WO2018045106A1 - Traitement antifongique - Google Patents

Traitement antifongique Download PDF

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Publication number
WO2018045106A1
WO2018045106A1 PCT/US2017/049493 US2017049493W WO2018045106A1 WO 2018045106 A1 WO2018045106 A1 WO 2018045106A1 US 2017049493 W US2017049493 W US 2017049493W WO 2018045106 A1 WO2018045106 A1 WO 2018045106A1
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Prior art keywords
compound
optionally substituted
pharmaceutical composition
alkyl
represented
Prior art date
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PCT/US2017/049493
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English (en)
Inventor
Karl A. Werbovetz
David W. Boykin
Chad A. RAPPLEYE
Abdelbasset FARAHAT
Ahmed ABDELHAMEED
Ching-Shih Chen
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Georgia State University Research Foundation Inc
Ohio State Innovation Foundation
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Georgia State University Research Foundation Inc
Ohio State Innovation Foundation
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Publication of WO2018045106A1 publication Critical patent/WO2018045106A1/fr
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    • 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
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin

Definitions

  • Fungal infections continue to be major causes of morbidity and mortality, particularly for vulnerable subjects with compromised or suppressed immune systems.
  • Most fungal infections e.g., aspergillosis, cryptococcosis, and histoplasmosis
  • Candidiasis often occurs in hospital settings since at-risk patients are often under inpatient care.
  • 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, individuals receiving anti-inflammatory therapeutics such as TNF-alpha blockers (e.g., Enbrel), burn patients, and the like.
  • TNF-alpha blockers e.g., Enbrel
  • 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 the like.
  • azoles such as fluconazole, itraconazole, and voriconazole
  • polyenes such as Amphotericin B, nystatin, and natamycin
  • echinocandins such as caspofungin
  • 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, long treatment durations that impact patient compliance, 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 anti-fungal treatment in a subject in need thereof may include providing the subject, the subject being infected by a fungus or at risk of infection by the fungus.
  • the method may include administering a compound to the subject in an amount effective to mitigate infection by the fungus in the subject.
  • the compound may be represented by Structural Formula (Ia):
  • Ar may be an optionally substituted aryl or nitrogen-containing heteroaryl.
  • R 1 and R 2 may independently be H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloalkyl, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted C 1 -C 14 alkyl or optionally substituted C 2 -C 14 alkenyl, e.g., optionally substituted C 1 -C 10 alkyl or optionally substituted C 2 - C 10 alkenyl, or optionally substituted C 1 -C 8 alkyl or optionally substituted C 2 -C 8 alkenyl.
  • Het 2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
  • a method of anti-fungal treatment in a subject in need thereof may include providing the subject, the subject being infected by a fungus or at risk of infection by the fungus.
  • the method may include administering a compound to the subject in an amount effective to mitigate infection by the fungus in the subject.
  • the compound may be represented by Structural Formula (I):
  • Het 1 may be an optionally substituted, nitrogen- containing heteroaryl.
  • R 1 and R 2 may independently be H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings.
  • Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloalkyl, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted C 1 -C 10 alkyl or optionally substituted C 2 -C 10 alkenyl.
  • Het 2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
  • a pharmaceutical composition may include a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition may include a compound represented by Structural Formula (Ia):
  • Ar may be an optionally substituted aryl or nitrogen-containing heteroaryl.
  • R 1 and R 2 may independently be H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloalkyl, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted C 1 -C 14 alkyl or optionally substituted C 2 -C 14 alkenyl, e.g., optionally substituted C 1 -C 10 alkyl or optionally substituted C 2 -C 10 alkenyl, or optionally substituted C 1 -C 8 alkyl or optionally substituted C 2 -C 8 alkenyl.
  • Het 2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
  • a pharmaceutical composition may include a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition may include a compound represented by Structural Formula (I):
  • Het 1 may be an optionally substituted, nitrogen- containing heteroaryl.
  • R 1 and R 2 may independently be H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings.
  • Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloalkyl, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted C 1 -C 10 alkyl or optionally substituted C 2 -C 10 alkenyl.
  • Het 2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
  • kits for anti-fungal treatment of a subject in need thereof may include any anti-fungal compound described herein, for example, the compound represented by Structural Formula (Ia):
  • Ar may be an optionally substituted aryl or nitrogen-containing heteroaryl.
  • R 1 and R 2 may independently be H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloalkyl, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted C 1 -C 14 alkyl or optionally substituted C 2 -C 14 alkenyl, e.g., optionally substituted C 1 -C 10 alkyl or optionally substituted C 2 -C 10 alkenyl, or optionally substituted C 1 -C 8 alkyl or optionally substituted C 2 -C 8 alkenyl.
  • Het 2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
  • the kit may include instructions. The instructions may direct a user to provide the subject, the subject being infected by a fungus or at risk of infection by the fungus. The instructions may direct a user to administer the compound or the pharmaceutical composition to the subject in an amount effective to mitigate infection by the fungus in the subject.
  • kits for anti-fungal treatment of a subject in need thereof may include any anti-fungal compound described herein, for example, the compound represented by Structural Formula (I):
  • Het 1 may be an optionally substituted, nitrogen-containing heteroaryl.
  • R 1 and R 2 may independently be H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloalkyl, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • the kit may include instructions.
  • the instructions may direct a user to provide the subject, the subject being infected by a fungus or at risk of infection by the fungus.
  • the instructions may direct a user to administer the compound or the pharmaceutical composition to the subject in an amount effective to mitigate infection by the fungus in the subject.
  • FIG. 1A is a synthetic scheme for various phenoxyalkyl linker anti-fungal compounds.
  • FIG.1B is a synthetic scheme for various phenoxyalkyl hybrid target compounds substituted meta to the arylimidamide group.
  • FIG. 1C is a synthetic scheme for various phenoxyalkyl hybrid target compounds substituted ortho to the arylimidamide group.
  • FIG. 1D is a synthetic scheme for various phenoxyalkyl hybrid target compounds substituted with pyrrole.
  • FIG. 2A is a synthetic scheme for various phenyl-unsubstituted diphenylfuran alkyloxy linker hybrid compounds.
  • FIG. 2B is a synthetic scheme for various phenyl substituted diphenylfuran alkyloxy linker hybrid compounds.
  • FIG. 2C is a synthetic scheme for various phenyl substituted diphenylfuran alkyloxy linker hybrid compounds.
  • FIG. 2D is a prophetic synthetic scheme for various diphenylfuran alkyloxy linker hybrid compounds.
  • FIG. 3 is a prophetic synthetic scheme for various alkylamide linker hybrid compounds.
  • FIG. 4A is a prophetic synthetic scheme for various phenylalkyl linker hybrid compounds 8a and 8b.
  • FIG.4B is a synthetic scheme for various phenylalkyl linker hybrid compounds.
  • FIG. 5A is a synthetic scheme for various unsubstituted and substituted biphenyl linker anti-fungal compounds.
  • FIG. 5B is a synthetic scheme for various substituted biphenyl linker anti- fungal compounds.
  • FIG. 5C is a synthetic scheme for various substituted biphenyl linker anti- fungal compounds.
  • FIG. 5D is a synthetic scheme for various substituted biphenyl linker anti- fungal compounds.
  • FIG. 6A is a synthetic scheme for various phenyl-piperazinyl-phenyl linker anti-fungal compounds.
  • FIG. 6B is a synthetic scheme for various phenyl-piperazinyl linker anti-fungal compounds.
  • FIG. 7 is a table depicting IC 50 values of various compounds against Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans, and Histoplasma capsulatum.
  • FIG. 8A is a graph depicting relative fungal growth of Aspergillus fumigatus versus concentration in ⁇ M of various compounds.
  • FIG. 8B is a graph depicting relative fungal growth of Candida albicans versus concentration in ⁇ M of various compounds.
  • FIG. 8C is a graph depicting relative fungal growth of Cryptococcus neoformans versus concentration in ⁇ M of various compounds.
  • FIG. 8D is a graph depicting relative fungal growth of Histoplasma capsulatum versus concentration in ⁇ M of various compounds.
  • a method of anti-fungal treatment in a subject in need thereof may include providing the subject, the subject being infected by a fungus or at risk of infection by the fungus.
  • the method may include administering a compound to the subject in an amount effective to mitigate infection by the fungus in the subject.
  • the compound may be represented by Structural Formula (Ia):
  • Ar may be an optionally substituted aryl or nitrogen-containing heteroaryl.
  • R 1 and R 2 may independently be H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloalkyl, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted C 1 -C 14 alkyl or optionally substituted C 2 -C 14 alkenyl, e.g., optionally substituted C 1 -C 10 alkyl or optionally substituted C 2 -C 10 alkenyl, or optionally substituted C 1 -C 8 alkyl or optionally substituted C 2 -C 8 alkenyl.
  • Het 2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
  • a method of anti-fungal treatment in a subject in need thereof may include providing the subject, the subject being infected by a fungus or at risk of infection by the fungus.
  • the method may include administering a compound to the subject in an amount effective to mitigate infection by the fungus in the subject.
  • the compound may be represented by Structural Formula (I):
  • Het 1 may be an optionally substituted, nitrogen- containing heteroaryl.
  • R 1 and R 2 may independently be H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloalkyl, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted C 1 -C 10 alkyl or optionally substituted C 2 -C 10 alkenyl.
  • Het 2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
  • the method may include administering the compound represented by Structural Formula (I) or (Ia) in the form of any pharmaceutical composition described herein.
  • 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 infection by the fungus in the subject. Additionally or alternatively, the subject may be at risk of infection by the fungus.
  • the method may include administering the compound to the subject in an amount effective to mitigate infection or re-infection of the subject by the fungus.
  • the fungus may include CYP51.
  • the fungus may include at least two distinct cytochrome P450 mediated biosterol synthesis pathways, e.g., one of which may include CYP51.
  • the fungus may belong to a genus that is one of: Aspergillus, Candida, Cryptococcus, Histoplasma, and the like.
  • the fungus may be one of: Aspergillus fumigatus, Candida albicans, Candida glabrata, Cryptococcus neoformans, Histoplasma capsulatum, and the like.
  • the subject may have, or be at risk of aspergillosis, candidiasis, cryptococcosis, histoplasmosis, and the like.
  • the subject may suffer from or be at risk of suffering from an infection by the fungus 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 a systemic infection by the fungus or be at risk of suffering from a systemic infection by the fungus.
  • the subject may be one of: suffering from cancer; undergoing chemotherapy; undergoing immune suppression therapy; a transplant recipient, e.g., one undergoing immune suppression therapy; suffering from an immuno- deficiency disease or condition, such as HIV infection; a burn patient; and the like.
  • the subject may be a human, dog, cat, cow, horse, sheep, pig, bird, amphibian, or fish.
  • the compound represented by Structural Formula (Ia) or (I) may exclude certain compounds.
  • the compound represented by Structural Formula (Ia) or (I) may exclude free-base (neutral or non-salt) forms of Compounds 1a-f, wherein: Het 1 is unsubstituted pyrid-2-yl; R 1 and R 2 are each H; X is O; Y is unbranched, unsubstituted C 2 -C 4 alkyl; and Het 2 is unsubstituted imidazole-1-yl or unsubstituted 1, 2, 4 triazol-2-yl:
  • the compound represented by Structural Formula (Ia) or (I) may include pharmaceutically acceptable salts of Compounds 1a-f.
  • the compound represented by Structural Formula (Ia) or (I) may exclude free-base forms of Compounds 1a-f and pharmaceutically acceptable salts of Compounds 1a-f.
  • the compound represented by Structural Formula (Ia) or (I) may exclude protonated forms of Compounds 1a-f.
  • the compound represented by Structural Formula (Ia) or (I) may exclude compounds wherein Het 1 is one of unsubstituted pyridyl and pyrid-2-yl substituted with methyl or ethyl, for example, when: R 1 and R 2 are each H; X is O; Y is unbranched, unsubstituted C 2 -C 4 alkyl; and Het 2 is unsubstituted imidazole-1-yl or unsubstituted 1,2,4-triazol-2-yl.
  • the compound represented by Structural Formula (Ia) or (I) may exclude compounds wherein one of R 1 and R 2 is H and the other is methyl or ethyl, for example, when: Het 1 is unsubstituted pyrid-2-yl; X is O; Y is unbranched, unsubstituted C 2 - C 4 alkyl; and Het 2 is unsubstituted imidazole-1-yl or unsubstituted 1,2,4-triazol-2-yl.
  • the compound represented by Structural Formula (Ia) or (I) may exclude compounds wherein X is S, for example, when: Het 1 is unsubstituted pyrid-2-yl; R 1 and R 2 are each H; Y is unbranched, unsubstituted C 2 -C 4 alkyl; and Het 2 is unsubstituted imidazole-1-yl or unsubstituted 1,2,4-triazol-2-yl.
  • the compound represented by Structural Formula (Ia) or (I) may exclude compounds wherein Y is C 2 -C 4 alkyl substituted with methyl or ethyl, unsubstituted or methyl substituted C 1 -C 5 alkyl, or unsubstituted C 1 -C 6 alkyl, for example, when: Het 1 is unsubstituted pyrid-2-yl; R 1 and R 2 are each H; X is O; and Het 2 is unsubstituted imidazole-1-yl or unsubstituted 1,2,4-triazol-2-yl.
  • the compound represented by Structural Formula (Ia) or (I) may exclude compounds wherein Het 2 is one of: methyl or ethyl substituted imidazole-1-yl; unsubstituted imidazolyl; methyl or ethyl substituted imidazolyl; methyl or ethyl substituted 1,2,4-triazol-2-yl; unsubstituted 1,2,4-triazolyl; methyl or ethyl substituted 1,2,4-triazolyl; unsubstituted triazolyl; and methyl or ethyl substituted triazolyl; for example, when: Het 1 is unsubstituted pyrid-2-yl; R 1 and R 2 are each H; X is O; and Y is unbranched, unsubstituted C 2 -C 4 alkyl.
  • Het 1 may be optionally substituted pyridyl, pyrazinyl, pyrimidinyl, or pyridizinyl.
  • Het 1 may be optionally substituted pyridyl.
  • the compound may be represented by Structural Formula (II):
  • the compound may be represented by Structural Formula (III):
  • each ring in the optionally substituted linking moiety represented by A may be independently and optionally substituted by one or more of: hydroxy, halo, and C 1 -C 6 alkoxy.
  • A may include an optionally substituted heteroaryl or optionally substituted heterocycloalkyl ring.
  • A may include an optionally substituted, oxygen-containing, heteroaryl or heterocycloalkyl ring.
  • A may include an optionally substituted furanyl or optionally substituted tetrahydrofuranyl ring.
  • A may include optionally substituted 2,5-furanyl.
  • A may include one or two optionally substituted phenyl rings.
  • A may include optionally substituted 1,4-phenyl.
  • A may be optionally substituted 1,4-phenyl.
  • A may be optionally substituted phenyl-heteroaryl-phenyl.
  • the compound of Structural Formula III may be represented by one of Structural Formulas (IIIa)-(IIIf):
  • Z, Z 1 , and Z 2 are each independently CH or N, n may be 1-14, e.g., 1-10, and R 3 may represent H, halogen, optionally halogenated C 1 -C 6 alkyl, or optionally halogenated C 1 -C 6 alkoxy.
  • the compound may be represented by one of Compounds 1g-1v, e.g., 1g-1n:
  • the compound may be, for example, represented by Structural Formula (IIIf) above, e.g., compound 14a:
  • the compound may be represented by Structural Formula (IV):
  • each R 3 may independently represent H, halogen, optionally halogenated C 1 -C 6 alkyl, or optionally halogenated C 1 -C 6 alkoxy.
  • the compound may be represented by Structural Formula (V):
  • Y may include at least 4 linking atoms between X and Het 2 .
  • X may be O or a bond and Y may be C 1 -C 14 , e.g., C 1 -C 10 alkyl optionally substituted with one or more of: optionally halogenated C 1 -C 8 alkyl and optionally halogenated aryl.
  • the compound may be represented by one of Structural Formulas (Va)-(Ve), wherein each Z, Z 1 , and Z 2 are independently CH or N:
  • Z, Z 1 , and Z 2 are each independently CH or N, n may be 1-14, e.g., 1-10, and R 3 may represent H, halogen, optionally halogenated C 1 -C 6 alkyl, or optionally halogenated C 1 -C 6 alkoxy.
  • the compound may be represented by Structural Formula (VII):
  • Z may be CH or N; each R 3 may independently be H, halogen, optionally halogenated C 1 -C 10 alkyl, or optionally halogenated C 1 -C 10 alkoxy; and n may be an integer from 1 to 10.
  • the compound may be one of Compounds 2a-2h:
  • the compound may be, for example, one of Compounds 3a-3g:
  • the compound may be, for example, one of Compounds 4a-4m, e.g., 4a-4i:
  • the compound may be, for example, represented by Structural Formula (Vd) above, e.g., one of compounds 13a-13c:
  • the compound may be represented by Structural Formula (VIa):
  • R 4 may be H, optionally halogenated C 1 -C 10 alkyl, or optionally halogenated aryl.
  • the compound may be represented by Structural Formula (VIb):
  • Het 2 may include an optionally substituted one of: pyrrole, diazole, thiadiazole, oxadiazole, and triazole.
  • Het 2 may be optionally substituted imidazole or optionally substituted 1, 2, 4 triazole.
  • the compound may be represented by Structural Formula (VIII):
  • each R 5 may independently be H, halogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy; and R 6 may be H, optionally halogenated C 1 -C 6 alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • the compound may be one of Compounds 5a-5f:
  • the compound may be represented by Structural Formula (IX):
  • each R 5 may independently be H, halogen, C 6
  • R may be H, optionally halogenated C 1 -C 6 alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • the compound may be one of Compounds 6a-6f:
  • the compound may be represented by Structural Formula (X):
  • each R 5 may independently be H, halogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy; and R 6 may be H, optionally halogenated C 1 -C 6 alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • the compound may be one of Compounds 7a-7f:
  • the compound may be represented by Structural Formula (XI):
  • each R 5 may independently be H, halogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy; and R 6 may be H, optionally halogenated C 1 -C 6 alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • the compound may be represented by Structural Formula (XII):
  • R 5 may independently be H, halogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy; and R 6 may be H, optionally halogenated C 1 -C 6 alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • A may be phenyl and X may be a bond.
  • the compound may be represented by Structural Formula (XIII):
  • Z may be CH or N; and n may be an integer from 1 to 10.
  • the compound may be one of Compounds 8a-8b: .
  • A may be a bond.
  • the compound may be represented by Structural Formula (XIV):
  • Z may be CH or N; and n may be an integer from 1 to 10.
  • the compound may be one of Compounds 9a-9d, e.g., 9a-9c:
  • A may be optionally substituted biphenyl.
  • the compound may be represented by Structural Formula (XV):
  • n may be 1-14, e.g., 1-10, and R 3 may represent H, halogen, optionally halogenated C 1 -C 6 alkyl, or optionally halogenated C 1 -C 6 alkoxy.
  • the compound may be one of Compounds 10a-10n:
  • A may be optionally substituted phenyl-piperazinyl-phenyl.
  • the compound may be represented by one of Structural Formulas (XVI) and (XVII):
  • the compounds may be represented by one of (XVIa)-(XVIb):
  • Z, Z 1 , and Z 2 are each independently CH or N, n may be 1-14, e.g., 1-10, and R 3 may represent H, halogen, optionally halogenated C 1 -C 6 alkyl, or optionally halogenated C 1 -C 6 alkoxy.
  • the compound may be one of Compounds 11a-11d:
  • the compounds may be represented by one of (XVIIa)-(XVIIb):
  • Z, Z 1 , and Z 2 are each independently CH or N, n may be 1-14, e.g., 1-10, and R 3 may represent H, halogen, optionally halogenated C 1 -C 6 alkyl, or optionally halogenated C 1 -C 6 alkoxy.
  • the compound may be Compound 12a:
  • a pharmaceutical composition may include a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition may include a compound represented by Structural Formula (Ia):
  • Ar may be an optionally substituted aryl or nitrogen-containing heteroaryl.
  • R 1 and R 2 may independently be H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloalkyl, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted C 1 -C 14 alkyl or optionally substituted C 2 -C 14 alkenyl, e.g., optionally substituted C 1 -C 10 alkyl or optionally substituted C 2 -C 10 alkenyl, or optionally substituted C 1 -C 8 alkyl or optionally substituted C 2 -C 8 alkenyl.
  • Het 2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
  • a pharmaceutical composition may include a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical composition may include a compound represented by Structural Formula (I):
  • Het 1 may be an optionally substituted, nitrogen- containing heteroaryl.
  • R 1 and R 2 may independently be H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloalkyl, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted C 1 -C 10 alkyl or optionally substituted C 2 -C 10 alkenyl.
  • Het 2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
  • the compound of the pharmaceutical composition may include any selection of variables or any compound described or encompassed by Structural Formula (I) or (Ia) of the method described herein.
  • the compound represented by Structural Formula (Ia) or (I) may include one of Compounds 1a-f.
  • each of Compounds 1a-f may be in the form of a solid.
  • each of Compounds 1a-f may be in the form of a pharmaceutically acceptable salt.
  • at least a portion of the pharmaceutically acceptable carrier or excipient may be in the form of a solid or gel.
  • the pharmaceutical composition may be configured for administration in unit dosage form.
  • the pharmaceutical composition may be configured for administration in the form of one of: a tablet; a capsule; a lozenge; a cream, a spray, a transdermal patch, an aerosol, a suppository, a depot preparation; a suture that is coated or impregnated with one of Compounds 1a-f; a bandage that is coated or impregnated with one of Compounds 1a-f; a medical device that is coated or impregnated with one of Compounds 1a-f; and the like.
  • pharmaceutically acceptable salts of Compounds 1a-1f are included.
  • free-base (neutral) Compounds 1a-f may be excluded.
  • protonated forms of Compounds 1a-1f may be excluded.
  • the pharmaceutical composition may incorporate any of the various embodiments described herein for excluding certain compounds represented by Structural Formula (Ia) or (I).
  • the compound represented by Structural Formula (Ia) or (I) may exclude free-base (neutral or non-salt) forms of Compounds 1a-f.
  • the compound represented by Structural Formula (Ia) or (I) may include pharmaceutically acceptable salts of Compounds 1a-f.
  • the compound represented by Structural Formula (Ia) or (I) may exclude free-base forms of Compounds 1a-f and pharmaceutically acceptable salts of Compounds 1a-f.
  • the compound represented by Structural Formula (Ia) or (I) may exclude protonated forms of Compounds 1a-f.
  • the compound may include any aspect of the compounds represented by Structural Formulas (Ia) or (I) as described herein.
  • the compounds of the pharmaceutical composition may be represented by, as described herein, any one of, or any group of, Structural Formulas: (I), (Ia), (II), (III), (IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf), (IV), (V), (Va), (Vb), (Vc), (Vd), (Ve), (Via), (VIb), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVa), (XVb), (XVc), (XVI), (XVIa), (XVIb), (XVII), (XVIIa), and (XVIIb).
  • the compound may be any one of, or any group of, as described herein, Compounds: 1a-1v; 2a-2h; 3a-3g; 4a-4m; 5a-5f; 6a-6f; 7a-7f; 8a-8b; 9a-9d; 10a-10n; 11a-11d; 12a; 13a-13c; and 14a.
  • the compounds represented by Structural Formulas (Ia) or (I) may exclude compounds wherein Het 1 is one of unsubstituted pyridyl and pyrid-2-yl substituted with methyl or ethyl, for example, when: R 1 and R 2 are each H; X is O; Y is unbranched, unsubstituted C 2 -C 10 alkyl; and Het 2 is unsubstituted imidazole-1-yl or unsubstituted 1, 2, 4 triazol-2-yl.
  • the compound represented by Structural Formula (Ia) or (I) may exclude compounds wherein one of R 1 and R 2 is H and the other is methyl or ethyl, for example, when: Het 1 is unsubstituted pyrid- 2-yl; X is O; Y is unbranched, unsubstituted C 2 -C 10 alkyl; and Het 2 is unsubstituted imidazole-1- yl or unsubstituted 1, 2, 4 triazol-2-yl.
  • the compound represented by Structural Formula (Ia) or (I) may exclude compounds wherein X is S, for example, when: Het 1 is unsubstituted pyrid-2-yl; R 1 and R 2 are each H; Y is unbranched, unsubstituted C 2 -C 10 alkyl; and Het 2 is unsubstituted imidazole-1-yl or unsubstituted 1, 2, 4 triazol-2-yl.
  • the compound represented by Structural Formula (Ia) or (I) may exclude compounds wherein Y is C 2 -C 4 alkyl substituted with methyl or ethyl, unsubstituted or methyl substituted C 1 -C 5 alkyl, or unsubstituted C 1 -C 6 alkyl, for example, when: Het 1 is unsubstituted pyrid-2-yl; R 1 and R 2 are each H; X is O; and Het 2 is unsubstituted imidazole-1-yl or unsubstituted 1, 2, 4 triazol-2-yl.
  • the compound represented by Structural Formula (Ia) or (I) may exclude compounds wherein Het 2 is one of: methyl or ethyl substituted imidazole-1-yl; unsubstituted imidazolyl; methyl or ethyl substituted imidazolyl; methyl or ethyl substituted 1,-2,-4-triazol-2-yl; unsubstituted 1,-2,-4-triazolyl; methyl or ethyl substituted 1,-2,- 4-triazolyl; unsubstituted triazolyl; and methyl or ethyl substituted triazolyl; for example, when: Het 1 is unsubstituted pyrid-2-yl; R 1 and R 2 are each H; X is O; and Y is unbranched, unsubstituted C 2 -C 4 alkyl.
  • Het 1 may be optionally substituted pyridyl, pyrazinyl, pyrimidinyl, or pyridizinyl.
  • Het 1 may be optionally substituted pyridyl.
  • the compound of the pharmaceutical composition may be represented by Structural Formula (II).
  • the compound of the pharmaceutical composition may be represented by Structural Formula (III).
  • Y may include at least 4 linking atoms between X and Het 2 .
  • X may be O or a bond and Y may be C 1 -C 14 , e.g., C 1 -C 10 alkyl optionally substituted with one or more of: optionally halogenated C 1 -C 8 alkyl and optionally halogenated aryl.
  • the compound may be one of Compounds 1a-n.
  • the compound of the pharmaceutical composition may be represented by any of Structural Formulas (IIIa), (IIIb), (IIIc), (IIId), (IIIe), and (IIIf), wherein Z, Z 1 , and Z 2 may be each independently CH or N, n may be 1-14, and R 3 may be H, halogen, optionally halogenated C 1 -C 6 alkyl, or optionally halogenated C 1 -C 6 alkoxy.
  • the compound of the pharmaceutical composition may be any one of Compounds 1a-1v.
  • the compound of the pharmaceutical composition may be any one of Compounds 1a-1n.
  • each ring in the optionally substituted linking moiety represented by A may be independently and optionally substituted by one or more of: hydroxy, halo, and C 1 -C 10 , e.g., C 1 -C 6 alkoxy.
  • A may include an optionally substituted heteroaryl or optionally substituted heterocycloalkyl ring.
  • A may include an optionally substituted, oxygen-containing, heteroaryl or heterocycloalkyl ring.
  • A may include an optionally substituted furanyl or optionally substituted tetrahydrofuranyl ring.
  • A may include optionally substituted 2,5-furanyl.
  • A may include one or two optionally substituted phenyl rings.
  • A may include optionally substituted 1,4-phenyl.
  • A may be optionally substituted 1,4-phenyl.
  • A may be optionally substituted phenyl-heteroaryl-phenyl.
  • the compound may be represented by Structural Formula (IV), wherein each R 3 may independently represent H, halogen, optionally halogenated C 1 -C 6 alkyl, or optionally halogenated C 1 -C 6 alkoxy.
  • the compound may be represented by Structural Formula (V).
  • the compound of the pharmaceutical composition may be represented by any of Structural Formulas (V), (Va), (Vb), (Vc), (Vd), and (Ve), wherein Z, Z 1 , and Z 2 may be each independently CH or N, n may be 1-14, and R 3 may be H, halogen, optionally halogenated C 1 -C 6 alkyl, or optionally halogenated C 1 -C 6 alkoxy.
  • the compound may be represented by Structural Formula (VIa) wherein R 4 may be H, optionally halogenated C 1 -C 8 alkyl, or optionally halogenated aryl.
  • the compound may be represented by Structural Formula (VIb).
  • Het 2 may include an optionally substituted one of: pyrrole, diazole, thiadiazole, oxadiazole, and triazole.
  • Het 2 may be optionally substituted imidazole or optionally substituted 1, 2, 4 triazole.
  • the compound may be represented by Structural Formula (VII), wherein: Z may be CH or N; each R 3 may independently be H, halogen, optionally halogenated C 1 -C 6 alkyl, or optionally halogenated C 1 -C 6 alkoxy; and n may be an integer from 1 to 10.
  • the compound may be one of Compounds 2a-2g.
  • the compound may be, for example, one of Compounds 3a-3g.
  • the compound may be, for example, one of Compounds 4a-4m, e.g., 4a-4i.
  • the compound may be, for example, one of Compounds 13a-13c.
  • the compound may be represented by Structural Formula (VIII), wherein each R 5 may independently be H, halogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy, and R 6 may be H, optionally halogenated C 1 -C 6 alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • R 5 may independently be H, halogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy
  • R 6 may be H, optionally halogenated C 1 -C 6 alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • the compound may be one of Compounds 5a-5f.
  • the compound may be represented by Structural Formula (IX), wherein: each R 5 may independently be H, halogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy; and R 6 may be H, optionally halogenated C 1 -C 6 alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • R 5 may independently be H, halogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy
  • R 6 may be H, optionally halogenated C 1 -C 6 alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • the compound may be one of Compounds 6a-5f.
  • the compound may be represented by Structural Formula (X) wherein: each R 5 may independently be H, halogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy; and R 6 may be H, optionally halogenated C 1 -C 6 alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • R 5 may independently be H, halogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy
  • R 6 may be H, optionally halogenated C 1 -C 6 alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • the compound may be one of Compounds 7a-7f.
  • the compound may be represented by Structural Formula (XI), wherein each R 5 may independently be H, halogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy; and R 6 may be H, optionally halogenated C 1 -C 6 alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • R 5 may independently be H, halogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy
  • R 6 may be H, optionally halogenated C 1 -C 6 alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • the compound may be represented by Structural Formula (XII), wherein each R 5 may independently be H, halogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy; and R 6 may be H, optionally halogenated C 1 -C 6 alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • R 5 may independently be H, halogen, C 1 -C 4 alkyl, or C 1 -C 4 alkoxy
  • R 6 may be H, optionally halogenated C 1 -C 6 alkyl, optionally halogenated phenyl, or optionally halogenated biphenyl.
  • the compound may be represented by Structural Formula (Ia) or (I), wherein A may be phenyl and X may be a bond.
  • the compound may be represented by Structural Formula (XIII), wherein Z may be CH or N; and n may be an integer from 1 to 10.
  • the compound may be one of Compounds 8a-8b.
  • the compound may be represented by Structural Formula (Ia) or (I), wherein A may be a bond.
  • the compound may be represented by Structural Formula (XIV), wherein Z may be CH or N; and n may be an integer from 1 to 10.
  • the compound may be one of Compounds 9a-9d, for example, 9a-9c.
  • the compound may be represented by Structural Formula (XV), wherein Z, Z 1 , and Z 2 may be each independently CH or N, n may be 1-14, and R 3 may be H, halogen, optionally halogenated C 1 -C 6 alkyl, or optionally halogenated C 1 -C 6 alkoxy.
  • the compound may be represented by one of Structural Formulas (XVa)-(XVc).
  • the compound may be one of Compounds 10a- 10n.
  • the compound may be represented by one of Structural Formulas (XVI) and (XVII), wherein Z, Z 1 , and Z 2 may be each independently CH or N, n may be 1-14, and R 3 may be H, halogen, optionally halogenated C 1 -C 6 alkyl, or optionally halogenated C 1 -C 6 alkoxy.
  • the compound may be represented by one of Structural Formulas (XVIa)-(XVIb).
  • the compound may be one of Compounds 11a-11d.
  • the compound may be represented by one of Structural Formulas (XVIIa)-(XVIIb), e.g., the compound may be Compound 12a.
  • a kit for anti-fungal treatment of a subject in need thereof is provided.
  • the kit may include any anti-fungal compound described herein, for example, the compound represented by Structural Formula (Ia):
  • Ar may be an optionally substituted aryl or nitrogen-containing heteroaryl.
  • R 1 and R 2 may independently be H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloalkyl, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted C 1 -C 14 alkyl or optionally substituted C 2 -C 14 alkenyl, e.g., optionally substituted C 1 -C 10 alkyl or optionally substituted C 2 -C 10 alkenyl, or optionally substituted C 1 -C 8 alkyl or optionally substituted C 2 -C 8 alkenyl.
  • Het 2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
  • the kit may include instructions. The instructions may direct a user to provide the subject, the subject being infected by a fungus or at risk of infection by the fungus. The instructions may direct a user to administer the compound or the pharmaceutical composition to the subject in an amount effective to mitigate infection by the fungus in the subject.
  • kits for anti-fungal treatment of a subject in need thereof may include any anti-fungal compound described herein, for example, the compound represented by Structural Formula (Ia):
  • Ar may be an optionally substituted aryl or nitrogen-containing heteroaryl.
  • R 1 and R 2 may independently be H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloalkyl, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • Y may be optionally substituted C 1 -C 14 alkyl or optionally substituted C 2 -C 14 alkenyl, e.g., optionally substituted C 1 -C 10 alkyl or optionally substituted C 2 -C 10 alkenyl, or optionally substituted C 1 -C 8 alkyl or optionally substituted C 2 -C 8 alkenyl.
  • Het 2 may be an optionally substituted five-membered nitrogen-containing heteroaromatic ring comprising 1, 2, or 3 ring heteroatoms.
  • the kit may include instructions. The instructions may direct a user to provide the subject, the subject being infected by a fungus or at risk of infection by the fungus. The instructions may direct a user to administer the compound or the pharmaceutical composition to the subject in an amount effective to mitigate infection by the fungus in the subject.
  • kits for anti-fungal treatment of a subject in need thereof may include any anti-fungal compound described herein, for example, the compound represented by Structural Formula (I):
  • Het 1 may be an optionally substituted, nitrogen-containing heteroaryl.
  • R 1 and R 2 may independently be H, optionally substituted C 1 -C 6 alkyl, or optionally substituted C 3 -C 6 cycloalkyl.
  • A may be a bond or an optionally substituted linking moiety comprising 1, 2, or 3 rings. Each ring in the optionally substituted linking moiety may independently be one of: aryl, cycloalkyl, heterocycloalkyl, and heteroaryl.
  • X may be O, S, amide, or a bond.
  • the kit may include instructions.
  • the instructions may direct a user to provide the subject, the subject being infected by a fungus or at risk of infection by the fungus.
  • the instructions may direct a user to administer the compound or the pharmaceutical composition to the subject in an amount effective to mitigate infection by the fungus in the subject.
  • the compound represented by Structural Formula (I) or (Ia) may include any aspect of the anti-fungal compounds described herein, either alone or as encompassed by any of the methods or anti-fungal pharmaceutical compositions described herein.
  • the instructions may direct a user to conduct any step or combination of steps described herein for the method.
  • FIG. 1A is a synthetic scheme various phenoxyalkyl linker anti-fungal Compounds 1a-1n and 1v.
  • Compounds 1a, 1b, 1c, 1e, 1f, 1g, 1i, 1m, and 1v were made according to FIG.1A.
  • reagents and conditions for synthesis of compounds according to FIG. 1A were made according to FIG.1A.
  • 1A included: a) ⁇ , ⁇ -dibromoalkane, K 2 CO 3 , acetone; b) imidazole or 1,2,4-triazole, K 2 CO 3 , CH 3 CN; c) SnCl 2 .2H 2 O, EtOAc; d) S-(2-naphthylmethyl)-2-pyridylthioimidate hydrobromide, CH 3 CN/EtOH (1:3), rt.
  • FIG. 1B is a synthetic scheme for various phenoxyalkyl hybrid target compounds substituted meta to the arylimidamide group, e.g., Compounds 1o-1q.
  • reagents and conditions for synthesis of compounds according to FIG.2B included: a) MOMCl, K 2 CO 3 , acetone, 30oC; b) RI, K 2 CO 3 , sealed tube, 80oC; c) HCl, MeOH/CH 2 Cl 2 , rt; d) 1,8- Dibromooctane, K 2 CO 3 , CH 3 CN, reflux; e) imidazole, K 2 CO 3 , CH 3 CN, reflux; f) SnCl .
  • FIG. 1C is a synthetic scheme for various phenoxyalkyl hybrid target compounds substituted ortho to the arylimidamide group, e.g., Compounds 1r-1t.
  • reagents and conditions for synthesis of compounds according to FIG. 2C included: a) RI, K 2 CO 3 , sealed tube, 80oC; b) NaOH, DMSO, reflux; c) 1,8-Dibromooctane, K 2 CO 3 , CH 3 CN, reflux; d) imidazole, K 2 CO 3 , CH 3 CN, reflux; e) SnCl .
  • FIG. 1D is a synthetic scheme for various phenoxyalkyl hybrid target compounds substituted with pyrrole, e.g., Compound 1u.
  • reagents and conditions for synthesis of Compound 1u according to FIG. 2D included: a) 1,8-dibromooctane, K 2 CO 3 , acetone; b) pyrrole, K 2 CO 3 , CH 3 CN; c) SnCl 2 .2H 2 O, EtOAc; d) S-(2-naphthylmethyl)-2- pyridylthioimidate hydrobromide, CH 3 CN/EtOH (1:3), rt.
  • FIG. 2A is a synthetic scheme for various phenyl-unsubstituted diphenylfuran alkyloxy linker hybrid Compounds 2a-2g and 3a-g.
  • Compounds 2a-e, 2g, 3a-e, and 3g were made according to FIG.2A.
  • Compound 2h was made according to FIG.2A, but starting with 1- bromo-2-oxy(prop-2-yl)-4-nitrobenzene.
  • 2A included: a) Pd(PPh 3 ) 4 , dioxane, 90°C; b) NBS, DMF, rt; c) K 2 CO 3 , acetone, reflux; d) Pd(PPh 3 ) 4 , K 2 CO 3 , MeOH, toluene, 80°C; e) azole, NaH, DMF, rt; f) H 2 , Pd(C), EtOH-EtOAc; g) (i) S-(2-naphthylmethyl-2-pyridylthioimidate hydrobromide, EtOH; (ii) NaOH; (iii) ethanolic HCl.
  • Tetrakistriphenylphosphine palladium (0.5 mmol) was added to a stirred mixture of the 2-(tributylstannyl) furan (11 mmol) and 1-bromo-4-nitrobenzene (10 mmol) in deaerated dioxane (25 mL) under a nitrogen atmosphere. The vigorously stirred mixture was heated at 90- 100 °C for 24 h. The solvent was evaporated under reduced pressure, the resulting solid was partitioned between ethyl acetate (200 mL) and 5 mL of concentrated ammonia to remove the palladium complex, washed with water, passed through celite to remove the catalyst, dried over sodium sulfate and evaporated.
  • N-bromosuccinimide (2.13 gm, 12 mmol) was added portion-wise to a stirred solution of the previous nitro compound (10 mmol) in dimethylformamide (20 mL). The reaction mixture was stirred at room temperature for 12 h then poured onto cold water, the precipitate was collected and dried. Purification was conducted by column chromatography on silica gel, using hexanes/ethyl acetate (95/5, v/v). Yellow solid, yield 96 %; m.p.
  • 1,4-dibromobutane (36 mmol) was added to a solution of the p- hydroxyphenylboronic acid ester (1.32 gm, 6 mmol), dry K 2 CO 3 (1.65 gm, 12 mmol) and Cs 2 CO 3 (0.39 gm, 1.2 mmol) in anhydrous dimethylacetamide (15 mL) under a nitrogen atmosphere. Stirring was continued for 12 h and ice water was added and the reaction mixture was filtered and air dried. Purification was performed by column chromatography on silica gel, using hexanes/ethyl acetate (93/7, v/v). White solid (73%) m.p.
  • the solid was dissolved in ethanol (2 mL); the solution was cooled to 0 o C in an ice bath and 10% NaOH was added until pH reached approximately 10.
  • the free base was extracted with ethyl acetate (3 ⁇ 50 mL). The organic layer was washed with distilled water, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting suspension was crystallized by adding dry hexanes and then filtered.
  • the free base was suspended in dry ethanol (20 mL) and cooled to 0 o C in an ice bath. Freshly prepared ethanolic HCl solution (2 mL) was added to the suspension and the mixture was stirred at room temperature for overnight. The resulting red solution was concentrated under reduced pressure.
  • FIG. 3B is a synthetic scheme for various phenyl substituted diphenylfuran alkyloxy linker hybrid compounds, each of which may be prepared, for example, from a suitably substituted aryl boronate according to FIG. 3A.
  • compounds may be prepared from the corresponding phenol and bromoalkyl imidazole, as shown in FIG. 3B.
  • the phenol may be prepared from a phenol protected aryl boronate according to FIG. 3A, followed by subsequent deprotection.
  • Compound 4j was made according to FIG. 3B.
  • 3B included: a) Pd(PPh 3 ) 4 , dioxane, 90°C; b) NBS, DMF, rt; c) K 2 CO 3 , Cs 2 CO 3 , DMA, rt; d) Pd(PPh 3 ) 4 , K 2 CO 3 , MeOH, toluene, 80°C; e) imidazole, NaH, DMF, rt; f) H 2 , Pd(C), EtOH-EtOAc; g) (i) S-(2-naphthylmethyl)-2- pyridylthioimidate hydrobromide, EtOH; (ii) NaOH.
  • FIG. 2C is a synthetic scheme for various phenyl substituted diphenylfuran alkyloxy linker hybrid compounds.
  • Compounds 2h, 4k, 13b, and 13c were made according to FIG.2C.
  • 2C included: aa) Pd(PPh 3 ) 4 , dioxane, 90°C; b) NBS, DMF, rt; c) K 2 CO 3 , Cs 2 CO 3 , DMA, rt; d) Pd(PPh 3 ) 4 , K 2 CO 3 , MeOH, toluene, 80°C; e) imidazole, NaH, DMF, rt; f) H 2 , Pd(C), EtOH-EtOAc; g) (i) S-(2-naphthylmethyl-2-pyridylthioimidate hydrobromide, EtOH; (ii) NaOH.
  • Example 2D Prophetic
  • FIG. 2D is a prophetic synthetic scheme for various diphenylfuran alkyloxy linker hybrid Compounds 4a-i, each of which may be prepared, for example, from a suitably substituted aryl boronate according to FIG. 2A.
  • Compounds 4a-i may be prepared from the corresponding phenol and bromoalkyl imidazole, as shown in FIG. 2D.
  • the phenol may be prepared from a phenol protected aryl boronate according to FIG. 2A, followed by subsequent deprotection.
  • FIG.3 is a synthetic scheme for various alkylamide linker hybrid Compounds 5a-f, 6a-f, and 7a-f.
  • precursor carboxylic acids were prepared similarly to FIG. 2A by a cross-coupling of a benzylalcohol boronate ester with 2-(4-nitrophenyl)furan, nitro reduction, and imidamide formation.
  • Oxidation of the benzyl alcohol provided the carboxylic acid compound shown in FIG.3, and subsequent peptide coupling with the illustrated imidazoyl amine is proposed to afford Compounds 5a and 5c.
  • Compound 6a may be prepared from 2-(4- nitrophenyl)furan, followed by nitro reduction and imidamide formation. Bromination of the resulting furanyl compound followed by a metal-mediated carboxylation may provide the carboxylic acid shown in FIG. 3. Subsequent peptide coupling with the illustrated imidazoyl amine may afford Compound 6a.
  • Compound 7a may be prepared from a suitable 4-aminobenzoic acid derivative. Imidamide formation may provide the carboxylic acid compound shown in FIG. 3, and subsequent peptide coupling with the illustrated imidazoyl amine may provide Compound 6a.
  • FIG.4A is a prophetic synthetic scheme for various phenylalkyl linker hybrid Compounds 8a and 8b.
  • Compound 8a and 8b may be prepared from phenyllithium and the corresponding dibromoalkane, as shown in FIG. 4A. Nitration of the resulting alkylaryl bromide followed by displacement of the bromide with imidazole can provide the nitrophenyl alkylimidazole. Subsequent reduction of the nitro group to the amine, followed by amidine synthesis with naphthalene-2-ylmethylpyridine-2-carbimidothioate may provide Compounds 8a and 8b.
  • FIG. 4B is a synthetic scheme for various phenylalkyl linker hybrid Compounds 9a-9d.
  • the synthesis of Compound 9d is representative, as follows.
  • Benzyl (8-aminooctyl)car m [00119] Benzyl chloroformate (1 g, 5.86 mmol) was added to 10 equivalents of 1,8- diaminooctane (8.45 g, 58.6 mmol) dissolved in 60 mL dry DCM/EtOH (1:1) in an ice bath. The mixture was allowed to stir for 3 hours at 0 oC and left to stir overnight at room temperature. The mixture was then filtered and partitioned between DCM (100 mL) and water (50 mL) and brine (50 mL) then dried over sodium sulfate.
  • Aqueous glyoxal (40%, 0.88 mL, 6.19 mmol), ammonium acetate (0.48 g, 6.19 mmol), and aqueous formaldehyde solution (37% w/v, 0.51 mL, 6.19 mmol) were added to benzyl (8-aminooctyl)carbamate (0.87 g, 3.12 mmol) in methanol (8 mL).
  • the reaction was heated to reflux overnight then the solution was evaporated under reduced pressure.
  • the pH was rendered alkaline by the addition of 2N NaOH and the mixture was extracted with DCM (100 mL). The organic phase was dried over sodium sulfate and the liquid was evaporated under reduced pressure.
  • the product was obtained after column chromatography purification over neutralized silica gel with DCM/MeOH (100:1) as a brown oil of the protected aminoalkyl imidazole, 0.48 g.
  • a dry 25 mL two-necked flask was charged with Pd/C (10%, 0.15 g) and the protected amine (0.48 g, 1.45 mmol) in 20 mL absolute ethanol under nitrogen. The mixture was stirred under 1 atmosphere of hydrogen for 24 hours.
  • the solid was dissolved in ethanol (2 mL); the solution was cooled to 0 o C in an ice bath and 10% NaOH was added until the pH reached approximately 10.
  • the free base was extracted with ethyl acetate (3 ⁇ 25 mL).
  • the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • the resulting suspension was purified by column chromatography over silica gel using DCM/MeOH/TEA (9.5:1.2:0.6) as eluent then further purified by 5 mL hexanes/diethyl ether (1:1) to yield a buff powder, 0.085 g, 55%.
  • FIG. 5A is a synthetic scheme for various unsubstituted and substituted biphenyl linker anti-fungal compounds, which was used to produce Compounds 10a, 10d, 10e, 10h, 10k, and 10l. Biphenyl linkers in these compounds were either unsubstituted or were substituted meta to the amidine group. Generally, reagents and conditions for synthesis of compounds according to FIG.
  • 5A included: dibromoalkane, K 2 CO 3 , CH 3 CN, reflux; b) imidazole, K 2 CO 3 , CH 3 CN, reflux; c) 2-alkoxy-4-nitroiodobenzene, Pd(dppf)Cl 2 , K 2 CO 3 , DMSO, 100°C; d) SnCl 2 .2H 2 O, EtOAc, reflux; e) S-(2-naphthylmethyl)-2-pyridylthioimidate hydrobromide, CH 3 CN/EtOH (1:3), rt.
  • the resulting suspension was purified by column chromatography over silica gel (neutralized by washing with trimethylamine) using DCM:MeOH (200:1 to 50:1) as eluent then further purified by crystallization from hexanes/ethyl acetate to yield yellow crystals, 0.135 g (68%).
  • FIG. 5B is a synthetic scheme for various substituted biphenyl linker anti- fungal compounds, which was used to produce Compounds 10b, 10c, 10i, and 10j. Biphenyl linkers in these compounds were substituted ortho to the amidine group. Generally, reagents and conditions for synthesis of compounds according to FIG.
  • 5B included: a) dibromoalkane, K 2 CO 3 , CH 3 CN, reflux; b) imidazole, K 2 CO 3 , CH 3 CN, reflux; c) 23a,b, Pd[P(Ph) 3 ] 4 , K 2 CO 3 , DMF, 100°C; d) SnCl 2 .2H 2 O, EtOAc, reflux; e) S-(2-naphthylmethyl)-2-pyridylthioimidate hydrobromide, CH 3 CN/EtOH (1:3), rt.
  • FIG. 5C is a synthetic scheme for various substituted biphenyl linker anti- fungal compounds, which was used to produce Compounds 10f and 10m. Biphenyl linkers in these compounds were substituted meta to the alkoxy linking group.
  • reagents and conditions for synthesis of compounds according to FIG.5C included: a) TsCl, K 2 CO 3 , acetone, reflux; b) MeI, K 2 CO 3 , sealed tube, CH 3 CN, reflux; c) bis(pinocolato)diboron, Pd(dppf)Cl 2 , AcOK; d) 4-nitro-iodobenzene, Pd(dppf)Cl 2 , dimethoxyethane/DMF/water (7:3:1), reflux; e) aq NaOH, EtOH/DMSO; f) 1,4-dibromobutane or 1,6-dibromohexane, K 2 CO 3 , CH 3 CN, reflux; g) imidazole, K 2 CO 3 , CH 3 CN, reflux; h) SnCl 2 .2H 2 O, EtOAc, reflux; i) S-(2-naphthylmethyl)-2
  • FIG. 5D is a synthetic scheme for various substituted biphenyl linker anti- fungal compounds, which was used to produce Compounds 10g and 10n. Biphenyl linkers in these compounds were substituted ortho to the alkoxy linking group. Generally, reagents and conditions for synthesis of compounds according to FIG.
  • 5D included: a) TsCl, acetonitrile, K 2 CO 3 , reflux ; b) Bis(pinacolato)diboron, Pd(dppf)Cl 2 , AcOK, dioxane, 100°C; c) 1-Iodo-4- nitrobenzene, Pd[P(Ph) 3 ] 4 or Pd(dppf)Cl 2 , K 2 CO 3 , DME:DMF:H 2 O (7:3:1),100°C; d) aq NaOH, EtOH/DMSO; e) dibromoalkane, acetonitrile, K 2 CO 3 , reflux; f) Imidazole, K 2 CO 3 .
  • FIG. 6A is a synthetic scheme for various phenyl-piperazinyl-phenyl linker anti-fungal compounds, which was used to produce Compounds 11a-11d. Generally, reagents and conditions for synthesis of compounds according to FIG.
  • 6A included: a) NMP, DIPEA, 4- chloronitrobenzene; b) ⁇ , ⁇ -dihaloalkane, K 2 CO 3 , acetone or Cs 2 CO 3 , DMF; c) imidazole or 1,2,4-triazole, Cs 2 CO 3 , DMF; d) Pd/C, H 2 , EtOAc/MeOH; e) S-(2-naphthylmethyl-2- pyridylthioimidate hydrobromide, CH 3 CN/EtOH.
  • FIG. 6B is a synthetic scheme for various phenyl-piperazinyl linker anti- fungal compounds, e.g., corresponding to Structural Formula (XVII). Generally, reagents and conditions for synthesis of compounds according to FIG.
  • 6B included: a) K 2 CO 3 /DMSO; b) ⁇ , ⁇ -dihaloalkane, e.g., 1,6-dibromohexane, Cs 2 CO 3 , DMF; c) imidazole, Cs 2 CO 3 , DMF; d) Pd/C, H 2 , MeOH; e) S-(2-naphthylmethyl-2-pyridylthioimidate hydrobromide, CH 3 CN/EtOH.
  • the synthesis of Compound 12a, N-(4-(4-(6-(1H-imidazol-1-yl)hexyl)piperazin-1- yl)phenyl)picolinimidamide is representative, as follows.
  • reaction mixture was cooled, diluted with ice water (40 mL), neutralized with 2N hydrochloric acid and then extracted with ethyl acetate (30 mL x 3). The combined organic layers were washed with water and brine, dried over Na 2 SO 4 , and concentrated under reduced pressure to yield 1-(4-nitrophenyl)piperazine as a yellow solid.
  • Step 5 Synthesis of N-(4-(4-(6-(1H-imidazol-1-yl)hexyl)piperazin-1-yl)phenyl) picolinimidamide
  • a two-fold concentration dilution series of each compound was added to 96-well microtiter plates in RPMI medium buffered to pH 7.0 with 20 mM HEPES.
  • fungal cells were added as follows: Aspergillus fumigatus conidia (final concentration 5000 per mL), Candida albicans yeasts (final concentration 2500 per mL), Cryptococcus neoformans (final concentration 10,000 per mL), Histoplasma capsulatum (final concentration 2,000,000 per mL).
  • FIG.7 is a table demonstrating IC 50 values in ⁇ M in Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans, and Histoplasma capsulatum for Compounds 1c, 1e, 1f, 1i, and 1m.. All tested compounds displayed excellent activity, in most cases demonstrating IC 50 values at or less than 10 ⁇ M.
  • FIGs.8A, 8B, 8C, and 8D are graphs showing concentration-dependent inhibition of fungal growth by the indicated compounds in ⁇ M for Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans, and Histoplasma capsulatum, respectively.
  • the graphs in FIGs. 8A, 8B, 8C, and 8D were used to determine the IC 50 values in ⁇ M shown in the table in FIG.7.
  • the disclosed anti-fungal compounds may also be counter-screened for toxicity to J774 macrophages and HepG2 hepatocellular carcinoma cells.
  • J774 cells (10 3 in 100 ⁇ L) or HepG2 cells (5 ⁇ 10 3 in 100 ⁇ L) 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 IC 50 values in each assay may permit the calculation of a selectivity index (SI, e.g., target fungus IC 50 versus mammalian cell line/IC 50 versus, 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, n- propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups.
  • branched alkyl groups include, e.g., isopropyl, iso-butyl, sec-butyl, tert-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, sec-butoxy, tert-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” 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.
  • 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.
  • 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.
  • 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.
  • 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
  • certain polymers may be described by use of the suffix“ene” in conjunction with a term describing the polymer repeat unit.
  • “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.
  • substituent groups include: halogens (F, Cl, Br, and I); hydroxyl; alkoxy, alkenoxy, aryloxy, aralkyloxy, heterocyclooxy, and heterocycloalkoxy groups; carbonyls (oxo); carboxyls; esters; urethanes; oximes; hydroxylamines; alkoxyamines; aralkoxyamines; 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, Cl, Br, and I
  • 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 F 12 I 2 , 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.
  • 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 C 1 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(O) 2 -(alkyl),–S(O) 2 –NH(alkyl),–S(O) 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-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbuty
  • 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 spores in a subject; a reduction in the rate of fungus growth in a subject; a reduction in fungus 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, 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 funguss, 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 terms“in” or“into” are used in the specification or the claims, it is intended to additionally mean“on” or“onto.”
  • selective 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.
  • 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.
  • 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.
  • the term“about” in conjunction with a number is intended to include ⁇ 10% of the number.
  • “about 10” may mean from 9 to 11.
  • the term“about” may mean ⁇ 10% of the number, or ⁇ 5, ⁇ 4, ⁇ 3, ⁇ 2, or ⁇ 1 of the number.

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Abstract

L'invention concerne des composés, des procédés et des compositions pharmaceutiques utiles pour le traitement d'infections fongiques, par exemple l'aspergillose, la candidose, la cryptococcose, l'histoplasmose, et analogues. Par exemple, la composition pharmaceutique peut comprendre un support ou un excipient pharmaceutiquement acceptable, et un composé représenté par Ar— C(=NR1)NR2— A---X— Y— Het2 et des sels pharmaceutiquement acceptables de ceux-ci. Ar peut être un aryle éventuellement substitué ou un hétéroaryle contenant de l'azote. R1 et R2 peut indépendamment être H, C1-C6 aikyi éventuellement substitué, ou C3-C6 cyeloalkyi éventuellement substitué. A peut être une liaison ou une fraction de liaison éventuellement substituée comprenant 1, 2 ou 3 cycles. Chaque cycle dans la fraction de liaison éventuellement substituée peut indépendamment être l'un de : aryle, cyeloalkyi, hétérocycloalkyle et hétéroaryle. X peut être O, S, amide ou une liaison. Y peut être C1-C10 alkyi éventuellement substitué ou C2-C10 alcényle éventuellement substitué. Het2 peut être un cycle hétéroaromatique contenant de l'azote à cinq chaînons éventuellement substitué comprenant 1, 2 ou 3 hétéroatomes cycliques.
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WO2023069613A1 (fr) * 2021-10-20 2023-04-27 Ohio State Innovation Foundation Arylimidamides destinés à être utilisés dans le traitement de cancers
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11919887B2 (en) 2019-12-06 2024-03-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US12247021B2 (en) 2019-12-06 2025-03-11 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
EP4603484A2 (fr) 2019-12-19 2025-08-20 Georgia State University Research Foundation, Inc. Composés pour le traitement d'infections bactériennes et la potentialisation d'antibiotiques
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
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WO2023069613A1 (fr) * 2021-10-20 2023-04-27 Ohio State Innovation Foundation Arylimidamides destinés à être utilisés dans le traitement de cancers

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