minimum inhibitory concentration (MIC) values in μg/mL measured for the indicated disclosed compounds, as well as known compound OSU-03012:
Figure imgf000055_0001
Example 8 (Prophetic): Screening The Disclosed Anti-Fungal Compounds For Toxicity and Therapeutic Activity In Vivo
[00151] Five-week-old male CD1 mice (-30 g) may be used in this assay. For infection, C. albicans SC5314, for example, may be cultured in liquid YPD broth overnight at 37°C and washed twice with sterile PBS buffer. Candida cells may be counted with a hemocytometer, and resuspended in sterile PBS buffer at 5x106 cells per mL. Dilutions of the cells may be plated onto YPD and may be incubated at 37°C for 24 hr in order to determine CFU and viability. Groups of five mice may be inoculated with C. albicans via tail-vein injection of 106 cells (in 200 μί). Compounds may be prepared as 10-fold stock in DMSO and diluted with ddH20 (0.5% methylcellulose (w/v) + 0.1% Tween-80 (v/v)) into 4.26 mg/ml and 1.42 mg/ml to make the final concentration for mice dose at 30 and 10 mg/kg. The diluted compounds may be sonicated for 1 hr to make homogeneous solution (in 200 μί), administered via oral gavage (22 gauge) after 4, 24, 48, and 72 hr following Candida infection. The conditions of the mice may be monitored twice daily, and moribund mice may be euthanized by cervical dislocation. Kaplan-Meier survival curves may be generated with Prism 5.03 (GraphPad software, La Jolla, CA, USA), and P values may be evaluated by a Log-rank (Mantel-Cox) test. A P value of <0.05 may be considered significant. The mice orally receive a disclosed antifungal compound at 10 or 30 mg/kg may exhibit less toxicity compared with known antifungal compounds, such as ketoconazole. Meanwhile, the therapeutic activity of a specific disclosed compound against C. albicans infection may be determined according to the respective survival curves.
Example 9 (Prophetic): Counterscreening The Disclosed Anti-Fungal Compounds For Toxicity
[00152] The disclosed anti-parasitic compounds may also be counterscreened for toxicity to J774 macrophages and HepG2 hepatocellular carcinoma cells. J774 cells (103 in 100 μί) or HepG2 cells (5 * 103 in 100 μί) may be incubated for 72 h with serial dilutions of compounds in DMEM (for J774 cells) or RPMI medium (for HepG2 cells) supplemented with 10% fetal bovine serum. MTT may then be added and absorbance at 570 nm may provide an assessment of cell proliferation. Determination of IC50 values in each assay may permit the calculation of a selectivity index (SI, e.g., target fungus IC50 vs. mammalian cell line/ICso vs., e.g., target fungi in genera such as Aspergillus, Candida, Cryptococcus , Histoplasma, and the like) for each target compound.
DEFINITIONS
[00153] As used herein, an "alkyl" group includes straight chain and branched chain alkyl groups having a number of carbon atoms, for example, from 1 to 12, 1 to 10, 1 to 8, 1 to 6, or 1 to 4. Examples of straight chain alkyl groups include groups such as methyl, ethyl, ^-propyl, n- butyl, ft-pentyl, w-hexyl, w-heptyl, and w-octyl groups. Examples of branched alkyl groups include, e.g., isopropyl, iso-butyl, sec-butyl, fert-butyl, neopentyl, isopentyl, and 2,2- dimethylpropyl groups. Representative substituted alkyl groups may be substituted one or more times with substituents such as those listed above and include, without limitation, haloalkyl (e.g., trifluoromethyl), hydroxyalkyl, thioalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, or carboxyalkyl.
[00154] As used herein, an "alkoxy" group means a hydroxyl group (-OH) in which the bond to the hydrogen atom is replaced by a bond to a carbon atom of a substituted or unsubstituted alkyl group. Examples of linear alkoxy groups include, e.g., methoxy, ethoxy, propoxy, butoxy, pentoxy, or hexoxy. Examples of branched alkoxy groups include, e.g., isopropoxy, seobutoxy, fert-butoxy, isopentoxy, or isohexoxy. Examples of cycloalkoxy groups include, e.g., cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, or cyclohexyloxy. Representative substituted alkoxy groups may be substituted one or more times.
[00155] As used herein, a "cycloalkyl" group includes mono-, bi- or tricyclic alkyl groups having from 3 to 12 carbon atoms in each ring, for example, 3 to 10, 3 to 8, or 3 to 4, 5, or 6 carbon atoms. Exemplary monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and the like. A cycloalkyl group may have a number of ring carbons of from 3 to 8, 3 to 7, 3 to 6, or 3 to 5. Bi- and tricyclic ring systems may include both bridged cycloalkyl groups and fused rings, e.g., bicyclo[2.1.1]hexane, adamantyl, decalinyl, and the like. Substituted cycloalkyl groups may be substituted one or more times with non-hydrogen and non-carbon groups as defined above. Substituted cycloalkyl groups may include rings that may be substituted with straight or branched chain alkyl groups. Representative substituted cycloalkyl groups may be mono-substituted or substituted more than once, for example, 2,2-, 2,3-, 2,4- 2,5- or 2,6-disubstituted cyclohexyl groups. [00156] As used herein, a "heterocycloalkyl" ring means an aromatic carbocyclic ring having one or more ring carbon atoms replaced by a heteroatom (e.g., N, S, or O). Non-aromatic heterocyclic rings may have 4, 5, 6, 7, or 8 ring atoms. Examples include oxazolinyl, thiazolinyl, oxazolidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahyrothiophenyl, morpholino, thiomorpholino, pyrrolidinyl, piperazinyl, piperidinyl, thiazolidinyl, and the like.
[00157] As used herein, an "aryl" group means a carbocyclic aromatic hydrocarbon. Aryl groups herein include monocyclic, bicyclic and tricyclic ring systems. Aryl groups include, e.g., phenyl, azulenyl, heptalenyl, biphenyl, fluorenyl, phenanthrenyl, anthracenyl, indenyl, indanyl, pentalenyl, naphthyl, and the like, for example, phenyl, biphenyl, and naphthyl. Aryl groups may contain, for example, 6 to 14, 6 to 12, or 6 to 10 ring carbons. In some embodiments, the aryl groups may be phenyl or naphthyl. Although the phrase "aryl groups" may include groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl or tetrahydronaphthyl), an "aryl" group, unless stated to be substituted or optionally substituted, does not include aryl groups that have other groups, such as alkyl or halo groups, bonded to one of the ring members. Rather, groups such as tolyl may be referred to as substituted aryl groups. Representative substituted aryl groups may be mono-substituted or substituted more than once. For example, monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6- substituted phenyl or naphthyl, which may be substituted with substituents such as those above.
[00158] As used herein, an "aralkyl" group means an alkyl group in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group. In some embodiments, aralkyl groups contain 7 to 16 carbon atoms, 7 to 14 carbon atoms, or 7 to 10 carbon atoms. Substituted aralkyl groups may be substituted at the alkyl, the aryl or both the alkyl and aryl portions of the group. Representative aralkyl groups include, e.g., benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-indanylethyl. Substituted aralkyls may be substituted one or more times.
[00159] As used herein, a "heteroaryl" group means a carbocyclic aromatic ring having one or more ring carbon atoms replaced by a heteroatom (e.g., N, S, or O). Heteroaryl groups may include, for example, imidazolyl, isoimidazolyl, thienyl, furanyl, pyridyl, pyrimidyl, pyranyl, pyrazolyl, pyrrolyl, pyrazinyl, thiazoyl, isothiazolyl, oxazolyl, isooxazolyl, 1,2,3-trizaolyl, 1,2,4- triazolyl, and tetrazolyl. Heteroaryl groups also include fused polycyclic aromatic ring systems in which a carbocyclic aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings. Examples of heteroaryl groups may include benzothienyl, benzofuranyl, indolyl, quinolinyl, benzothiazolyl, benzoisothiazolyl, benzooxazolyl, benzoisooxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl and isoindolyl. [00160] Groups described herein having two or more points of attachment (e.g., divalent, trivalent, or polyvalent) within the compound of the technology may be designated by use of the suffix, "ene." For example, divalent alkyl groups may be alkylene groups, divalent aryl groups may be arylene groups, divalent heteroaryl groups may be heteroarylene groups, and so forth. In particular, certain polymers may be described by use of the suffix "ene" in conjunction with a term describing the polymer repeat unit.
[00161] As used herein, "optionally substituted" means a compound or group that may be substituted or unsubstituted. The term "substituted" refers to an organic group (e.g., an alkyl group) in which one or more bonds to a hydrogen atom contained therein may be replaced by a bond to non-hydrogen or non-carbon atoms. Substituted groups also include groups in which one or more bonds to a carbon or hydrogen atom may be replaced by one or more bonds, including double or triple bonds, to a heteroatom. A substituted group may be substituted with one or more substituents, unless otherwise specified. In some embodiments, a substituted group may be substituted with 1, 2, 3, 4, 5, or 6 substituents.
[00162] Examples of substituent groups include: halogens (F, CI, Br, and I); hydroxyl; alkoxy, alkenoxy, aryloxy, aralkyloxy, heterocyclyloxy, and heterocyclylalkoxy groups; carbonyls (oxo); carboxyls; esters; urethanes; oximes; hydroxylamines; alkoxyamines; aralkoxy amines; thiols; sulfides; sulfoxides; sulfones; sulfonyls; sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitro groups; or nitriles. A "per"- substituted compound or group is a compound or group having all or substantially all substitutable positions substituted with the indicated substituent. For example, 1,6-diiodo perfluoro hexane indicates a compound of formula C6F12I2, where all the substitutable hydrogens have been replaced with fluorine atoms.
[00163] In particular, suitable substituents for an alkyl group, cycloalkyl group, heterocycloalkyl group, or an aryl group ring carbon are those which do not substantially interfere with the activity of the disclosed compounds. Examples include -OH, halogen (-Br, -, - I and -F), -ORA, -0(CO)RA, -(CO)RA, -CN, -N02, -C02H, -SO3H, -NH2, -NHRA, -N(RARB), - (CO)ORA, -(CO)H, -CONH2, -CONHRA, -CON(RARB), -NHCORA, -NRCORA, -NHCONH2, - NHCONRAH, -NHCON(RARB), -NRcCONH2, -NRcCONRAH, -NRcCON(RARB), -C(=NH)- NH2, -C(=NH)-NHRA, -C(=NH)-N(RARB), -C(=NRC)-NH2, -C(=NRC)-NHRA, -C(=NRC)- N(RARB), -NH-C(=NH)-NH2, -NH-C(=NH)-NHRA, -NH-C(=NH)-N(RARB), -NH-C(=NRC)- NH2, -NH-C (=NRC)-NHRA, -NH-C(=NRC)-N(RARB), NRDH-C(=NH)-NH2, -NRD-C(=NH)- NHRA, -NRD-C(=NH)-N(RARB), -NRD-C(=NRC)NH2, -NRD-C(=NRC)-NHRA, -NRD- C(=NRC)-N(RARB), -NHNH2, -NHNHRA, -NHRARB, -S02NH2, -S02NHRA, -S02NRARB, - CH=CHRA, -CH=CRARB, -CRC=CRARB, -CRC=CHRA, -CRC=CRB, -CCRA, -SH, -SOkRA (k is 0, 1 or 2) and -NH-C(=NH)-NH2. Each of RA-RD may independently be an aliphatic, substituted aliphatic, benzyl, substituted benzyl, aryl or substituted aryl group, for example, an alkyl, benzylic or aryl group. Further, -NRARD, taken together, may form a substituted or unsubstituted non-aromatic heterocyclic group. A non-aromatic heterocyclic group, benzylic group or aryl group may also have an aliphatic or substituted aliphatic group as a substituent. A substituted aliphatic group may also have a non-aromatic heterocyclic ring, a substituted a non- aromatic heterocyclic ring, benzyl, substituted benzyl, aryl or substituted aryl group as a substituent. A substituted aliphatic, non-aromatic heterocyclic group, substituted aryl, or substituted benzyl group may have more than one substituent.
[00164] Suitable substituents for heteroaryl ring nitrogen atoms having three covalent bonds to other heteroaryl ring atoms may include -OH and Ci to C10 alkoxy. Substituted heteroaryl ring nitrogen atoms that have three covalent bonds to other heteroaryl ring atoms are positively charged, which may be balanced by counteranions such as chloride, bromide, formate, acetate and the like. Examples of other suitable counteranions may include counteranions found in the described pharmacologically acceptable salts.
[00165] Suitable substituents for heteroaryl ring nitrogen atoms having two covalent bonds to other heteroaryl ring atoms include alkyl, substituted alkyl (including haloalkyl), phenyl, substituted phenyl, -S(0)2-(alkyl), -S(0)2-NH(alkyl), -S(0)2-NH(alkyl)2, and the like.
[00166] Also included are pharmaceutically acceptable salts of the compounds described herein. Compounds disclosed herein that possess a sufficiently basic functional group may react with any of a number of organic or inorganic acids to form a salt. Likewise, compounds disclosed herein that possess a sufficiently acidic functional group may react with any of a number of organic or inorganic bases to form a salt. Acids commonly employed to form acid addition salts from compounds with basic groups may include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic acid, methanesulfonic acid, oxalic acid, p- bromophenyl-sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such salts may include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, gamma- hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1- sulfonate, naphthalene-2-sulfonate, mandelate, and the like. Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of the described compounds may include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, and the like.
[00167] An "effective amount" is the quantity of compound in which a beneficial clinical outcome may be achieved when the compound is administered to a subject suffering from the described fungus. A "beneficial clinical outcome" may include one or more of: a reduction in number of fungal cells in a subject; a reduction in the rate of fungal growth in a subject; a reduction in fungal metabolism or consumption of a subject's bodily resources; a reduction in biomarkers, toxins, proteins, peptides, and other biomolecules associated with infection of the subject by the fungus; a reduction in inflammatory, allergic, toxic, disfigurement, or other effects on the subject by the fungus; a reduction in the severity of the symptoms associated with the fungus and/or an increase in the longevity or health of the subject compared with the absence of the treatment.
[00168] The precise amount of compound administered to a subject may depend on the species, lifecycle, and course of the fungal infection. The precise amount of compound administered to a subject may also depend on the characteristics of the subject, such as general health, age, sex, body weight and tolerance to drugs. A skilled artisan may determine appropriate dosages depending on these and other factors. Effective amounts of the disclosed compounds typically range between about 1 mg/mm2 per day and about 10 grams/mm2 per day, and preferably between 10 mg/mm2 per day and about 5 grams/mm2.
[00169] The disclosed compounds and pharmaceutical compositions may be administered by any suitable route, including, for example, orally in tablets, pills, gelcaps, lozenges, or suspensions; by parenteral administration. Parenteral administration can include, for example, systemic administration, such as by intramuscular, intravenous, subcutaneous, or intraperitoneal injection. The compounds may also be administered, for example, orally (e.g., dietary); topically, in the form of creams, sprays, patches, and the like; by inhalation (e.g., intrabronchial, intranasal, or oral inhalation of an aerosol formulation, by intranasal drops, and the like); via absorption through mucus membranes (e.g., tissues such as oral, nasal, rectal, vaginal, and the like) via, for example, creams, lozenges, sprays, drops, suppositories, and the like); depot preparations; coatings on sutures, bandages, medical devices, and the like. In some embodiments, oral or parenteral administration are exemplary modes of administration. [00170] The disclosed compounds may be administered to the subject in conjunction with an acceptable pharmaceutical carrier as part of a pharmaceutical composition for treatment of infection by the described fungus. Formulation of the compound to be administered may vary according to the route and vehicle of administration selected (e.g., solution for injection, capsule or tablet for ingestion, and the like). Suitable pharmaceutical carriers may contain inert ingredients that do not interact with the described compound. Standard pharmaceutical formulation techniques may be employed, such as those described in Remington's Pharmaceutical Sciences, 22nd ed., Mack Publishing Company, Easton, PA, 2012. Suitable pharmaceutical carriers for parenteral administration may include, for example, sterile water, physiological saline, bacteriostatic saline (e.g., saline containing about 0.9% mg/ml benzyl alcohol, and the like), phosphate-buffered saline, Hank's solution, Ringer's-lactate and the like. Methods for encapsulating compositions (such as in a coating of hard gelatin or cyclodextrin) or tableting compositions are known in the art (Baker, et al, "Controlled Release of Biological Active Agents," John Wiley and Sons, New York, 1986).
[00171] A "subject" may be any animal subject to infection by the described fungi, e.g., the subject may be a mammal, bird, marsupial, fish, or amphibian. For example, the subject may be a mammal, such as a human. The subject may also be a domestic or wild animal in need of veterinary treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, sheep, pigs, horses, and the like), laboratory animals (e.g., rats, mice, guinea pigs, and the like), birds, fish, marsupials, and the like.
[00172] To the extent that the term "includes" or "including" is used in the specification or the claims, it is intended to be inclusive in a manner similar to the term "comprising" as that term is interpreted when employed as a transitional word in a claim. Furthermore, to the extent that the term "or" is employed (e.g., A or B) it is intended to mean "A or B or both." When the applicants intend to indicate "only A or B but not both" then the term "only A or B but not both" will be employed. Thus, use of the term "or" herein is the inclusive, and not the exclusive use. See Bryan A. Gamer, A Dictionary of Modem Legal Usage 624 (2d. Ed. 1995). Also, to the extent that the terms "in" or "into" are used in the specification or the claims, it is intended to additionally mean "on" or "onto." To the extent that the term "selectively" is used in the specification or the claims, it is intended to refer to a condition of a component wherein a user of the apparatus may activate or deactivate the feature or function of the component as is necessary or desired in use of the apparatus. To the extent that the term "operatively connected" is used in the specification or the claims, it is intended to mean that the identified components are connected in a way to perform a designated function. To the extent that the term "substantially" is used in the specification or the claims, it is intended to mean that the identified components have the relation or qualities indicated with degree of error as would be acceptable in the subject industry.
[00173] As used in the specification and the claims, the singular forms "a," "an," and "the" include the plural unless the singular is expressly specified. For example, reference to "a compound" may include a mixture of two or more compounds, as well as a single compound.
[00174] As used herein, the term "about" in conjunction with a number is intended to include ± 10% of the number. In other words, "about 10" may mean from 9 to 11. Where the term "about" is used with respect to a number that is an integer, the term "about" may mean ± 10% of the number, or ± 5, ± 4, ± 3, ± 2, or ± 1 of the number.
[00175] As used herein, the terms "optional" and "optionally" mean that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.
[00176] In addition, where features or aspects of the disclosure are described in terms of Markush groups, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the Markush group. As will be understood by one skilled in the art, for any and all purposes, such as in terms of providing a written description, all ranges disclosed herein also encompass any and all possible sub-ranges and combinations of sub-ranges thereof. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, and the like. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, and the like. As will also be understood by one skilled in the art all language such as "up to," "at least," "greater than," "less than," include the number recited and refer to ranges which can be subsequently broken down into sub-ranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. For example, a group having 1 -3 members refers to groups having 1, 2, or 3 members. Similarly, a group having 1 -5 members refers to groups having 1, 2, 3, 4, or 5 members, and so forth. While various aspects and embodiments have been disclosed herein, other aspects and embodiments will be apparent to those skilled in the art.
[00177] As stated above, while the present application has been illustrated by the description of embodiments thereof, and while the embodiments have been described in considerable detail, it is not the intention of the applicants to restrict or in any way limit the scope of the appended claims to such detail. Additional advantages and modifications will readily appear to those skilled in the art, having the benefit of the present application. Therefore, the application, in its broader aspects, is not limited to the specific details, illustrative examples shown, or any apparatus referred to. Departures may be made from such details, examples, and apparatuses without departing from the spirit or scope of the general inventive concept.

Claims

1. A method of anti-fungal treatment, comprising:
providing a subject that has a fungal infection or is at risk of the fungal infection;
administering a compound to the subject in an amount effective to mitigate the fungal infection in the subject, the compound being represented by Structural Formula (I):
(I)
Figure imgf000064_0001
and pharmaceutically acceptable salts thereof,
wherein:
R1 is H, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro;
R2 is H and R3 is: sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl, a β-amino carbonyl, a γ-amino carbonyl, an α-β-unsaturated carbonyl, guanidine, or urea; or, the aniline nitrogen of Structural Formula (I), R2, and R3 together form an optionally substituted heterocyclic group;
Ar is an optionally substituted aryl or heteroaryl group consisting of 1, 2, 3, or 4 rings that are one or more of linked and fused;
Het is a heteroaryl group comprising a first ring that is a nitrogen-containing, five or six- membered heteroaryl group, the first ring being optionally fused to one or more of a second ring and a third ring to form a bi cyclic or tricyclic heteroaryl group consisting of 8, 9, 10, 1 1 , 12, or 13 ring atoms, wherein R1 and phenyl ring A are bonded to the first ring, and Ar is bonded to the first ring, the second ring, or the third ring;
provided that when the compound is 2-amino-N-[4-[5-phenanthren-2-yl-3- (trifluoromethyl)pyrazol-l-yl]phenyl]acetamide, the fungal infection does not correspond to one of: Candida albicans, Cryptococcus neoformans, Cryptococcus gattii, Candida tropicalis, Candida krusei, Candida glabrata, Candida dubliniesis, and Candida parapsilosis .
2. The method of claim 1, the subject being infected by the fungus, the method comprising administering the compound to the subject in an amount effective to mitigate one or more symptoms of the fungal infection in the subj ect.
3. The method of claim 1, the subject being at risk of the fungal infection, the method comprising administering the compound to the subj ect in an amount effective to mitigate the fungal infection of the subject.
4. The method of claim 1, the fungus comprising phosphoinositide-dependent kinase- 1, and the compound being effective to modulate the phosphoinositide-dependent kinase- 1 effective to mitigate the fungal infection in the subject.
5. The method of claim 1, the administering being one or more of: oral administration, intraperitoneal administration, intravenous administration, and intranasal administration.
6. The method of claim 1, wherein the subject suffers from infection by the fungus or is at risk of suffering from infection by the fungus, the infection being of one or more of: skin, nail, hoof, hair, fur, scale, mucosal membrane, blood, lymph, brain, lung, heart, liver, pancreas, spleen, kidney, bladder, stomach, and intestine.
7. The method of claim 1, wherein the subject suffers from or is at risk of suffering from a systemic infection by the fungus.
8. The method of claim 1, wherein the subject is one or more of: suffering from cancer; undergoing chemotherapy; undergoing immune suppression therapy; a transplant recipient; suffering from an immuno-deficiency, and a burn patient.
9. The method of claim 1, wherein the subject is a human, dog, cat, cow, horse, sheep, pig, bird, amphibian, or fish.
10. The method of claim 1, the amount of the composition administered to the subject being between about 1 and about 100 mg per kg of subject weight.
11. The method of claim 1, comprising administering the compound to the subject in a range in mg/kg between one or more of about: 1 and 5, 1 and 10, 1 and 15, 5 and 10, 5 and 15, and 5 and 20.
12. The method of claim 1, the amount of the composition administered to the subject being administered in a dosage of one or more of: a single dosage, a daily dosage, a weekly dosage, a monthly dosage, and an annual dosage.
13. The method of claim 1, the fungus being one of: Candida albicans, Cryptococcus neoformans, Aspergillus fumigatus, Trichophyton rubrum, and Fusarium solani.
14. The method of claim 1, further comprising co-administering an antifungal to the subject.
15. The method of claim 1, wherein the compound is represented by Structural Formula (II):
(II)
Figure imgf000065_0001
wherein: R1 is C1-C4 alkyl or C1-C4 haloalkyl;
Ar is phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl, and Ar is optionally substituted with one or more of: halogen, C1-C4 haloalkyl, C1-C4 alkyl, C1-C4 alkoxy, nitrile, and nitro;
R2 is H and R3 is S02NH2, C(=0)CH2NH2, C(=0)CH2N(CH3)2,
C(=0)C(cyclopropyl)NH2, C(=0)C(CH3)2NH2„ C(=0)C≡CH, C(=0)CH2NH(CH3),
C(=0)CH(NH2)CH(CH3)2, C(=0)CH(NH2)CH2CH(CH3)2, C(=0)CH(CH2Ph)NH2,
C(=0)CH(CH3)NH(CH3), C(=0)CH[CH2CH(CH3)2]NH(CH3), C(=0)CH(CH2Ph)NH(CH3), C(=0)CH(CH2Ph)N(CH3)2; or, R2, R3, and the aniline nitrogen of Structural Formula (II) together form:
Figure imgf000066_0001
wherein R4 and R5 are each independently: H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; and n is an integer from 1-6.
16. The method of claim 15, wherein the compound is represented by Structural Formula (III)
Figure imgf000066_0002
wherein:
R1 is CF3;
Ar is phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl; and Ar is optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 haloalkyl; and
Ar is 2-phenanthryl, 3 -phenanthryl, 9-anthracenyl, 4-biphenyl, 4-(4'-CF3)-biphenyl, 4- (3',5'-dimethyl)-biphenyl, 4-(3',5'-dimethoxy)-biphenyl, phenyl, l-(4-CF3)-phenyl, 1-naphthyl, or 2-naphthyl; and
R2 is H and R3 is S02NH2, C(=0)CH2NH2, C(=0)CH2N(CH3)2,
C(=0)C(cyclopropyl)NH2, C(=0)C(CH3)2NH2, C(=0)C≡CH, C(=0)CH2NH(CH3),
C(=0)CH(NH2)CH(CH3)2, C(=0)CH(NH2)CH2CH(CH3)2, C(=0)CH(CH2Ph)NH2,
C(=0)CH(CH3)NH(CH3), C(=0)CH[CH2CH(CH3)2]NH(CH3), C(=0)CH(CH2Ph)NH(CH3), C(=0)CH(CH2Ph)N(CH3)2; or, R2, R3, and the aniline nitrogen of Structural Formula (III) together form:
Figure imgf000067_0001
17. The method of claim 16, wherein the compound is:
2-amino-N-(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)acetamide (III-l);
2-amino-N-(4-(2-(phenanthren-3-yl)-4-(trifluoromethyl)-lH-pyrrol-l - yl)phenyl)acetamide (III-2);
2-amino-N-(4-(2-(naphthalen-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l-yl)phenyl)acetamide
(III-3);
2-amino-N-(4-(2-(naphthalen-l -yl)-4-(trifluoromethyl)-lH-pyrrol-l-yl)phenyl)acetamide
(III-4);
2-amino-N-(4-(4-(trifluoromethy l)-2-(4-(trifluoromethy l)pheny 1)- lH-pyrrol- 1 - yl)phenyl)acetamide (III-5);
N-(4-(2-([ 1 , 1 '-bipheny 1] -4-y l)-4-(trifluoromethy 1)- lH-pyrrol- 1 -y l)pheny l)-2- aminoacetamide (III-6);
2-amino-N-(4-(4-(trifluoromethyl)-2-(4'-(trifluoromethyl)-[l,r-biphenyl]-4-yl)-lH- py rrol- 1 -y l)pheny l)acetamide (III-7);
2-amino-N-(4-(2-(3 ',5'-dimethy l-[ 1 , 1 '-bipheny 1] -4-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)acetamide (III-8);
2-amino-N-(4-(2-(3',5'-dimethoxy-[l,r-biphenyl]-4-yl)-4-(trifluoromethyl)-lH-pyrrol-l- yl)phenyl)acetamide (III-9);
2-(methy lamino)-N-(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)acetamide (III- 10);
2-(methylamino)-N-(4-(2-(naphthalen-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l- yl)phenyl)acetamide (III-ll);
2-(methy lamino)-N-(4-(2-(naphthalen- 1 -y l)-4-(trifluoromethy 1)- lH-pyrrol- 1 - yl)phenyl)acetamide (III- 12);
N-(4-(2-([ 1 , 1 '-bipheny 1] -4-y l)-4-(trifluoromethy 1)- lH-pyrrol- 1 -y l)pheny l)-2- (methylamino)acetamide (III- 13);
N-(4-(2-(3',5'-dimethyl-[l, l '-biphenyl]-4-yl)-4-(trifluoromethyl)-lH-pyrrol-l -yl)phenyl)- 2-(methylamino)acetamide (111-14); N-(4-(2-(3',5'-dimethoxy-[l,r-biphenyl]-4-yl)-4-(trifluoromethyl)-lH-pyrrol-l- yl)phenyl)-2-(methylamino)acetamide (111-15);
2-(dimethy lamino)-N-(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)acetamide (III- 16);
2-(dimethy lamino)-N-(4-(2-(naphthalen-2-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)acetamide (111-17);
(^-2-amino-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l-yl)phenyl)-3- phenylpropanamide (III- 18);
(5 -2-(methy lamino)-N-(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)-3-phenylpropanamide (III- 19);
(5 -2-(methy lamino)-N-(4-(2-(naphthalen-2-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)-3-phenylpropanamide (111-20);
(i?)-2-(dimethy lamino)-N-(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)-3-phenylpropanamide (111-21);
(i?)-2-amino-4-methyl-N-(4-(2-(phenanthre^
yl)phenyl)pentanamide (111-22);
(i?)-4-me l-2-(me lamino)-N-(4-(2-^henanthren-2-yl)-4-(trifluoromethyl)-lH- pyrrol- 1 -yl)phenyl)pentanamide (111-23);
(^-4-methyl-2-(methylamino)-N-(4-(2-(naphthalen-2-yl)-4-(trifluoromethyl)-lH-^ l-yl)phenyl)pentanamide (111-24);
(i?)-2-amino-3-me l-N-(4-(2-^henanthren-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l- yl)phenyl)butanamide (111-25);
(i?)-2-amino-3-me l-N-(4-(2-(naphthalen-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l- yl)phenyl)butanamide(III-26);
(i?)-2-(methylamino)-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l- yl)phenyl)propanamide (111-27);
2-amino-2-methyl-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l- yl)phenyl)propanamide (111-28);
2-amino-2-methyl-N-(4-(2-(naphthalen-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l- yl)phenyl)propanamide (111-29);
1 -amino-N-(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)cyclopropane-l-carboxamide (111-30);
l-amino-N-(4-(4-(trifluorome l)-2-(4'-(trifluoromethyl)-[l,r-biphenyl]-4-yl)-lH- pyrrol-l-yl)phenyl)cyclopropane-l-carboxamide (111-31); N-(4-(4-(trifluoromethy l)-2-(4'-(trifluoromethy 1)- [ 1 , 1 '-bipheny 1] -4-y 1)- IH-py rrol- 1 - yl)phenyl)propiolamide (111-32);
NN-dimethy 1- 1 -(1 -(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- IH-py rrol- 1 -y l)pheny 1)- lH-l,2,3-triazol-4-yl)methanamine (111-33);
l-(l-(4-(2-(anthracen-9-yl)-4-(trifluoromethyl)-lH-pyrrol-l-yl)phenyl)-lH-l,2,3-triazol- 4-yl)-N,N-dimethylmethanamine (111-34);
NN-dimethy 1- 1 -(1 -(4-(4-(trifluoromethy l)-2-(4'-(trifluoromethy l)-[ 1 , 1 '-bipheny 1] -4-y 1)- lH-pyrrol-l-yl)phenyl)-lH-l,2,3-triazol-4-yl)methanamine (111-35);
N-(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- IH-py rrol- 1 -y l)pheny l)aminosulfonamide (111-36);
N-(4-(2-(phenanthren-3 -y l)-4-(trifluoromethy 1)- IH-py rrol- 1 -y l)pheny l)aminosulfonamide (111-37);
N-(4-(2-(anthracen-9-yl)-4-(trifluoromethyl)-lH-pyrrol-l-yl)phenyl)aminosulfonamide (111-38); or
N-(4-(4-(trifluoromethy l)-2-(4'-(trifluoromethy 1)- [ 1 , 1 '-bipheny 1] -4-y 1)- IH-py rrol- 1 - yl)phenyl)aminosulfonamide (111-39).
18. The method of claim 1, wherein the compound is represented by Structural Formula (IV):
(IV)
Figure imgf000069_0001
wherein:
R1 is Ci-C4 alkyl or C1-C4 haloalkyl;
Ar is phenanthryl, anthracenyl, biphenyl, phenyl, naphthyl, pyridyl, or pyrrolyl, and Ar is optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, nitrile, or
SO2-C1-C4 alkyl;
R2 is Η and R3 is S02NH2, C(=0)CH2NH2, C(=0)CH2N(CH3)2,
C(=0)C(cyclopropyl)NH2, C(=0)C(CH3)2NH2i, C(=0)C≡CH, C(=0)CH2NH(CH3),
C(=0)CH(NH2)CH(CH3)2, C(=0)CH(NH2)CH2CH(CH3)2, C(=0)CH(CH2Ph)NH2,
C(=0)CH(CH3)NH(CH3), C(=0)CH[CH2CH(CH3)2]NH(CH3), C(=0)CH(CH2Ph)NH(CH3), C(=0)CH(CH2Ph)N(CH3)2; or, R2, R3, and the aniline nitrogen of Structural Formula (IV) together form:
Figure imgf000070_0001
wherein R4 and R5 are optionally H or C1-C4 alkyl.
The method of claim 18, wherein the compound is represented by Structural Formula
(V)
Figure imgf000070_0002
wherein:
R1 is C1-C4 alkyl or C1-C4 haloalkyl;
Ar is l-(4-CF3)-phenyl, l-(4-CN)-phenyl, 1 -(4-Me)-phenyl, 5-(2-CF3)-pyridyl, l-(4- S02Me)-phenyl, 9-anthracenyl, l-(4-OMe)-phenyl, l-(4-F)-phenyl, 1 -(4-fl3u)-phenyl, l-(4-Et)- phenyl, 1 -(4-zPr)-phenyl, or N-Me-3-pyrrolyl;
R2 is H and R3 is C(=0)CH2NH2, S02NH2, C(=0)C(CH3)2NH2,
C(=0)C(cyclopropyl)NH2, C(=0)(CH2)2NH2, C(=0)CH(NH2)(4-imidazole), S02N(CH3)2, C(=0)CH2NH(CH3); or, R2, R3, and the nitrogen of Structural Formula (V) together form:
Figure imgf000070_0003
20. The method of claim 19, wherein the compound is:
2-amino-N-(4-(3 -isopropy l-6-(4-(trifluoromethy l)pheny 1)- lH-indol- 1 - yl)phenyl)acetamide (V-l);
2- amino-N-(4-(3-isopropyl-6-(4-(methylsulfonyl)phenyl)-lH-indol-l- yl)phenyl)acetamide (V-2);
3- (l-(4-(2-aminoacetamido)phenyl)-6-(4-(trifluoromethyl)phenyl)-lH-indol-3-yl)-N- methylpropanamide (V-3);
N-(4-(3-isopropyl-6-(4-(trifluoromethyl)phenyl)-lH-indol-l-yl)phenyl)-2- (methylamino)acetamide (V-4); (^-2-anTino-2-(lH-inTidazol-4-yl)-N-(4 3-isopropyl-6-(4-(trifluoromethyl)phenyl)-lH- indol- 1 -yl)phenyl)acetamide (V-5);
2- anTino-N-(4-(3-isopropyl-6-(4-(trifluoromethyl)phenyl)-lH-indol-l-yl)phenyl)-2- methylpropanamide (V-6);
1 -amino-N-(4-(3 -isopropy l-6-(4-(trifluoromethy l)pheny 1)- lH-indol- 1 - yl)phenyl)cyclopropane-l-carboxamide (V-7);
3- amino-N-(4-(3 -isopropy l-6-(4-(trifluoromethy l)pheny 1)- lH-indol- 1 - yl)phenyl)propanamide (V-8);
l-(l-(4-(3-isopropyl-6-(4-(trifluoromethyl)phenyl)-lH-indol-l-yl)phenyl)-lH-l,2,3- triazol-4-yl)-N,N-dimethylmethanamine (V-9);
N-(4-(3-isopropyl-6-(4-(trifluoromethyl)phenyl)-lH-indol-l- yl)phenyl)aminosulfonamide (V-10);
N-(4-(6-(4-cyanophenyl)-3-isopropyl-lH-indol-l-yl)phenyl)anTinosmfonamide (V-ll);
N-(4-(3-isopropyl-6-(p olyl)-lH-indol-l-yl)phenyl)aminosulfonamide (V-12);
N-(4-(3-isopropyl-6-(p olyl)-lH-indol-l-yl)phenyl)dimethylaminosmfonamide (V-13);
N-(4-(6-(4-(tert-bufyl)phenyl)-3-isopropyl-lH-indol-l-yl)phenyl)aminosulfonamide (V-
14);
N-(4-(6-(4-ethylphenyl)-3-isopropyl-lH-indol-l-yl)phenyl)aminosulfonamide (V-15); N-(4-(3-isopropyl-6-(4-isopropylphenyl)-lH-indol-l-yl)phenyl)aminosulfonamide (V-
16);
N-(4-(3-isopropyl-6-(4-methoxyphenyl)-lH-indol-l-yl)phenyl)aminosmfonamide (V-17); N-(4-(6-(4-fluorophenyl)-3 -isopropy l-lH-indol-l-yl)phenyl)aminosulfonamide (V-18); N-(4-(3-isopropyl-6-(4-(methylsulfonyl)phenyl)-lH-indol-l-yl)phenyl)aminosulfonamide
(V-19);
N-(4-(6-(anthracen-9-yl)-3 -isopropy l-lH-indol-l-yl)phenyl)aminosulfonamide (V-20); N-(4-(3-isopropyl-6-(6-(trifluoromethyl)pyridin-3-yl)-lH-indol-l- yl)phenyl)aminosulfonamide (V-21); or
N-(4-(3-isopropyl-6-(l-methyl-lH-pyrrol-3-yl)-lH-indol-l-yl)phenyl)aminosulfonamide
(V-22).
21. The method of claim 1, wherein the compound is represented by Structural Formula (VI):
Figure imgf000072_0001
wherein:
R1 is C1-C4 alkyl, C2-C6 cycloalkyl, or C1-C4 haloalkyl;
Ar is phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl, and Ar is optionally substituted with haloalkyl;
R2 is H and R3 is S02NH2, C(=0)CH2NH2, C(=0)CH2N(CH3)2,
C(=0)C(cyclopropyl)NH2, C(=0)C(CH3)2NH2i, C(=0)C≡CH, C(=0)CH2NH(CH3), C(=0)CH(NH2)CH(CH3)2, C(=0)CH(NH2)CH2CH(CH3)2, C(=0)CH(CH2Ph)NH2, C(=0)CH(CH3)NH(CH3), C(=0)CH[CH2CH(CH3)2]NH(CH3), C(=0)CH(CH2Ph)NH(CH3), C(=0)CH(CH2Ph)N(CH3)2; or, R2, R3, and the aniline nitrogen of Structural Formula (V) together form:
Figure imgf000072_0002
wherein R4 and R5 are optionally H or C1-C4 alkyl.
22. The method of claim 21, wherein the compound is represented by Structural Formula
(VII)
(VII)
Figure imgf000072_0003
wherein:
R is CF3 or cyclopropyl;
Ar is CF3-phenyl; and
R2 is H and R3 is C(=0)CH2NH2 or S02NH2.
23. The method of claim 22, wherein the compound is:
2-amino-N-(4-(3-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)-lH-indazol-l- yl)phenyl)acetamide (VII- 1);
2-amino-N-(4-(3-cyclopropyl-6-(4-(trifluoromethyl)phenyl)-lH-indazol-l- yl)phenyl)acetamide (VII-2);
N-(4-(3-cyclopropyl-6-(4-(trifluoromethyl)phenyl)-lH-indazol-l- yl)phenyl)aminosulfonamide (VII-3); or
N-(4-(3-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)- lH-indazol- 1 - yl)phenyl)aminosulfonamide (VII-4).
24. The method of claim 1, wherein the compound is represented by Structural Formula (VIII)
(VIII)
Figure imgf000073_0001
,
wherein:
R1 is C1-C4 alkyl, C2-C6 cycloalkyl, or C1-C4 haloalkyl;
Ar is phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl, and Ar is optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 haloalkyl;
R2 is Η and R3 is S02NH2, C(=0)CH2NH2, C(=0)CH2N(CH3)2,
C(=0)C(cyclopropyl)NH2, C(=0)C(CH3)2NH2i, C(=0)C≡CH, C(=0)CH2NH(CH3), C(=0)CH(NH2)CH(CH3)2, C(=0)CH(NH2)CH2CH(CH3)2, C(=0)CH(CH2Ph)NH2, C(=0)CH(CH3)NH(CH3), C(=0)CH[CH2CH(CH3)2]NH(CH3), C(=0)CH(CH2Ph)NH(CH3), C(=0)CH(CH2Ph)N(CH3)2; or, R2, R3, and the aniline nitrogen of Structural Formula (VIII) together form:
Figure imgf000073_0002
wherein R4 and R5 are optionally H or C1-C4 alkyl.
25. The method of claim 24, wherein the compound is represented by Structural Formula (IX):
Figure imgf000074_0001
wherein:
R1 is CF3;
Ar is phenanthryl; and
R2 is H and R3 is C(=0)CH2NH2 or S02NH2.
26. The method of claim 25, wherein the compound is:
2-amino-N-(4-(6-(phenanthren-2-yl)-4-(trifluoromethyl)pyridin-2-yl)phenyl)acetamide
(IX- 1); or
N-(4-(6-(phenanthren-2-yl)-4-(trifluoromethyl)pyridin-2-yl)phenyl)aminosulfonamide
(IX-2).
27. The method of claim 1, wherein the com ound is represented by Structural Formula (X):
(X)
Figure imgf000074_0002
,
wherein:
R1 is C1-C4 alkyl, C2-C6 cycloalkyl, or C1-C4 haloalkyl;
Ar is phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl, and Ar is optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 haloalkyl; and
R2 is H and R3 is S02NH2, C(=0)CH2NH2, C(=0)CH2N(CH3)2,
C(=0)C(cyclopropyl)NH2, C(=0)C(CH3)2NH2i, C(=0)C≡CH, C(=0)CH2NH(CH3),
C(=0)CH(NH2)CH(CH3)2, C(=0)CH(NH2)CH2CH(CH3)2, C(=0)CH(CH2Ph)NH2,
C(=0)CH(CH3)NH(CH3), C(=0)CH[CH2CH(CH3)2]NH(CH3), C(=0)CH(CH2Ph)NH(CH3), C(=0)CH(CH2Ph)N(CH3)2; or, R2, R3, and the aniline nitrogen of Structural Formula (X) together form:
Figure imgf000075_0001
wherein R4 and R5 are optionally H or C1-C4 alkyl.
28. The method of claim 27, wherein the compound is represented by Structural Formula (XI):
(XI)
Figure imgf000075_0002
wherein:
R1 is CF3;
Ar is anthracenyl, phenanthryl, CF3-biphenyl, CF3-phenyl, or Br-phenyl;
R2 is H and R3 is S02NH2, C(=0)CH2NH2, C(=0)CH2NH(CH3), C(=0)CH2N(CH3)2, C(=0)CH[CH2CH(CH3)2]NH(CH3), C(=0)CH[CH(CH3)2]NH(CH3); or, or, R2, R3, and the aniline nitrogen of Structural Formula (XI) together form:
Figure imgf000075_0003
29. The method of claim 28, wherein the compound is:
2-amino-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-imidazol-l- yl)phenyl)acetamide (XI-1);
2-aniino-N-(4-(4-(trifluoromethyl)-2-(4'-(trifluoromethyl)-[l,r-biphenyl]-4-yl)-lH- imidazol- 1 -y l)pheny l)acetamide (XI-2);
2-amino-N-(4-(2-(4-bromopheny l)-4-(trifluoromethy 1)- lH-imidazol- 1 - yl)phenyl)acetamide (XI-3);
2-amino-N-(4-(4-(trifluoromethyl)-2-(4-(trifluoromethyl)phenyl)-lH-imidazol-l- yl)phenyl)acetamide (XI-4);
2-(dimethy lamino)-N-(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- lH-imidazol- 1 - yl)phenyl)acetamide (XI-5); 2-(methylamino)-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-imidazol-l - yl)phenyl)acetamide (XI-6);
(^-4-methyl-2-(methylamino)-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH- imidazol-1 -yl)phenyl)pentanamide (XI- 7);
(i?)-3-methyl-2-(methylamino)-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH- imidazol-1 -yl)phenyl)butanamide (XI-8);
NN-dimethy 1- 1 -(1 -(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- lH-imidazol- 1 - yl)phenyl)-lH-l ,2,3-triazol-4-yl)methanamine (XI-9);
N-(4-(2-(anthracen-9-yl)-4-(trifluoromethyl)-lH-imidazol-l -yl)phenyl)aminosulfonamide (XI-10);
N-(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- lH-imidazol- 1 - yl)phenyl)aminosulfonamide (XI-11);
N-(4-(4-(trifluoromethy l)-2-(4-(trifluoromethy l)pheny 1)- lH-imidazol- 1 - yl)phenyl)aminosulfonamide (XI- 12);
N-(4-(4-(trifluorome l)-2-(4'-(trifluoromethyl)-[l,r-biphenyl]-4-yl)-lH-imidazol-l - yl)phenyl)aminosulfonamide (XI- 13);
(^-2-amino-N-(4 2 phenanthren-2-yl)-4-(trifluoromethyl)-lH-imidazol-l-yl)phenyl)-3- phenylpropanamide (XI-14);
N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-imidazol-l -yl)phenyl)propiolamide (XI-15);
2-amino-N-(4-(2 3^5'-dimethyl-[lJ '-biphenyl]-4-yl)-4-(trifluoromethyl)-lH-imidazol-l - yl)phenyl)acetamide (XI-16);
2-amino-N-(4-(2-(3^5'-dimethoxy-[l J'-biphenyl]-4-yl)-4-(trifluorome l)-lH-imidazol- l -yl)phenyl)acetamide (XI-17);
2-amino-N-(4-(2-(naphthalen-2-yl)-4-(trifluoromethyl)-lH-imidazol-l - yl)phenyl)acetamide (XI-18);
2-amino-N-(4-(2-(naphthalen-l -yl)-4-(trifluoromethyl)-lH-imidazol-l - yl)phenyl)acetamide (XI-19);
2-amino-N-(4-(2-(3^5'-bis(trifluoromethyl) 14'-biphenyl]-4-yl)-4 trifluoromethyl)-lH- imidazol-l-yl)phenyl)acetamide (XI-20); or
N-(4 2-(3 5'-bis(trifluoromethyl) 1J'-biphenyl]-4-yl)-4-(trifluoromethyl)-lH-imidazol- 1 -yl)phenyl)-2-(methylamino)acetamide (XI-21).
30. The method of claim 1, wherein the compound is represented by Structural Formula
(xii) (XII)
Figure imgf000077_0001
wherein
R1 is C1-C4 alkyl, C2-C6 cycloalkyl, C1-C4 haloalkyl, or an optionally alkylated alkyl amide;
Ar is phenanthryl, anthracenyl, biphenyl, phenyl, or naphthyl, and Ar is optionally substituted with halogen, C1-C4 alkyl, C1-C4 alkoxy, or C1-C4 haloalkyl; and
R2 is H and R3 R2' is H, and R3' is sulfonamide, sulfanamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl other than glycine, a β-amino carbonyl, a γ-amino carbonyl, or an α-β-unsaturated carbonyl; or, R2, R3, and the aniline nitrogen of Structural Formula (XII) together form:
Figure imgf000077_0002
wherein R4 and R5 are optionally H or C1-C4 alkyl.
31. The method of claim 30, wherein the compound is represented by Structural Formula
(XIII)
(XIII)
Figure imgf000077_0003
wherein
R1 is CH2CH2C(=0)NHCH3;
Ar is biphenyl optionally substituted with halogen or C1-C4 haloalkyl; and
R2 is H and R3 is S02NH2, C(=0)CH2NH2, C(=0)CH2NH(CH3), C(=0)CH2N(CH3)2, C(=0)CH[CH2CH(CH3)2]NH(CH3), or C(=0)CH[CH(CH3)2]NH(CH3).
32. The method of claim 31, wherein the compound is 3-(l-(4-(2-aminoacetamido)phenyl)-5- (4'-(trifluoromethy 1)- [1,1 '-bipheny 1] -4-y 1)- IH-py razol-3 -y l)-N-methy Ipropanamide (XIII- 1).
33. The method of claim 1, wherein Het is one of: pyrrole, imidazole, triazole, tetrazole, oxazole, thiazole, indole, indazole, benzimidazole, benzoxazole, benzothiazole, carbazole, quinoline, isoquinoline, quinoxaline, quinazoline, pyridine, pyrazine, pyrimidine, and triazine.
34. The method of claim 1, wherein R1 is H, C1-C4 alkyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C3-C6 halocycloalkyl, halogen, nitrile, alkyl amide, or nitro.
35. The method of claim 1, wherein R1 is CF3, isopropyl, cyclopropyl, or
-(CH2)2C(0)NH(CH3).
36. The method of claim 1, wherein R2 is H, and:
R3 is S02NH2, S02NH(CH3), S02N(CH3)2, S(=0)-Ci-C4 alkyl amine, S02-Ci-C4 alkyl amine, C(=0)CH2NH2, C(=0)CH2N(CH3)2, C(=0)CH2NH(CH3), C(=0)(CH2)2NH2,
C(=0)(CH2)3NH2, C(=0)C(CH3)2NH2, C(=0)CH(NH2)(4-imidazole),
C(=0)CH(NH2)CH(CH3)2, C(=0)CH(NH2)CH2CH(CH3)2, C(=0)CH[CH2CH(CH3)2]NH(CH3), C(=0)CH(CH2Ph)NH2, C(=0)CH(CH2Ph)NH(CH3), C(=0)CH(CH2Ph)N(CH3)2,
C(=0)CH(CH3)NH(CH3), C(=0)C(cyclopropyl)NH2, C(=0)C≡CH, or C(=0)CHCH2; or
R3, together with the aniline nitrogen of Structural Formula (I) to which R3 is bonded, represents an amide-bonded: glycine, alanine, serine, threonine, cysteine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tyrosine, tryptophan, aspartic acid, glutamic acid, asparagine, glutamine, histidine, lysine, or arginine.
37. The method of claim 1, wherein the compound is represented by Structural Formula (XIV):
Figure imgf000078_0001
wherein: R4 and R5 are each independently: H, C1-C6 alkyl, C3-C6 cycloalkyl, or C1-C6 haloalkyl; and n is an integer from 1-6.
38. The method of claim 1, wherein R2, R3, and the aniline nitrogen of Structural Formula (I) together form an optionally substituted triazole or tetrazole.
39. The method of claim 38, wherein the triazole is substituted with an alkylamino group.
40. The method of claim 1, wherein Ar is an optionally substituted: phenyl, pyridinyl, pyrazinyl, pyrimidinyl, naphthalenyl, quinolinyl, isoquinolinyl, quinoxalyl, quinazolinyl, biphenyl, bipyridinyl, phenanthrenyl, phenanthrolinyl, anthracenyl, tetracenyl, phenalenyl, pyrenyl, chrysenyl, acridinyl, phenazinyl, carbazolyl, fluorenyl, dibenzofuran, indolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, indenyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, or tetrazolyl.
41. The method of claim 1, where Ar is optionally substituted with one or more of: C1-C6 alkyl, C3-C6 cycloalkyl, C1-C6 haloalkyl, C3-C6 halocycloalkyl, nitrile, C1-C6 alkylsulfone, alkyl sulfoxide, Ci-Ce O-alkyl, O-phenyl, Ci-C6 NH-alkyl, C2-C12 N-alkyl2, hydroxyl, NH2, halogen, dioxole, dioxolane, N02, aldehyde, C2-C7 alkyl or aryl ketone, C2-C7 alkyl or aryl ester, C2-C? alkyl or aryl amide, guanidine, amidine, N-OH amidine, urea, imide, oxime, hydrazone, and hydrazide.
42. The method of claim 1, where Ar is optionally substituted with one or more of: methyl, ethyl, isopropyl, tertbutyl, CF3, CN, methoxy, S(0)2-Ci-C4 alkyl, Br, and F.
43. The method of claim 1, provided that when the compound is represented by Structural Formula (Γ):
( )
Figure imgf000079_0001
wherein R1' is trifluoromethyl; Ar' is 2-phenanthrenyl; R2' is H, and R3' is one of:
CONH2, C(=NH)NH2, C(=0)CH2NH2, CH2C(=0)NH2, C(=0)-(para-phenylene)-S02NH2, C(=0)CH2NHC(=NH)NH2, and C(=0)CH2NHCO-phenyl,
the fungus is not one of: Candida albicans, Cryptococcus neoformans, Cryptococcus gattii, Candida tropicalis, Candida krusei, Candida glabrata, Candida dubliniesis, and Candida parapsilosis.
44. The method of claim 1, provided that when the fungus is one of: Candida albicans, Cryptococcus neoformans, Cryptococcus gattii, Candida tropicalis, Candida krusei, Candida glabrata, Candida dubliniesis, and Candida parapsilosis, the compound is represented by Structural Formula (Γ):
Figure imgf000080_0001
wherein:
R1 ' is H, cycloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro;
Ar' is optionally substituted and is one of: tetracene, phenalenyl, pyrenyl, chrysenyl, phenanthrolinyl, acridinyl, phenazinyl, carbazolyl, dibenzofuranyl, quinolinyl, isoquinolinyl, quinoxalyl, quinazolinyl, bipyridyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, and indenyl;
R2' is H, and R3' is sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl other than glycine, a β-amino carbonyl, a γ-amino carbonyl, or an α-β-unsaturated carbonyl; or, R2', R3', and the aniline nitrogen of Structural Formula (Γ) together form an optionally substituted heterocyclic group.
45. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier or excipient;
an antifungal drug; and
a compound, represented by Structural Formula (I):
(I)
Figure imgf000080_0002
and pharmaceutically acceptable salts thereof,
wherein:
R1 is H, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro;
R2 is H and R3 is: sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl, a β-amino carbonyl, a γ-amino carbonyl, an α-β-unsaturated carbonyl, guanidine, or urea; or, the aniline nitrogen of Structural Formula (I), R2, and R3 together form an optionally substituted heterocyclic group; Ar is an optionally substituted aryl or heteroaryl group consisting of 1, 2, 3, or 4 rings that are one or more of linked and fused;
Het is a heteroaryl group comprising a first ring that is a nitrogen-containing, five or six- membered heteroaryl group, the first ring being optionally fused to one or more of a second ring and a third ring to form a bi cyclic or tricyclic heteroaryl group consisting of 8, 9, 10, 1 1 , 12, or 13 ring atoms, wherein R1 and phenyl ring A are bonded to the first ring, and Ar is bonded to the first ring, the second ring, or the third ring.
46. The pharmaceutical composition of claim 45, wherein the compound is one of III-l to 111-39, V-l to V-22, VII-1 to VII-4, IX- 1, IX-2, XI-1 to XI-21, or XIII-1:
2-amino-N-(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)acetamide (III-l);
2-amino-N-(4-(2-(phenanthren-3-yl)-4-(trifluoromethyl)-lH-pyrrol-l - yl)phenyl)acetamide (III-2);
2-amino-N-(4-(2-(naphthalen-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l-yl)phenyl)acetamide
(III-3);
2-amino-N-(4-(2-(naphthalen-l -yl)-4-(trifluoromethyl)-lH-pyrrol-l-yl)phenyl)acetamide
(III-4);
2-amino-N-(4-(4-(trifluoromethy l)-2-(4-(trifluoromethy l)pheny 1)- lH-pyrrol- 1 - yl)phenyl)acetamide (III-5);
N-(4-(2-([ 1 , 1 '-bipheny 1] -4-y l)-4-(trifluoromethy 1)- lH-pyrrol- 1 -y l)pheny l)-2- aminoacetamide (III-6);
2-amino-N-(4-(4-(trifluoromethyl)-2-(4'-(trifluoromethyl)-[l,r-biphenyl]-4-yl)-lH- py rrol- 1 -y l)pheny l)acetamide (III-7);
2-amino-N-(4-(2-(3 ',5'-dimethy l-[ 1 , 1 '-bipheny 1] -4-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)acetamide (III-8);
2-amino-N-(4-(2-(3',5'-dimethoxy-[l,r-biphenyl]-4-yl)-4-(trifluoromethyl)-lH-pyrrol-l- yl)phenyl)acetamide (III-9);
2-(methy lamino)-N-(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)acetamide (III- 10);
2-(methylamino)-N-(4-(2-(naphthalen-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l- yl)phenyl)acetamide (III-ll);
2-(methylamino)-N-(4-(2-(naphthalen-l -yl)-4-(trifluoromethyl)-lH-pyrrol-l- yl)phenyl)acetamide (III- 12);
N-(4-(2-([ 1 , 1 '-bipheny 1] -4-y l)-4-(trifluoromethy 1)- lH-pyrrol- 1 -y l)pheny l)-2- (methylamino)acetamide (III- 13); N-(4-(2-(3',5'-dimethyl-[l,r-biphenyl]-4-yl)-4-(trifluoromethyl)-lH-pyrrol-l-yl)phenyl)- 2-(methylamino)acetamide (111-14);
N-(4-(2-(3',5'-dimethoxy-[l,r-biphenyl]-4-yl)-4-(trifluoromethyl)-lH-pyrrol-l- yl)phenyl)-2-(methylamino)acetamide (111-15);
2-(dimethy lamino)-N-(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)acetamide (III- 16);
2-(dimethy lamino)-N-(4-(2-(naphthalen-2-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)acetamide (111-17);
(^-2-amino-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l-yl)phenyl)-3- phenylpropanamide (III- 18);
(5 -2-(methy lamino)-N-(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)-3-phenylpropanamide (III- 19);
(5 -2-(methy lamino)-N-(4-(2-(naphthalen-2-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)-3-phenylpropanamide (111-20);
(i?)-2-(dimethy lamino)-N-(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)-3-phenylpropanamide (111-21);
(i?)-2-amino-4-methy l-N-(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)pentanamide (111-22);
(i?)-4-methyl-2-(methylamino)-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH- pyrrol- 1 -yl)phenyl)pentanamide (111-23);
(^-4-methyl-2-(methylamino)-N-(4-(2-(naphthalen-2-yl)-4-(trifluoromethyl)-lH-pyrrol- l-yl)phenyl)pentanamide (111-24);
(i?)-2-amino-3 -methy l-N-(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)butanamide (111-25);
(i?)-2-amino-3 -methy l-N-(4-(2-(naphthalen-2-yl)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)butanamide(III-26);
(i?)-2-(methy lamino)-N-(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)propanamide (111-27);
2-amino-2-methy l-N-(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)propanamide (111-28);
2-amino-2-methyl-N-(4-(2-(naphthalen-2-yl)-4-(trifluoromethyl)-lH-pyrrol-l- yl)phenyl)propanamide (111-29);
1 -amino-N-(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- lH-py rrol- 1 - yl)phenyl)cyclopropane-l-carboxamide (111-30); l-amino-N-(4-(4-(trifluorome l)-2-(4'-(trifluoromethyl)-[l,r-biphenyl]-4-yl)-lH- pyrrol-l-yl)phenyl)cyclopropane-l-carboxamide (111-31);
N-(4-(4-(trifluoromethy l)-2-(4'-(trifluoromethy 1)- [ 1 , 1 '-bipheny 1] -4-y 1)- IH-py rrol- 1 - yl)phenyl)propiolamide (111-32);
NN-dimethy 1- 1 -(1 -(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- IH-py rrol- 1 -y l)pheny 1)- lH-l,2,3-triazol-4-yl)methanamine (111-33);
1- (l-(4-(2-(anthracen-9-yl)-4-(trifluoromethyl)-lH-pyrrol-l-yl)phenyl)-lH-l,2,3-triazol- 4-yl)-NN-dimethylmethanamine (111-34);
NN-dimethy 1- 1 -(1 -(4-(4-(trifluoromethy l)-2-(4'-(trifluoromethy l)-[ 1 , 1 '-bipheny 1] -4-y 1)- lH-pyrrol-l-yl)phenyl)-lH-l,2,3-triazol-4-yl)methanamine (111-35);
N-(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- IH-py rrol- 1 -y l)pheny l)aminosulfonamide (111-36);
N-(4-(2-(phenanthren-3-yl)-4-(trifluoromethyl)-lH-pyrrol-l-yl)phenyl)aminosulfonamide (111-37);
N-(4-(2-(anthracen-9-yl)-4-(trifluoromethyl)-lH-pyrrol-l-yl)phenyl)aminosulfonamide (111-38);
N-(4-(4-(trifluoromethy l)-2-(4'-(trifluoromethy 1)- [ 1 , 1 '-bipheny 1] -4-y 1)- IH-py rrol- 1 - yl)phenyl)aminosulfonamide (111-39);
2- amino-N-(4-(3 -isopropy l-6-(4-(trifluoromethy l)pheny 1)- lH-indol- 1 - yl)phenyl)acetamide (V-l);
2- amino-N-(4-(3-isopropyl-6-(4-(methylsulfonyl)phenyl)-lH-indol-l- yl)phenyl)acetamide (V-2);
3- (l-(4-(2-aminoacetamido)phenyl)-6-(4-(trifluoromethyl)phenyl)-lH-indol-3-yl)-N- methylpropanamide (V-3);
N-(4-(3-isopropyl-6-(4-(trifluoromethyl)phenyl)-lH-indol-l-yl)phenyl)-2- (methylamino)acetamide (V-4);
(^-2-amino-2-(lH-imidazol-4-yl)-N-(4-(3-isopropyl-6-(4-(trifluoromethyl)phenyl)-lH- indol- 1 -yl)phenyl)acetamide (V-5);
2- amino-N-(4-(3 -isopropy l-6-(4-(trifluoromethyl)phenyl)-lH-indol-l-yl)phenyl)-2- methylpropanamide (V-6);
1 -amino-N-(4-(3 -isopropy l-6-(4-(trifluoromethy l)pheny 1)- lH-indol- 1 - yl)phenyl)cyclopropane-l-carboxamide (V-7);
3- amino-N-(4-(3 -isopropy l-6-(4-(trifluoromethy l)pheny 1)- lH-indol- 1 - yl)phenyl)propanamide (V-8); 1- (l-(4-(3-isopropyl-6-(4-(trifluoromethyl)phenyl)-lH-indol-l-yl)phenyl)-lH-l,2,3- triazol-4-yl)-N,N-dimethylmethanamine (V-9);
N-(4-(3-isopropyl-6-(4-(trifluoromethyl)phenyl)-lH-indol-l- yl)phenyl)aminosulfonamide (V-10);
N-(4-(6-(4-cyanophenyl)-3-isopropyl-lH-indol-l-yl)phenyl)aminosulfonamide (V-ll); N-(4-(3-isopropyl-6-(p olyl)-lH-indol-l-yl)phenyl)aminosulfonamide (V-12);
N-(4-(3-isopropyl-6-(p olyl)-lH-indol-l-yl)phenyl)dimethylaminosulfonamide (V-13); N-(4-(6-(4-(tert-butyl)phenyl)-3-isopropyl-lH-indol-l-yl)phenyl)aminosulfonamide (V-
14);
N-(4-(6-(4-ethylphenyl)-3-isopropyl-lH-indol-l-yl)phenyl)aminosulfonamide (V-15); N-(4-(3-isopropyl-6-(4-isopropylphenyl)-lH-indol-l-yl)phenyl)aminosulfonamide (V-
16);
N-(4-(3-isopropyl-6-(4-methoxyphenyl)-lH-indol-l-yl)phenyl)aminosulfonamide (V-17); N-(4-(6-(4-fluorophenyl)-3-isopropyl-lH-indol-l-yl)phenyl)aminosulfonamide (V-18); N-(4-(3-isopropyl-6-(4-(methylsulfonyl)phenyl)-lH-indol-l-yl)phenyl)aminosulfonamide
(V-19);
N-(4-(6-(anthracen-9-yl)-3-isopropyl-lH-indol-l-yl)phenyl)aminosulfonamide (V-20); N-(4-(3-isopropyl-6-(6-(trifluoromethyl)pyridin-3-yl)-lH-indol-l- yl)phenyl)aminosulfonamide (V-21);
N-(4-(3-isopropyl-6-(l-methyl-lH-pyrrol-3-yl)-lH-indol-l-yl)phenyl)aminosulfonamide
(V-22);
2- amino-N-(4-(3-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)-lH-indazol-l- yl)phenyl)acetamide (VII- 1);
2-amino-N-(4-(3-cyclopropyl-6-(4-(trifluoromethyl)phenyl)-lH-indazol-l- yl)phenyl)acetamide (VII-2);
N-(4-(3-cy clopropyl-6-(4-(trifluoromethyl)phenyl)- lH-indazol- 1 - yl)phenyl)aminosulfonamide (VII-3);
N-(4-(3-(trifluoromethyl)-6-(4-(trifluoromethyl)phenyl)- lH-indazol- 1 - yl)phenyl)aminosulfonamide (VII-4);
2-amino-N-(4-(6-(phenanthren-2-yl)-4-(trifluoromethyl)pyridin-2-yl)phenyl)acetamide
(IX-1);
N-(4-(6-(phenanthren-2-yl)-4-(trifluoromethyl)pyridin-2-yl)phenyl)aminosulfonamide
(IX-2);
2-amino-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-imidazol-l- yl)phenyl)acetamide (XI-1); 2-amino-N-(4-(4-(trifluoromethyl)-2-(4'-(trifluoromethyl)-[l,r-biphenyl]-4-yl)-lH- imidazol- 1 -y l)pheny l)acetamide (XI-2);
2-amino-N-(4-(2-(4-bromopheny l)-4-(trifluoromethy 1)- lH-imidazol- 1 - yl)phenyl)acetamide (XI-3);
2-amino-N-(4-(4-(trifluoromethyl)-2-(4-(trifluoromethyl)phenyl)-lH-imidazol-l- yl)phenyl)acetamide (XI-4);
2-(dimethy lamino)-N-(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- lH-imidazol- 1 - yl)phenyl)acetamide (XI-5);
2-(methylamino)-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-imidazol-l- yl)phenyl)acetamide (XI-6);
(^-4-methyl-2-(methylamino)-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH- imidazol-1 -yl)phenyl)pentanamide (XI- 7);
(i?)-3-methyl-2-(methylamino)-N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH- imidazol-1 -yl)phenyl)butanamide (XI-8);
NN-dimethy 1- 1 -(1 -(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- lH-imidazol- 1 - yl)phenyl)-lH-l,2,3-triazol-4-yl)methanamine (XI-9);
N-(4-(2-(anthracen-9-yl)-4-(trifluoromethyl)-lH-imidazol-l-yl)phenyl)aminosulfonamide (XI-10);
N-(4-(2-(phenanthren-2-y l)-4-(trifluoromethy 1)- lH-imidazol- 1 - yl)phenyl)aminosulfonamide (XI-11);
N-(4-(4-(trifluoromethy l)-2-(4-(trifluoromethy l)pheny 1)- lH-imidazol- 1 - yl)phenyl)aminosulfonamide (XI- 12);
N-(4-(4-(trifluorome l)-2-(4'-(trifluoromethyl)-[l,r-biphenyl]-4-yl)-lH-imidazol-l- yl)phenyl)aminosulfonamide (XI- 13);
(^-2-amino-N-(4 2 phenanthren-2-yl)-4-(trifluoromethyl)-lH-imidazol-l-yl)phenyl)-3- phenylpropanamide (XI-14);
N-(4-(2-(phenanthren-2-yl)-4-(trifluoromethyl)-lH-imidazol-l-yl)phenyl)propiolamide (XI-15);
2-amino-N-(4-(2 3^5'-dimethyl-[lJ'-biphenyl]-4-yl)-4-(trifluoromethyl)-lH-imidazol-l- yl)phenyl)acetamide (XI-16);
2-amino-N-(4-(2-(3^5'-dimethoxy-[lJ'-biphenyl]-4-yl)-4-(trifluorome l)-lH-imidazol- l-yl)phenyl)acetamide (XI-17);
2-amino-N-(4-(2-(naphthalen-2-yl)-4-(trifluoromethyl)-lH-imidazol-l- yl)phenyl)acetamide (XI-18); 2-amino-N-(4-(2-(naphthalen-l-yl)-4-(trifluoromethyl)-lH-imidazol-l- yl)phenyl)acetamide (XI-19);
2- amino-N-(4-(2-(3^5'-bis(trifluorome ^
imidazol- 1 -y l)pheny l)acetamide (XI-20);
N-(4 2-(3 5'-bis(trifluoromethyl) 1,r-biphenyl]-4-yl)-4-(trifluoromethyl)-lH-imidazol- l-yl)phenyl)-2-(methylamino)acetamide (XI-21); or
3- (l -(4-(2-aminoacetamido)phenyl)-5-(4'-(trifluoromethyl)-[ 1 , 1 '-biphenyl] -4-yl)- 1H- pyrazol-3-yl)-N-methylpropanamide (XIII-1).
47. A kit, comprising:
instructions, the instructions directing a user to:
provide a subject that has a fungal infection or is at risk of the fungal infection; and
administer a compound to the subject in an amount effective to mitigate the fungal infection in the subject;
the compound, represented by Structural Formula (I):
Figure imgf000086_0001
and pharmaceutically acceptable salts thereof,
wherein:
R1 is H, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro;
R2 is H and R3 is: sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl, a β-amino carbonyl, a γ-amino carbonyl, an α-β-unsaturated carbonyl, guanidine, or urea; or, the aniline nitrogen of Structural Formula (I), R2, and R3 together form an optionally substituted heterocyclic group;
Ar is an optionally substituted aryl or heteroaryl group consisting of 1, 2, 3, or 4 rings that are one or more of linked and fused;
Het is a heteroaryl group comprising a first ring that is a nitrogen-containing, five or six- membered heteroaryl group, the first ring being optionally fused to one or more of a second ring and a third ring to form a bi cyclic or tricyclic heteroaryl group consisting of 8, 9, 10, 11, 12, or 13 ring atoms, wherein R1 and phenyl ring A are bonded to the first ring, and Ar is bonded to the first ring, the second ring, or the third ring; provided that when the compound is re resented b :
Figure imgf000087_0001
one or more of:
the kit further comprises an antifungal drug and the instructions direct the user to co-administer the compound and the antifungal drug to the subject;
R1' is H, cycloalkyl, halocycloalkyl, halogen, nitrile, alkyl amide, or nitro;
Ar' is optionally substituted and is one of: tetracene, phenalenyl, pyrenyl, chrysenyl, phenanthrolinyl, acridinyl, phenazinyl, carbazolyl, dibenzofuranyl, quinolinyl, isoquinolinyl, quinoxalyl, quinazolinyl, bipyridyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, and indenyl;
R2' is H, and R3' is sulfonamide, sulfinamide, alkylamino sulfone, alkylamino sulfoxide, an a-amino carbonyl other than glycine, a β-amino carbonyl, a γ-amino carbonyl, or an α-β-unsaturated carbonyl; or, the aniline nitrogen of Structural Formula (Γ), R2, and R3 together form an optionally substituted heterocyclic group.
48. The kit of claim 47, further comprising the antifungal drug, the instructions further directing the user to co-administer the compound and the antifungal drug to the subject.
49. The kit of claim 47, the instructions directing the user to conduct the method of any of claims 1-45.
50. The kit of claim 47, comprising the pharmaceutical composition of claims 45 or 46.
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WO2018186365A1 (en) * 2017-04-03 2018-10-11 京都薬品工業株式会社 Read-through inducing agent and pharmaceutical application thereof
JP2022535613A (en) * 2019-06-25 2022-08-09 エムティックスバイオ カンパニー リミテッド Novel derivative compound in which biphenyl group is introduced into aminoalkanoic acid, and antifungal pharmaceutical composition containing the same
JP7290361B2 (en) 2019-06-25 2023-06-13 エムティックスバイオ カンパニー リミテッド Novel derivative compound in which biphenyl group is introduced into aminoalkanoic acid, and antifungal pharmaceutical composition containing the same
US11117888B2 (en) * 2020-01-22 2021-09-14 China Medical University Irreversible inhibitors of pyruvate kinase M2 and the use thereof
WO2021263278A1 (en) * 2020-06-23 2021-12-30 The Scripps Research Institute Rev-erb agonists for the treatment of th17-mediated inflammatory disorders

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