WO2017100171A1 - Composés antifongiques et procédés s'y rapportant - Google Patents

Composés antifongiques et procédés s'y rapportant Download PDF

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Publication number
WO2017100171A1
WO2017100171A1 PCT/US2016/065097 US2016065097W WO2017100171A1 WO 2017100171 A1 WO2017100171 A1 WO 2017100171A1 US 2016065097 W US2016065097 W US 2016065097W WO 2017100171 A1 WO2017100171 A1 WO 2017100171A1
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Prior art keywords
compound
optionally substituted
formula
alkyl
group
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PCT/US2016/065097
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English (en)
Inventor
Joseph Robert Pinchman
Kevin Duane Bunker
Peter Qinhua HUANG
Deborah Helen Slee
Chad Daniel Hopkins
Mehmet Kahraman
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Kalyra Pharmaceuticals, Inc.
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Publication of WO2017100171A1 publication Critical patent/WO2017100171A1/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
    • A61P31/10—Antimycotics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
    • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
    • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

Definitions

  • the present application relates to antifungal compounds and methods of using them to treat fungal infections.
  • Amphotericin B is a potent anti-fungal compound having the following chemical structure:
  • AmB has been used for treating severe fungal infections for over half a century. AmB is an especially valuable treatment for severe fungal infections because it is effective against a wide variety of fungi, and fungal pathogens have been relatively unsuccessful at developing resistance to it. However, despite its potency and ability to evade the development of resistance, the use of AmB is often precluded due to its highly toxic side effects including nephrotoxicity, hepatoxieity, and anemia-related symptoms. There have been many attempts to reduce toxicity while retaining therapeutic effectiveness. See WO 2014165676, WO 2015054148, WO 201 5190587, W 2016168568 and Stephen A. Davis et al , "Nontoxic antimicrobials that evade drug resistance," Nature Chemical Biology (June 1 2015). Thus, there remains a need for better tolerated compounds and methods of treatment for fungal infections that are therapeutically effective.
  • a first embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Formula (I) has the structure:
  • R 2 is selected from the group consisting of - R 8A R 8B ; -(NR 9A R 9B R 9C ) + and -NHC(0)R 10 .
  • R ⁇ R 4 , R ⁇ A , R "B and R b are each independently selected from the group consisting of hydrogen, an unsubstituted C 1-6 alkyl, a substituted C 1-6 alkyl, an optionally substituted C3-7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocvclyi; or, in another embodiment, R JA and R 38 , together with the N to which they are attached, form an optionally substituted monocyclic heterocvclyi.
  • R A , R 8r5 , R 9A , R 9B and R 9C are each independently selected from the group consisting of hydrogen, an optionally substituted Ci_6 alkyl, an optionally substituted C3-6 cycloalkyl, - ⁇ C 2 - 6 alkyl)-OR n , -(C 2 possibly 6 alkyl)-NR 12A R 12B , -
  • R 1 is selected from the group consisting of an optionally substituted C 1-6 alkyl, an optionally substituted C 3 _6 cycloalkyl, - -OR J J , -(C 2-6 alkyl)-NR f 2A R f 2B , -(C 2 diligent 6 alky!)- ⁇ 3A R i3B R 33C ) + , and
  • R f f , R 12A , R f 2B , R 13A R 3 ⁇ 43B and R i3C are each independently selected from the group consisting of hydrogen and an unsubstituted Ci_6 alkyl; and X ! is O or S.
  • R 5A and R 5B are H, then the other of R 5A and R 5B is not -CH 3 , - CH 2 CH 2 NH 2 , or -CH 2 CH 2 C(0)OH.
  • R is selected from the group consisting of ----NR 8A R 8B ; -(NR 9A R 9B R 9C ) + and -NHC(0)R 10 .
  • R J , R 4 , R iA , R "B and R b are each independently selected from the group consisting of hydrogen, an unsubstituted C 1-6 alkyl, a substituted C 1-6 alkyl, an optionally substituted C 3-7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocvclyi; or, in another embodiment, " and R "" , together with the N to which they are attached, form an optionally substituted monocyclic heterocvclyi.
  • R 8A R B , R 9A , R 9B and R 9C are each independently selected from the group consisting of hydrogen, an optionally substituted Ci-6 alkyl, an optionally substituted C 3-6 cycloalkyl, -(C 2-6 alkyl)-OR n , -(C 2- 6 alk l)-
  • R " is selected from the group consisting of an optionally substituted C 1-6 alkyl, an optionally substituted C 3-6 cycloalkyl, - ! ; A R ' ;
  • R ! ,c are each independently selected from the group consisting of hydrogen and an unsubstituted Ci angle6 alkyl.
  • n is zero or an integer in the range of 1 to about 40.
  • R 4 is not an N-linked optionally substituted monocyclic heterocvclyl.
  • R 1 is -C(0)R 4 and R 2 is NH 2
  • R " is not selected from substituents A, B, C, D, E, F, G, H, I or J, as follows:
  • R 4 is not selected from the group consisting of methyl, ethyl, propyl, isopropyl, propenyl,
  • R 1 is -C(0)NR 5A R 5B
  • R is -NH 2 and one or the other of R 5A and R 5b is H
  • the other of R 5A and R 5si is not -CH 3 , -CH 2 CH 2 NH 2 , or - CH 2 CH 2 C(0)OH.
  • An embodiment provides a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a compound of Formula (1), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • An embodiment provides a method of inhibiting the growth of a fungus, comprising contacting the fungus with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • An embodiment provides a method of inhibiting the growth of a fungus, comprising contacting the fungus with an effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • An embodiment provides a method of treating a fungal infection, comprising identifying a subject in need thereof and administering to said subject an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • An embodiment provides a method of treating a fungal infection, comprising contacting the fungus with an effective amount of a pharmaceutical composition, wherein the pharmaceutical composition comprises an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • An embodiment provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment and/or diagnosis of a fungal infection.
  • An embodiment provides a pharmaceutical composition for use in the treatment and/or diagnosis of a fungal infection, wherein the pharmaceutical composition comprises an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • An embodiment provides a compound of Formula (II), or a pharmaceutically acceptable salt thereof, as described below.
  • Embodiments of such compounds of Formula (II) and/or salts thereof are useful in the methods and/or uses summarized above and described elsewhere herein.
  • An embodiment provides a pharmaceutical composition comprising an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • a pharmaceutically acceptable carrier diluent, excipient or combination thereof.
  • Embodiments of compounds of Formula (II) and/or salts thereof are useful as starting materials or intermediates for the preparation of other compounds, such as compounds of Formula (I), (la) and/or (lb), and/or pharmaceutically acceptable salts thereof, as described below.
  • An embodiment provides a process of making a compound of Formula (la) and/or (lb) using a compound of Formula (II) as a starting material or intermediate.
  • the process is an acylation process, a reductive animation process or an alleviation process.
  • FIG. 1A illustrates General Scheme 1.
  • FIG. IB illustrates the chemical structure of Compound 1.
  • FIG. 1C illustrates a reaction scheme for making Compound 1.
  • FIG. ID illustrates another reaction scheme for making Compound 1
  • FIG. IE illustrates another reaction scheme for making Compound 1.
  • FIG. IF illustrates another reaction scheme for making Compound 1.
  • FIG. 2A illustrates the chemical structure of Compound 2.
  • FIG. 2B illustrates a reaction scheme for making Compound 2.
  • FIG. 3 illustrates the chemical structure of Compound 3.
  • FIG. 4 illustrates the chemical structure of Compound 4.
  • FIG. 5 illustrates the chemical structure of Compound 5.
  • FIG. 6 illustrates the chemical structure of Compound 6.
  • FIG. 7 illustrates the chemical structure of Compound 7.
  • FIG. 8 illustrates the chemical structure of Compound 8.
  • FIG. 9 illustrates the chemical structure of Compound 9.
  • FIG. 10 illustrates the chemical structure of Compound 10.
  • FIG. 11 illustrates the chemical structure of Compound 11.
  • FIG. 12 illustrates the chemical structure of Compound 12
  • FIG. 13 illustrates the chemical structure of Compound 13.
  • FIG. 14 illustrates the chemical structure of Compound 14.
  • FIG 15 illustrates the chemical structure of Compound 15.
  • FIG. 16 illustrates the chemical structure of Compound 16.
  • FIG 17 illustrates the chemical structure of Compound 17.
  • FIG. 18A illustrates the chemical structure of Compound 18.
  • FIG 18B illustrates a reaction scheme for making Compound 18.
  • FIG. 19 illustrates the chemical structure of Compound 19.
  • FIG 20A illustrates the chemical structure of Compound 20.
  • FIG. 20B illustrates a reaction scheme for making Compound 20.
  • FIG. 21 illustrates the chemical structure of Compound 21.
  • FIG. 22A illustrates the chemical structure of Compound 22.
  • FIG 22B illustrates a reaction scheme for making Compound 22.
  • FIG. 23 illustrates the chemical structure of Compound 23.
  • FIG. 24A illustrates the chemical structure of Compound 24.
  • FIG. 24B illustrates a reaction scheme for making Compound 24.
  • FIG. 24C illustrates another reaction scheme for making Compound 24.
  • FIG. 24D illustrates another reaction scheme for making Compound 24.
  • FIG. 25 illustrates the chemical structure of Compound 25.
  • FIG. 26A illustrates the chemical structure of Compound 26.
  • FIG. 26B illustrates a reaction scheme for making Compound 26.
  • FIG. 27A illustrates the chemical structure of Compound 27.
  • FIG. 27B illustrates a reaction scheme for making Compound 27.
  • FIG. 27C illustrates another reaction scheme for making Compound 27.
  • FIG. 28 illustrates the chemical structure of Compound 28.
  • FIG. 29 illustrates the chemical structure of Compound 29.
  • FIG. 30 illustrates the chemical structure of Compound 30.
  • FIG. 31 A illustrates the chemical structure of Compound 31.
  • FIG. 31 B illustrates a reaction scheme for making Compound 31.
  • FIG 32 illustrates the chemical structure of Compound 32.
  • FIG. 33 illustrates the chemical structure of Compound 33.
  • FIG 34 illustrates the chemical structure of Compound 34.
  • FIG. 35A illustrates the chemical structure of Compound 35.
  • FIG 35B illustrates a reaction scheme for making Compound 35.
  • FIG. 36 illustrates the chemical structure of Compound 36.
  • FIG 37 illustrates the chemical structure of Compound 37.
  • FIG. 38 illustrates an acylation process for making a compound of
  • FIG. 39 illustrates a reductive amination process for making a compound of Formula (lb) using a compound of Formula (II).
  • FIG. 40 illustrates an alkylation process for making a compound of Formula (lb) using a compound of Formula (II).
  • the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), cycloalkyl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-armdo, S-sulfonaraido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyana
  • the indicated group can contain from “a” to “b”, inclusive, carbon atoms.
  • a “Cj to C 4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (Ci h bC! i-. ( ⁇ ! -,( ⁇ ⁇ . ⁇ 1 ⁇ ⁇ ⁇ . CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-. If no "a” and "b” are designated, the broadest range described in these definitions is to be assumed.
  • R groups are described as being “taken together” the R groups and the atoms they are attached to can form a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle.
  • R a and R b of an NR a R group are indicated to be “taken together,” it means that they are covalently bonded to one another to form a ring:
  • alk l refers to a fully saturated aliphatic hydrocarbon group.
  • the alkyl moiety may be branched or straight chain.
  • branched alkyl groups include, but are not limited to, iso-propyl, sec-butyl, t-butyl and the like.
  • straight chain alkyl groups include, but are not limited to, methyl, ethyl, n- propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl and the like.
  • the alkyl group may have 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as “1 to 30" refers to each integer in the given range; e.g., "1 to 30 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, although the present definition also covers the occurrence of the term "alkyl” where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 12 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 6 carbon atoms.
  • An alkyl group may be substituted or unsubstituted.
  • alkenyi refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon double bond(s) including, but not limited to, 1-propenyl, 2-propenyl, 2-methyl-l-propenyl, 1- butenyl, 2-butenyl and the like.
  • An alkenyi group may be unsubstituted or substituted.
  • alkynyl refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon triple bond(s) including, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl and the like.
  • An alkynyl group may be unsubstituted or substituted.
  • cycloalkyl refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion. Cycloalkyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the nng(s) or 3 to 6 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted.
  • fused refers to a connectivity between two rings in which two adjacent atoms sharing at least one bond (saturated or unsaturated) are common to the rings.
  • rings A and B are fused
  • fused ring structures include, but are not limited to, decahydronaphthalene, lH-indole, quinolone, chromane, bicyclo[2.1.0]pentane and 6,7,8,9- tetrahydro-5H-benzo[7]annulene.
  • bridged refers to a connectivity wherein three
  • bridged rings because the indicated atoms are shared between at least two rings.
  • Examples of bridged ring structures include, but are not limited to, bicyclo[l . l . l ]pentane, 2-oxabicyclo[l.. l . l]pentane, 5-azabicyclo[2.1.1 ]hexane, 6- azabicyclo[3.1. ljheptane, adamantane and norbornane.
  • spiro refers to a connectivity betwe rings
  • rings C and D are joined by a spiro connection.
  • spiro connected ring structures include, but are not limited to, spiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 2-oxa-6- azaspiro[3.3]heptane, spiro[4.5]decane and 2,6-dioxaspiro[3.3]heptane.
  • cycloalkenyl refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocahzed pi- electron system throughout all the rings (otherwise the group would be "aryl,” as defined herein).
  • Cycloalkenyl groups can contain 3 to 30 atoms in the rmg(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the rmg(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). When composed of two or more rings, the rings may be connected together in a fused, bridged or spiro fashion.
  • a cycloalkenyl group may be unsubstituted or substituted.
  • cycloalkynyi refers to a mono- or muiti- cyclic hydrocarbon ring system that contains one or more triple bonds in at least one ring. If there is more than one triple bond, the triple bonds cannot form a fully delocalized pi-electron system throughout all the rings.
  • Cycloalkynyi groups can contain 8 to 30 atoms in the ring(s), 8 to 20 atoms in the ring(s) or 8 to 10 atoms in the ring(s). When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion.
  • a cycloalkynyi group may be unsubstituted or substituted.
  • aryl refers to a carboeyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carboeyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings.
  • the number of carbon atoms in an aryl group can vary.
  • the aryl group can be a C 6 -C 14 aryl group, a ( Cio aryl group, or a C 6 aryl group.
  • Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene.
  • An aryl group may be substituted or unsubstituted.
  • heteroaryl refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1, 2, 3, 4 or 5 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur.
  • the number of atoms in the rmg(s) of a heteroaryl group can vary.
  • the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s).
  • heteroaryl includes fused ring systems.
  • heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazme, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, ,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, mdazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazoie, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, ptendine, quinolme, isoquinoline, quinazoline, quinoxaline, cmnoline and triazine.
  • a heteroaryf group may be
  • heterocyclyl or “heteroalicyclyl” refers to three-, four-, five-, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicychc and tricyclic ring systems wherein carbon atoms together with from 1 to 5 heteroatonis constitute said ring system.
  • a heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings.
  • the heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur and nitrogen.
  • a heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio- systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion. Additionally, any nitrogens in a heteroalicyclic may be quaternized. Heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted.
  • heterocyclyl or “heteroalicyclyl” groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1 ,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4- oxathiin, 1 ,3-oxathiolane, 1 ,3-dithiole, 1 ,3-dithiolane, 1 ,4-oxathiane, tetrahydro-l ,4-thiazine, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazme, hydantoin, dihydrouracil, tnoxane, hexahydro-l,3,5-triazine, imidazoline, imidazoline, imid
  • bridged heterocyclic compounds include, but are not limited to, l,4-diazabicyclo[2.2.2]octane and 1 ,4- diazabicyclo[3.1.1]heptane.
  • spiro-connected heterocyclic compounds include, but are not limited to, 2-azaspiro[3,3]heptane, 2,6-diazaspiro[3,3]heptane, and 2-oxa-6- azaspiro [3 , 3 ]heptane.
  • araikyl and “aryl(alkyl)” refer to an aryl group connected, as a substituent, via a lower alkylene group.
  • the lower alkyiene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenylalkyl, 3-phenylalkyl and naphthylalkyl.
  • heteroarylkvl and “heteroaryl(alkyl)” refer to a heteroaryl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and heteroaryl group of heteroaralkvl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl and imidazolylalkyl and their benzo-fused analogs.
  • heteroalicyclyl(alkyl) and “heterocyclyl(alkyl)” refer to a heterocyclic or a heteroalicyclylic group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-y] (ethyl), piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl) and 1 ,3- thiazinan-4-y 1 (methyl) .
  • lower alkylene groups are straight-chained -CH 2 - tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -) and butylene (-CH 2 CH 2 CH 2 CH 2 -).
  • a lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group and/or b - substituting both hydrogens on the same carbon with a cycloalkyl group (e.g.,
  • hydroxy refers to a -OH group.
  • alkoxy refers to the Formula -OR wherein R is an alkyl, an aikenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein.
  • R is an alkyl, an aikenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein.
  • alkoxys are methoxy, ethoxy, n-propoxy, 1 -methylethoxy (isopropoxy), n-butoxy, iso-butoxy,
  • acyl refers to a hydrogen, alkyl, aikenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) and heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include forniyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted. [0116] A "cyano" group refers to a "-CN" group.
  • halogen atom or “halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.
  • a thiocarbonyl may be substituted or unsubstituted.
  • An O-carbamyl may be substituted or unsubstituted.
  • An N-carbamyl may be substituted or unsubstituted.
  • An O-thiocarbamyl may be substituted or unsubstituted.
  • An N-thiocarbamyl may be substituted or unsubstituted.
  • a C-amido may be substituted or unsubstituted.
  • An N-amido may be substituted or unsubstituted.
  • S-sulfonaniido refers to a "-S0 2 N(R A 3 ⁇ 4)" group in which R A and R B can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyi, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(aikyl).
  • An S-sulfonamido may be substituted or unsubstituted.
  • N-sulfonamido refers to a "RS0 2 N(R A )-" group in which R and R A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyi, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyi), heteroaryl(alkyl) or heterocyclyl (alkyl).
  • R and R A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyi, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyi), heteroaryl(alkyl) or heterocyclyl (alkyl).
  • An N-sulfonamido may be substituted or unsubstituted.
  • An O-carboxy may be substituted or unsubstituted.
  • An ester and C-carboxy may be substituted or unsubstituted.
  • An "isocyanato” group refers to a "-NCO” group.
  • a "thiocyanato" group refers to a "-CNS” group.
  • An "isothiocyanato" group refers to an " -NCS” group.
  • a "nitro” group refers to an " -N0 2 " group.
  • a “suifenyi” group refers to an "-SR" group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyi, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cydoalkyl(alkyf), aryl(alkyl), heteroaryl(alkyf) or heterocyciylfalkyi).
  • a suifenyi may be substituted or unsubstituted.
  • a sulfinyl may be substituted or unsubstituted.
  • a "sulfonyl” group refers to an “S0 2 R” group in which R can be the same as defined with respect to suifenyi.
  • a sulfonyl may be substituted or unsubstituted.
  • haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haioaikyl, di-haloalkyi and tri- haioalkyl).
  • a halogen e.g., mono-haioaikyl, di-haloalkyi and tri- haioalkyl.
  • groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, l-chloro-2-fluoromethyl and 2-fluoroisobutyl.
  • a haioalkyl may be substituted or unsubstituted.
  • haloalkoxy refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy).
  • a halogen e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy.
  • groups include but are not limited to, chloromethoxy, fluoromethoxy, difiuoromethoxy, trifluoromethoxy, l-chloro-2-fluoromethoxy and 2- fluoroisobutoxy.
  • a haloalkoxy may be substituted or unsubstituted.
  • a "mono-substituted amino” group refers to a " - ⁇ IK " group in which R can be an alkyl, an aikenyl, an alkynyi, a cycloaikyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl (alkyl), as defined herein.
  • a mono-substituted ammo may be substituted or unsubstituted. Examples of mono- substituted amino groups include, but are not limited to, -NH(methyl), -NH(phenyl) and the like.
  • a "di ⁇ substituted ammo" group refers to a "-NR A R B " group in which R A and R B can be independently an alkyl, an aikenyl, an alkynyi, a cycloaikyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein.
  • a di-substituted ammo may be substituted or unsubstituted. Examples of di-substituted amino groups include, but are not limited to, -N(methyl) 2 , -N(phenyl)(methyl), -N(ethyl)(methyl) and the like.
  • substituents there may be one or more substituents present.
  • haioalkyl may include one or more of the same or different halogens.
  • C-.-Cj alkoxyphenyl may include one or more of the same or different alkoxy groups containing one, two or three atoms.
  • a radical indicates species with a single, unpaired electron such that the species containing the radical can be covalently bonded to another species.
  • a radical is not necessarily a free radical. Rather, a radical indicates a specific portion of a larger molecule.
  • the term "radical” can be used interchangeably with the term "group.”
  • asterisk indicates a point of attachment of the group or unit to another structure.
  • salts refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • the salt is an acid addition salt of the compound.
  • Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), a sulfuric acid, a nitric acid and a phosphoric acid (such as 2,3- dihydroxypropyl dihydrogen phosphate).
  • Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, trifluoroaeetie, benzoic, salicylic, 2- oxopentanedioic, or naphthalenesulfonic acid.
  • an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids
  • Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium, a potassium or a lithium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of a carbonate, a salt of a bicarbonate, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, eyclohexylarmne, triethanol amine, ethylenediamine, and salts with amino acids such as arginine and lysine.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium, a potassium or a lithium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of a carbonate, a salt of a bicarbonate, a salt of
  • a salt is formed by protonation of a nitrogen-based group (for example, NH 2 )
  • the nitrogen-based group can be associated with a positive charge (for example, NH 2 can become NH3 "1 and the positive charge can be balanced by a negatively charged counterion (such as CI " ).
  • each center may independently be of R-configuration or S-configuration or a mixture thereof.
  • the compounds provided herein may be enantiomericafly pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomencally enriched, or a stereoisomeric mixture.
  • each double bond may independently be E or Z a mixture thereof.
  • ail tautomeric forms are also intended to be included.
  • valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen- 1 (protium) and hydrogen-2 (deuterium).
  • each chemical element as represented in a compound structure may include any isotope of said element.
  • a hydrogen atom may be explicitly disclosed or understood to be present in the compound.
  • the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium).
  • reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
  • the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates.
  • the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or the like.
  • the compounds described herein exist in unsolvated form.
  • Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may ⁇ be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • the term 'including' should be read to mean 'including, without limitation,' 'including but not limited to,' or the like;
  • the term 'comprising' as used herein is synonymous with 'including,' 'containing,' or 'characterized by,' and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps;
  • the term 'having' should be interpreted as 'having at least;
  • the term 'includes' should be interpreted as 'includes but is not limited to;
  • the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least”.
  • the term “comprising” means that the process includes at least the recited steps, but may include additional steps.
  • the term “comprising” means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components.
  • a group of items linked with the conjunction 'and' should not be read as requiring that each and every one of those items be present in the grouping, but rather should be read as 'and/or' unless the context indicates otherwise.
  • a group of items linked with the conjunction Or' should not be read as requiring mutual exclusivity among that group, but rather should be read as 'and/or' unless the context indicates otherwise.
  • the compounds of Formula (I) are useful for ameliorating, treating and/or diagnosing a fungal infection. Additional details regarding various uses and methods of treatment are described elsewhere herein.
  • the variable R 1 in Formula (I) is -R or -C(0)R + .
  • variable R " in Formula (I) is selected from the group consisting of — NR 8A R 8B ; -(NR 9A R 9B R 9C ) + and - HC(0)R 10 .
  • the variables R J , R 4 , R 5 i , R sb , R 6 , and X 1 in the description of the variable R 1 and the variables R 8A , R 8ci , R 9A , R 9B , R 9C and R l0 in the description of the variable R " are as described elsewhere herein.
  • Examples of compounds of the Formula (I) thus include those having the general structures summarized in Table 1 . TABLE 1 : General structures of compounds of the Formula (I)
  • variable R 3 is selected from the group consisting of hydrogen, an unsubstituted C3 ⁇ 4 .6 a iky I. a substituted C 1-6 alkyl, an optionally substituted C3..7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl.
  • the variable R 3 is not hydrogen.
  • R 3 is not an unsubstituted C 1-6 alkyl.
  • R 3 is not a substituted Ci-e alkyl
  • R 3 is not an optionally- substituted C3-7 cycloalkyl.
  • R 3 is not an optionally substituted aryl.
  • R 3 is not an optionally substituted heteroaryl.
  • 5 is not an optionally substituted monocyclic heterocyclyl.
  • R 3 is selected from the group consisting of an unsubstituted C 1-6 alkyl, a substituted C 1-6 alkyl, and an optionally substituted C3-7 cycloalkyl.
  • R 3 is a substituted C 1 -6 alkyl that is substituted with a moiety selected from the group consisting of hydroxy, alkoxy, amino, C3-7 cycloalkyl, halogen, a mono- substituted amine, a di-substituted amine, an optionally substituted N-linked monocyclic heteroaryl, an optionally substituted aryl, an optionally substituted monocyclic heterocyclyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, and an optionally substituted N-linked monocyclic heterocyclyl.
  • R is a C 1-6 haloalkyl.
  • R is an optionally substituted C 3-7 cycloalkyl that is selected from the group consisting of optionally substituted cyclopropane, optionally substituted cyclobutane, optionally substituted bicyciobutane, optionally substituted eyeiopentane, optionally substituted bicvclopentane, and optionally substituted cyclohexane.
  • R 3 is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl.
  • Examples of include hydrogen, methyl, ethyl, benzyl, hydroxyethyl, aminoethyl, cyclopropyl, cyclobutyi, cyclopentyl, aminocyclopentyl, hydroxycyclopentyl, bicyclobutyl, bi cyclopentyl, hydroxymethyl bic clopentyl, amino bicyclopentyl, aminomethyl bicyclopentyl, imidazolyl, amino imidazolyl, phenyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl.
  • variable R 4 is selected from, the group consisting of hydrogen, an unsubstituted C3 ⁇ 4 .6 alkyl, a substituted C 1-6 alkyl, an optionally substituted C3..7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl.
  • R is not hydrogen.
  • R * is not an unsubstituted C 1-6 alkyl.
  • R 4 is not a substituted Ci-e alkyl.
  • R 4 is not an optionally substituted C 3-7 cycloalkyl.
  • R 4 is not an optionally substituted aryl.
  • R 4 is not an optionally substituted heteroaryl.
  • R " is not an optionally substituted monocyclic heterocyclyl.
  • R 4 is selected from the group consisting of an unsubstituted C 1-6 alkyl, a substituted C 1-6 alkyl, and an optionally substituted C 3-7 cycloalkyl.
  • R 4 is a substituted C 1-6 alkyl that is substituted with a moiety selected from the group consisting of hydroxy, alkoxy, amino, C 3-7 cycloalkyl, halogen, a mono- substituted amine, a di-substituted amine, an optionally substituted N-linked monocyclic heteroaryl, an optionally substituted aryl, an optionally substituted monocyclic heterocyclyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, and an optionally substituted N-linked monocyclic heterocyclyl.
  • R 4 is a C 1-6 haloalkyl.
  • R 4 is an optionally substituted C -7 cycloalkyl that is selected from the group consisting of optionally substituted cyclopropane, optionally substituted cyclobutane, optionally substituted bicyclobutane, optionally substituted cyclopentane, optionally substituted bicyclopentane, and optionally substituted cyclohexane.
  • R * is selected from the group consisting of an optionally substituted aryi, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl.
  • R 4 examples include methyl, ethyl, benzyl, hydroxyethyl, aminoethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminocyclopentyl, hydroxycyclopentyl, bicyclobutyl, bicyclopentyl, hydroxymethyl bicyciopentyl, amino bicyclopentyl, aminomethyl bicyclopentyl, imidazolyi, amino imidazolyl, phenyl, morpholinyl, piperazinyl, piperidmyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl.
  • variable R 5A is selected from the group consisting of hydrogen, an unsubstituted C e alkyl, a substituted C 1-6 alkyl, an optionally substituted C 3-7 cycloalkyl, an optionally substituted aryi, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl.
  • R 5A is not hydrogen.
  • R 5A is not an unsubstituted C 1-6 alkyl.
  • R sA is not a substituted C 1-6 alkyl.
  • R ⁇ A is not an optionally substituted C3.7 cycloalkyl.
  • R " A is not an optionally substituted aryi.
  • R sA is not an optionally substituted heteroaryl.
  • R sA is not an optionally substituted monocyclic heterocyclyl.
  • R 5 i is selected from the group consisting of an unsubstituted C 1-6 alkyl, a substituted C 1-6 alkyl, and an optionally substituted C 3-7 cycloalkyl.
  • R ⁇ is a substituted C 1-6 alkyl that is substituted with a moiety selected from the group consisting of hydroxy, alkoxy, ammo, C 3-7 cycloalkyl, halogen, a mono- substituted amine, a di-substituted amine, an optionally substituted N-linked monocyclic heteroaryl, an optionally substituted aryi, an optionally substituted monocyclic heterocyclyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, and an optionally substituted N-linked monocyclic heterocyclyl.
  • R JA is a C 1-6 haloalkyl.
  • R 5A is an optionally substituted C 3-7 cycloalkyl that is selected from the group consisting of optionally substituted cyclopropane, optionally substituted cvclobutane, optionally substituted bicyclobutane, optionally substituted cyclopentane, optionally substituted bicyclopentane, and optionally substituted cyclohexane.
  • R 5A is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl.
  • R 5A examples include methyl, ethyl, benzyl, hydroxyethyl, ammoethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminocyclopentyl, hydroxycyclopentyl, bicyclobutyl, bicyclopentyl, hydroxymethyl bicyciopentyl, amino bicyclopentyl, aminomethyl bicyclopentyl, imidazolyl, amino imidazolyl, phenyl, morpholinyl, piperazinyl, piperidmyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl.
  • variable R " is selected from the group consisting of hydrogen, an unsubstituted C , alkyl, a substituted Ci wind6 alkyi, an optionally substituted C 3-7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl
  • R 5B is not hydrogen.
  • R 5B is not an unsubstituted C 1-6 alkyl.
  • R 5B is not a substituted Cj.e alkyl.
  • R 5B is not an optionally substituted C3.7 cycloalkyl.
  • R 5B is not an optionally substituted aryl.
  • R 5B is not an optionally substituted heteroaryl.
  • R sb is not an optionally substituted monocyclic heterocyclyl.
  • R 5B is selected from the group consisting of an unsubstituted C 1-6 alkyl, a substituted C 1-6 alkyl, and an optionally substituted C 3-7 cycloalkyl.
  • R sb is a substituted C 1-6 alkyl that is substituted with a moiety selected from the group consisting of hydroxy, alkoxy, amino, C 3-7 cycloalkyl, halogen, a mono- substituted amine, a di-substituted amine, an optionally substituted N-linked monocyclic heteroaryl, an optionally substituted aryl, an optionally substituted monocyclic heterocyclyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, and an optionally substituted N-linked monocyclic heterocyclyl.
  • R 5B is a Cj-6 haloalkyl.
  • R 5B is an optionally substituted C 3- cycloalkyl that is selected from the group consisting of optionally substituted cyclopropane, optionally substituted cvclobutane, optionally substituted bicyclobutane, optionally substituted cyclopentane, optionally substituted bicyclopentane, and optionally substituted cyclohexane.
  • R 5B is selected from the group consisting of an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl.
  • R " examples include methyl, ethyl, benzyl, hydroxyethyl, aminoethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminocyclopentyl, hydroxycyclopentyl, bicyclobutyl, bicyclopentyl, hydroxymethyl bicyclopentyl, amino bicyclopentyl, aminomethyl bicyclopentyl, imidazolyi, amino imidazolyl, phenyl, morpholinyl, piperazinyl, piperidmyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl.
  • R 5A and R 5B together with the N to which they are attached, form an optionally substituted monocyclic heterocyclyl.
  • optionally substituted monocyclic heterocyciyls include pyrrolidinyl, imidazolidmyl, pyrazolidinyl, piperidinyi, morpholinyl, and piperazinyl.
  • the formed monocyclic heterocyciyls may be optionally substituted by one or more groups selected from alkyl, halogen, amino, hydroxy, alkoxy, hydroxyalkyl, aminoalkyl, cycloalkyl, aryl, and heteroaryi.
  • X 1 is O or S.
  • variable R b is selected from the group consisting of hydrogen, an unsubstituted C e alkyl, a substituted C 1-6 alkyl, an optionally substituted C 3-7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryi, and an optionally substituted monocyclic heterocyclyl.
  • R° is not hydrogen.
  • R 6 is selected from the group consisting of an unsubstituted C 1-6 alkyl, a substituted C 1-6 alkyl, and an optionally substituted C 3-7 cycloalkyl.
  • R 6 is a substituted C 1-6 alkyl that is substituted with a moiety selected from the group consisting of hydroxy, alkoxy, ammo, C 3-7 cycloalkyl, halogen, a mono- substituted amine, a di-substituted amine, an optionally substituted N-linked monocyclic heteroaryi, an optionally substituted aryl, an optionally substituted monocyclic heterocyclyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryi, and an optionally substituted N-linked monocyclic heterocyclyl.
  • R° is a C 1-6 haloalkyl.
  • R 6 is an optionally substituted C 3-7 cycloalkyl that is selected from the group consisting of optionally substituted cyclopropane, optionally substituted cyclobutane, optionally substituted bicyclobutane, optionally substituted cyclopentane, optionally substituted bicvclopentane, and optionally substituted cyclohexane.
  • R 6 is selected from the group consisting of an optionally substituted aryi, an optionally substituted heteroaiyl, and an optionally substituted monocyclic heterocyclyl.
  • R 6 examples include methyl, ethyl, benzyl, hydroxyethvl, aminoethyl, cyclopropyl, cyclobutyl, cyclopentyl, aminocyclopentyl, hydroxycyclopentyl, bicyelobutyl, bicyclopentyl, hydroxymethyl bicyciopentyl, amino bicyclopentyl, aminomethyl bicyclopentyl, imidazolyi, amino imidazolyl, phenyl, morpholinyl, piperazinyl, piperidmyl, pyrrolidinyl, oxetanyl, tetrahydrofuranyl and tetrahydropyranyl.
  • R " is selected from the group consisting of hydrogen, an optionally substituted Cj-6 alkyi, an optionally substituted C3.6 cycloalkyl, -(C 2-6 aikyl)-OR H , ⁇ (C 2-6 alkyl)-NR l2A R l2B , -(C 2 . 6 alkyl)-(NR 13A R 13B R !3C ) + , and
  • R 8A is not hydrogen. In an embodiment, R 8A is not alkyl. In an embodiment, R 8A is not optionally substituted alkyl. In an embodiment, R 8A is methyl. In another embodiment, R SA is ethyl or aminoethyl, for example -(CH 2 ) 2 -NH 2 .
  • R 8B is selected from the group consisting of hydrogen, an optionally substituted C 1-6 alkyl, an optionally substituted C3-6 cycloalkyl, -(C 2-6 alkyl)-OR n , -(C 2-6 alkyl)-NR 12A R 12B , -(C 2 _ 6 alkyl) ⁇ (NR 13A R 13B R I3C ) + , and
  • R is not hydrogen. In an embodiment, R is not alkyl. In an embodiment, R ' is not optionally substituted alkyl. In an embodiment, R 1 is methyl. In another embodiment, R 8B is ethyl or aminoethyl, for example -(CH 2 ) 2 -NH 2 . In an embodiment, R 8A is hydrogen.
  • R" is selected from the group consisting of hydrogen, an optionally substituted C 1-6 alkyl, an optionally substituted C3-6 cycloalkyl, -(C 2-6 alkyl)-OR j j , -(C 2-6 alkyl)- R. 12A R 12B , ⁇ (C 2 _ 6 alkyl)-(NR 13A R 13B R i3C ) + , and
  • R ' is not hydrogen. In an embodiment, R" is not alkyl. In an embodiment, R A is not optionally substituted alkyl. In an embodiment, R ' is methyl. In another embodiment, R 9A is ethyl or aminoethyl, for example -(CH 2 ) 2 ⁇ NH 2 . [0175] In various embodiments, R 9B is selected from the group consisting of hydrogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-6 cycloalkyl, -(C 2-6 alky! -OR ; ; . -(C 2 - 6 alkyl)-NR f 2A R f 2B , ⁇ (C 2 . 6 aikyl) ⁇ (NR 13A R 13B R i3C ) + , and
  • R 9B is not hydrogen. In an embodiment, R 9B is not alkyl. In an embodiment, R "" is not optionally substituted alkyl. In an embodiment, is methyl. In another embodiment, R 9B is ethyl or aminoethyl, for example -(CH 2 ) 2 -NH 2 .
  • R 9C is selected from the group consisting of hydrogen, an optionally substituted C 1-6 alkyl, an optionally substituted C 3-6 cycloalkyl, -(C 2-6 alkyl )-OR ". ⁇ -(( -, alkyl)-NR l2A R l2B , -(C 2 . 6 alkyl)-(NR 13A R 13B R 13C ) + , and
  • R 9C is not hydrogen. In an embodiment, R 9C is not alkyl. In an embodiment, R l is not optionally substituted alkyl. In an embodiment, R " is methyl. In another embodiment, R 9C is ethyl or aminoethyl, for example -(CH 2 ) 2 -NH 2 .
  • R 10 is selected from the group consisting of an optionally substituted C 1-6 alkyl, an optionally substituted C 3 - 6 cycloalkyl, -(C 2-6 aikyl)-OR H ,
  • R 1G is ethyl, methyl, propyl or butyl.
  • R 8A , R 8B , R 9A , R 9B , R 9C and/or R 10 are positively charged
  • the positive charge can be balanced by association with a negatively- charged counterion (such as CI " ) to form a salt, which may be a pharmaceutically acceptable salt.
  • R 11 , R 12A , R i2B , R i3A , R 13B and R 5 C are each independently selected from the group consisting of hydrogen and an unsubstituted C 1-6 alkyl.
  • one or more of R 11 , R 3 ⁇ 4 A , R i2B , R 1 A , R 3 ⁇ 4 3B and/or R r3C are not hydrogen.
  • 2B , ⁇ R i iA , R i B and/or R J jC are selected from the group consisting of ethyl, methyl, propyl and butyl.
  • each n is independently zero or an integer in the range of 1 to about 40. In an embodiment, each n is independently zero or an integer in the range of 1 to about 10. For example, in an embodiment each n is independently zero, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10.
  • R 1 is -C(G)NR 5A R 5B
  • R 2 is -NH 2 and one or the other of R 3A and R 5B is H
  • the other of R 5ft and R 3B is not -C3 ⁇ 4.
  • R 1 when R 1 is -QC NR ⁇ R 36 , R 2 is -Nil?, and one or the other of R 5A and R 5B is H, then the other of R 5A and R 5B is not -O S -C ' HAl k
  • R 1 when R 1 is - C(0)NR 5A R 5B , R is -NH 2 and one or the other of R 5A and R 5B is H, then the other of R 5A and R 5B is not -CH 2 CH 2 C(0)OH.
  • R 1 when R 1 is ⁇ C(0)NR 5A R 5B and R 2 is Ni k then -M R cannot be -N(H) -N(H)CH 2
  • R 2 is selected from -NR 8A R 8B and - HC(O)R 3 ⁇ 40 .
  • R when R is -C(0)R and R is NH 2 , then R " is not an N-linked optionally substituted monocyclic heterocyclyl.
  • R is -C(0)R
  • R " is not selected from substituents A, B, C, D, E, F, G, H, I or J, as follows;
  • R 4 is not selected from substituents A, B, C, D, E, F, G, FI, I or J.
  • R 4 is not selected from the group consisting of methyl, ethyl, propyl, isopropyl, propenyl,
  • the compound of Formula (I), or a pharmaceutically acceptable salt thereof is not a compound that is disclosed in any of the following publications: WO 201 6/168568, WO 201 5/190587, WO 2015/054148, and WO 2014/165676, each of which is incorporated herein by reference in its entirety and for the express purpose of describing particular compounds that are not, in various embodiments, a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
  • R 3A is hydrogen, an unsubstituted Cj-6 alkyl, a substituted Ci-6 alkyl, an optionally substituted C3-7 cycioalkyl, an optionally substituted CH 2 -aryl, an optionally substituted -CH 2 -heteroaryl, or an optionally substituted monocyclic heterocyclyl.
  • R A is a substituted C 1-6 alkyl that is substituted with a moiety selected from the group consisting of hydroxy, alkoxy, amino, C3-7 cycioalkyl, halogen, a mono- substituted amine, a di-substituted amine, an optionally substituted N-linked monocyclic heteroaryl, an optionally substituted aryl, an optionally substituted monocyclic heterocyclyl, an optionally substituted heterocyclyl, an optionally substituted heteroaryl, and an optionally substituted N-lmked monocyclic heterocyclyl.
  • R A is hydrogen.
  • R 3A is methyl.
  • R 3A is ethyl or propyl.
  • R 3B is methyl.
  • R B is ethyl or propyl.
  • R 3C is hydrogen.
  • R jC is a protecting group.
  • R jC can be allyloxycarbonyl (Alloc), fluorenylmethyloxycarbonyl (Fmoc) or carboxybenzyl (Cbz).
  • R 3C is not a silyl protecting group.
  • R D is hydrogen.
  • R 3D is a protecting group.
  • R 3D can be allyloxycarbonyl (Alloc), fluorenylmethyloxycarbonyl (Fmoc), or carboxybenzyl (Cbz).
  • R jD is not a silyl protecting group.
  • protecting groups suitable for R jC and R 3D including selecting suitable protecting groups from among those described in Kocienski, P.J. Protecting Groups (3 rd Ed., Theme, 2004), and/or Wuts, P. G. M. and Greene, T.W., Greene's Protective Groups in Organic Synthesis, (4 th Ed., Wiley, 2006), which are hereby incorporated herein by reference and particularly for the purpose of describing protective groups.
  • Figure 24C and Example 24 describe the preparation of compound 24- 1 , which is a compound of Formula (II) in which R J " is hydrogen, R jB is -CH 3 , and R jC and R 3D are both Alloc protecting groups.
  • compounds of Formula (II) can be used as starting materials or intermediates to prepare other compounds.
  • compounds of Formula (II) can be used to prepare compounds of Formula (I).
  • Figure 27C and Example 27 describe the preparation of compound 27, a compound of Formula (I) in which R f is -C(0)CH 3 and R 2 is -NH , using a process in which compound 24-1 is a starting material and compounds 27-1 and 27-2 are intermediates.
  • An embodiment provides an acylation process, comprising reacting a compound of Formula (II) with a carboxylic acid of formula R -C0 2 H under acylation conditions selected to form a compound of Formula (la), as illustrated in FIG. 38.
  • R jA , R 3b , R 3C and R jD in Formula (II) and (la) are defined as described elsewhere herein for Formula (II).
  • R in Formula (la) and in the formula R -C0 2 H are defined as described elsewhere herein for Formula (I).
  • R 3A is hydrogen
  • R iB is an unsubstituted C-. -3 alkyi
  • R iC is a protecting group
  • R' 0 is a protecting group
  • R 4 is selected from the group consisting of an unsubstituted C 1-6 alkyl, a substituted C 1-6 alkyl, an optionally substituted C3-7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl.
  • Compound 27-1 is an example of a compound of the Formula (la).
  • acylation conditions selected to form a compound of Formula (la) include conducting the reaction of the compound of Formula (II) with the carboxylic acid of formula 4 -C0 2 PI in the presence of an organic solvent suitable for acylation reactions, such as a polar organic solvent or a non-polar organic solvent.
  • organic solvents are known to those skilled in the art, and include, for example, dichloromethane (DCM), tetrahydrofuran (THF), and dimethylformamide (DMF).
  • acylation conditions selected to form a compound of Formula (la) include conducting the reaction of the compound of Formula (II) with the carboxylic acid of formula R 4 -C0 2 H in the presence of an acylating agent that promotes acylation reactions.
  • acylating agents include, for example, 1- [bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3- oxidhexafluorophosphate) (HATU), diisopropylcarbodiimide (DIG), dicyclohexylcarbodiimide (DCC), N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide ⁇ HC1 (EDC ⁇ HC1), ⁇ , -Car bony ldiimidazole, benzotriazol-l-yloxy-tripyrrolidino-phosphonium hexafluorophosphate (PyBOP 3 ⁇ 4 ), 7- Aza-benzotriazol- 1 -yloxy-tripyrrolidinophosphonium hexafluorophosphate (Py AOP), 2 ⁇ ( 1 H-Benzotria
  • acylation conditions selected to form a compound of Formula (la) include conducting the reaction of the compound of Formula (II) with the carboxylie acid of formula R 4 -C0 2 H in the presence of a base that promotes acylation reactions.
  • bases are known to those skilled in the art.
  • the base is an inorganic base.
  • inorganic bases include, for example, Na 2 C0 3 , K 2 C0 3 , Li 2 C0 3 , Cs 2 C0 3 , KOtBu, K2HPO4, Na 2 HP04, Na 3 P0 4 , :! ⁇ '().:.
  • the base is an organic base.
  • organic bases include, for example, triethylamine (TEA), pyridine, N,N- diisopropylethylamine (DIPEA), piperidine, morpholine, Proton SpongeTM, 4- (Dimethylamino)pyridine, and 1 ,8-Diazabicyclo[5.4.0]undec-7-ene (DBU).
  • An embodiment provides a reductive amination process, comprising reacting a compound of Formula (II) with an aldehyde of formula R 4 -COH under conditions selected to form a compound of Formuia (lb), as illustrated in FIG. 39.
  • R , R , R and R ,D in Formula (II) and (lb) are defined as described elsewhere herein for Formula (II).
  • R 4 in Formula (lb) and in the formula R 4 -CQH are defined as described elsewhere herein for Formula (I).
  • R ,A is hydrogen
  • R' B is an unsubstituted Cj_3 alkyl
  • R C is a protecting group
  • R ,D is a protecting group
  • R 4 is selected from the group consisting of an unsubstituted C 1-6 alkyl, a substituted C 1-6 alkyl, an optionally substituted C3-7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic heterocyclyl.
  • reductive amination conditions selected to form a compound of Formula (lb) include conducting the reaction of the compound of Formula (II) with the aldehyde of formula R 4 ⁇ COH in the presence of a solvent suitable for reductive ammation reactions, such as a polar aprotic solvent.
  • a solvent suitable for reductive ammation reactions such as a polar aprotic solvent.
  • solvents include, for example, chloroform, ,2-dichloroethane (DCE), tetrahydrofuran (THF), N,N-dimethyiformamide (DMF), and acetonitrile.
  • reductive amination conditions selected to form a compound of Formula (lb) include conducting the reaction of the compound of Formula (II) with the aldehyde of formula R 4 -COH in the presence of a solvent suitable for reductive ammation reactions, such as a polar protic solvent.
  • solvents are known to those skilled in the art, and include, for example, methanol (MeOH).
  • reductive amination conditions selected to form a compound of Formula (lb) include conducting the reaction of the compound of Formula (II) with the aldehyde of formula R 4 -COH in the presence of an acid that promotes reductive ammation reactions.
  • reductive amination conditions selected to form a compound of Formula (lb) include conducting the reaction of the compound of Formula (II) with the aldehyde of formula R 4 -COH in the presence of a reducing agent that promotes reductive ammation reactions.
  • reducing agents include, for example, sodium borohydnde, sodium cyaiioborohydride, sodium triacetoxyborohydride, trietliylsilane, and phenyl silane.
  • a compound of formula (lb) can also be prepared from a compound of Formula (II) via an alkylation process as illustrated in FIG. 40.
  • an embodiment provides an alkylation process, comprising reacting a compound of Formula (II) with a compound of formula R' t -CH 2 -X under conditions selected to form a compound of Formula (lb).
  • R' A , K iB , R 3C and R' D in Formula (II) and (lb) are defined as described elsewhere herein for Formula (II).
  • R 4 in Formula (lb) and in the formula R 4 -CH 2 -X are defined as described elsewhere herein for Formula (I).
  • X in the formula R 4 -CH 2 -X is a halide or pseudohalide.
  • X is a halide (such as chloride, bromide or iodide) or a pseudohalide (such as triflate, mesylate, tosylate, nitrophenyl sulfonate, bromophenyl sulfonate, benzene sulfonate or phosphate)
  • R 3A is hydrogen
  • R 3B is an unsubstituted Ci- 3 alkyl
  • R 3C is a protecting group
  • R 3D is a protecting group
  • R 4 is selected from the group consisting of an unsubstituted C 1-6 alkyl, a substituted C3 ⁇ 4 .6 alkyl, an optionally substituted C 3-7 cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted monocyclic hetero
  • alkylation conditions selected to form a compound of Formula (lb) include conducting the reaction of the compound of Formula (II) with the compound of formula R 4 -CH 2 -X in the presence of a solvent suitable for alkylation reactions, such as an organic solvent.
  • solvents are known to those skilled in the art, and include, for example, N,N-dimethylformamide (DMF), N-methyl pyrrolidinone, tetrahydrofuran, methylene chloride, and 1,2-dichloroethane.
  • alkylation conditions selected to form a compound of Formula (lb) include conducting the reaction of the compound of Formula (II) with the compound of formula R 4 -CH 2 -X in the presence of a base that promotes alkylation reactions.
  • bases are known to those skilled in the art.
  • the base is an inorganic base, for example, Na 2 C0 3 , K ⁇ ' ()-.. Li 2 C0 3 , Cs 2 C0 3 , KOtBu, K2HPO4, Na 2 HP0 4 , Na 3 P0 4 , K3PO4, NaOAc, OAc, CsOAc, LiOAc, NaHC €>3, HCO3, CsHC0 3 and i.il ICO-..
  • the base is an organic base.
  • organic bases include, for example, triethylamine (TEA), pyridine, ⁇ , ⁇ -diisopropylethylamiiie (DIPEA), piperidine, morpholine, Proton SpongeTM, 4 ⁇ (Dimethylamino)pyridine, and l,8-Diazabicyclo[5.4.0]undec-7-ene (DBU).
  • TAA triethylamine
  • DIPEA ⁇ , ⁇ -diisopropylethylamiiie
  • DBU l,8-Diazabicyclo[5.4.0]undec-7-ene
  • one or more compounds of Formula (I), (la), (lb) and/or (II), or pharmaceutically acceptable salts thereof, or a pharmaceutical composition as described herein can be used to inhibit the growth of a fungus. Growth of a fungus can be inhibited by contacting the fungus with an effective amount of at least one of the compounds described herein, or pharmaceutically acceptable salts thereof.
  • Such contacting of the one or more compounds, or pharmaceutically acceptable salts thereof can take place in various ways and locations, including without limitation away from a living subject (e.g., in a laboratory, diagnostic and/or analytical setting) or in proximity to a living subject (e.g., within or on an exterior portion of an animal, e.g., a human).
  • a living subject e.g., in a laboratory, diagnostic and/or analytical setting
  • a living subject e.g., within or on an exterior portion of an animal, e.g., a human.
  • an embodiment provides a method of treating a fungal infection, comprising identifying a subject in need thereof and administering to said subject an effective amount of one or more compounds of Formula (I), (la), (lb) and/or (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, as described elsewhere herein.
  • compounds of Formula (I), (la), (lb) and/or (II), or a pharmaceutically acceptable salt thereof! can be administered to such subjects by a variety of methods.
  • administration can be by various routes known to those skilled in the art, including without limitation oral, intravenous, intramuscular, topical, systemic, and/or intraperitoneal administration to a subject in need thereof.
  • treat do not necessarily mean total cure or abolition of the fungal infection. Any alleviation of any undesired signs or symptoms of the fungal infection, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject's overall feeling of well-being or appearance.
  • a therapeutically effective amount of compound can be the amount needed to prevent, alleviate or ameliorate symptoms of the fungal infection or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the fungal infection being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein.
  • the therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
  • the amount of the compound of Formula (I), (la), (lb) and/or (II), or a pharmaceutically acceptable salt thereof, required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature and/or symptoms of the fungal infection being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician. In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the dosage ranges described herein in order to effectively and aggressively treat particularly aggressive fungal infections.
  • a suitable dose will often be in the range of from about 0.05 mg/kg to about 10 mg/kg.
  • a suitable dose may be in the range from about 0.10 mg/kg to about 7.5 mg/kg of body weight per day, such as about 0.15 mg/kg to about 5.0 mg/kg of body weight of the recipient per day, about 0.2 mg/kg to 4.00 mg/kg of body weight of the recipient per day.
  • the compound may be administered in unit dosage form; for example, containing 1 to 200 mg, 10 to 100 mg or 5 to 50 mg of active ingredient per unit dosage form.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
  • the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, and mammalian species treated, the particular compounds employed, and the specific use for which these compounds are employed.
  • effective dosage levels that is the dosage levels necessary to achieve the desired result
  • useful dosages of a compound of Formula (I), (la), (lb) and/or (II), or pharmaceutically acceptable salts thereof can be determined by comparing their in vitro activity and in vivo activity in animal models. Such comparison can be done by comparison against an established drug, such as Amphotericin B.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vivo and/or in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value.
  • Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
  • the attending physician would know how to and when to terminate, interrupt or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity).
  • the magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the fungal infection to be treated and to the route of administration. The seventy of the fungal infection may, for example, be evaluated, in pari, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.
  • Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods.
  • the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
  • the toxicity of particular compounds in an animal model such as mice, rats, rabbits, dogs or monkeys, may be determined using known methods.
  • the efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime.
  • compositions that can include an effective amount of one or more compounds described herein (e.g., a compound of Formula (I), (la), (lb) and/or (II), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
  • a pharmaceutically acceptable carrier e.g., a compound of Formula (I), (la), (lb) and/or (II), or a pharmaceutically acceptable salt thereof.
  • compositions refers to a mixture of one or more compounds disclosed herein with other chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanes ulfonic acid, ethanesulfomc acid, p-toluenesulfonic acid, and salicylic acid.
  • Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
  • a carrier refers to a compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • a "diluent” refers to an ingredient in a pharmaceutical composition that lacks appreciable pharmacological activity but may be pharmaceutically necessary or desirable.
  • a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation.
  • a common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the pH and isotonicity of human blood.
  • an “excipient” refers to an essentially inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition.
  • a “diluent” is a type of excipient.
  • compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.
  • compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.
  • a targeted drug delivery system for example, in a liposome coated with a tissue-specific antibody.
  • the liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or pulmonary delivery to target a respiratory infection may be desirable.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions that can include a compound described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • the compounds of Formula (1) and (II) illustrated in FIGURES 1-37 can be prepared in various ways, using techniques known to those skilled in the art as guided by the detailed teachings provided herein.
  • the compounds of Formula (I) illustrated in FIGURES 1-37 can be prepared in accordance with General Scheme 1 as described in Examples 1-37 below, winch are exemplary and can be used as a starting point to prepare a large number of additional compounds beyond those specifically described.
  • Compounds of Formula (II) can also be prepared in accordance with the methods provided in General Scheme 1 and Examples 1-37 below.
  • compounds of Formula (II) can be used as starting materials or intermediates to prepare other compounds.
  • compounds of Formula (II) can be used to prepare compounds of Formula (la) and/or (lb), e.g., via a process that includes an acylation as illustrated in FIG. 38, a reductive animation as illustrated in FIG. 39, and/or an alkylation as illustrated in FIG. 40.
  • acylation as illustrated in FIG. 38
  • reductive animation as illustrated in FIG. 39
  • alkylation as illustrated in FIG. 40.
  • Compound 1 (FIGURE IB) is prepared by Method I, Method 2, Method 3 and/or Method 4, as follows:
  • Step 1 A suspension of Amphotericin B (1 eq.) in DMF:MeOH(2: l ) is treated with pyridine (5 eq.) and Frnoc-Succ (1.5 equi .) at room temperature. After 3 h the reaction mixture is poured into Et 2 0 at 0 °C to precipitate out the product. The crude product is collected using a Buchner funnel, and is washed with additional Et 2 0. The crude product is dried under vacuum and then dissolved in a solution of THF:MeOH (1 : 1) at 0 °C. The solution is treated with CSA (0.5 eq.).
  • Step 2 A solution of Int-1 and 2,6-lutidine (25 eq.) in DCM at 0 °C is treated with a triethylsilyltrifiate (20 eq.) After the reaction is complete, the reaction is quenched with saturated aqueous sodium bicarbonate solution, and diluted with Et 2 0. The organic layer is washed with saturated aqueous sodium bicarbonate solution, and brine. The organic layer is then dried over sodium sulfate, filtered and concentrated under vacuum to provide the crude product. Purification by column chromatography provides Int-2. [0225] Step 3: A solution of Int-2 in THF is treated with triethylamine (1.1 eq.
  • Step 4 A solution of Int-3 in THF:H 2 0 (9: 1) is treated with CSA (5 eq.) and stirred until completion, at which point the reaction is quenched with E N, and concentrated under vacuum to provide the crude product. The crude product is purified by RP-HPLC to provide Compound 1.
  • FIGURE IE Method 3 ( Figure IE): Compound 1 is synthesized as illustrated in FIGURE IE in a manner analogous to that described in Davis, S.A, et al. Nat. Chem. Biol. 2015, 1 1 , 481-487, With respect to the structures illustrated in FIGURE IE, R and R" represent any suitable protecting group such as those described in Kocienski, PJ. Protecting Groups (3 rd Ed., Theme, 2004), and/or Wuts, P. G. M. and Greene, T.W., Greene's Protective Groups in Organic Synthesis, (4 th Ed., Wiley, 2006).
  • R' is depicted as l- butyloxycarbonyl (Boc) in FIGURE IE; other specific examples of amine protecting groups that can be represented by R' include trifluoroacetyl, fluorenylmethyloxycarbonyl (Fmoc) and carboxybenzyl (Cbz).
  • the R" in FIGURE IE is depicted as ethyl; other specific examples of alcohol protecting groups that can be represented by R" include other optionally substituted C-.-io alkyl groups such as methyl, n-propyl, i -propyl.
  • such alcohol protecting groups are formed in a manner similar to that described in Step 1 of Method 1 using an optionally substituted C 1-10 alkyl alcohol.
  • Method 4 ( Figure I F): Compound 1 is synthesized as illustrated in FIGURE I F in a manner analogous to that described in WO2015190587.
  • R' and R" represent any suitable protecting group such as those described in Kocienski, P.J. Protecting Groups (3 ui Ed., Theme, 2004), and/or Wuts, P. G. M. and Greene, T.W., Greene's Protective Groups in Organic Synthesis, (4 th Ed., Wiley, 2006).
  • R is depicted as allyioxycarbonyl (Alloc) in FIGURE.
  • amine protecting groups that can be represented by R' include trifluoroacetyl, fiuorenylmethyloxycarbonyl (Fmoc) and carboxybenzyl (Cbz).
  • the R" in FIGURE IF is depicted as methyl: other specific examples of alcohol protecting groups that can be represented by R" include other optionally substituted d.jo alkyl groups such as ethyl, n-propyl, i-propyl. In an embodiment, such alcohol protecting groups are formed in a manner similar to that described in Step 1 of Method 1 using an optionally substituted C M O alkyl alcohol.
  • Step 2 To a solution of compound 2-1 (4,0 g, 3.97 mmol) in a mixture of THF:MeOH (1 : 1 160 raL) was added camphor sulfonic acid (553.3 mg, 2.38 mmol) at 0 °C. The reaction mixture was stirred for 45 min and then quenched with triethylamine (0.335 ml, 2,38 mmol) at 0 °C. The reaction was filtered and the filtrate was concentrated to roughly half the starting volume and resulting solution was poured into cold diethyl ether to afford a yellow precipitate. The solid was filtered to afford compound 2-2 as a yellow solid. LC/MS (ESI): m/z 1020.7 [M-H] " .
  • Step 3 To a solution of compound 2-2 (20.0 g, 19.56 mmol) in DMF (220 ml) was added DIPEA (6.9 ml, 39.1 mmol ) at room temperature. The reaction mixture was cooled to 0 °C and all loxycarbonyl chloride (2.36 g, 19.56 mmol) was added slowly drop- wise at 0 °C. The reaction mixture was maintained at an internal temperature below 4 °C and stirred for 3 h at 0 °C. The reaction mixture was then allowed to warm to room temperature and stirring was continued for 16 h.
  • Step 4 To a solution of compound 2-3 (1.0 g, 0.90 mmol) in DMF (10 ml), was added DIPEA (0.95 ml, 1.37 mmol) followed by DPP A (0.29 ml, 1.37 mmol) at 0 °C. The reaction mixture was stirred at 50 °C for 2 h and then cooled to room temperature. Bicyclo[l. l.
  • Step 5 To a stirred solution of compound 2-4 (600 mg, 0.505 mmol) in DMF (5.0 ml) was added morpholine (0.87 ml, 10.12 mmol) followed by Pd(PPh 3 ) 4 (1 16.9 mg, 0.1 mmol) at room temperature. After 2 h, the reaction mixture was diluted with Et 2 0, to give a yellow solid. The crude product was filtered and dried under reduced pressure to afford compound 2-5 as a brown solid. LC/MS (ESI): m/z 1062.6 [M+HC0 2 H-H] " .
  • Step 6 To a stirred solution of compound 2-5 (450 mg, 0.44 mmol) in ACN:3 ⁇ 40 (1 : 1, 10 ml) was added camphor sulphonic acid (20.53 mg, 0.09 mmol) at 0 °C. The reaction mixture was warmed to rt and stirred for 1 h and then was directly lyophilized to provide crude compound 2. The crude product was purified by HPLC (CI 8, 5 ⁇ , 40:60 to 10:90 lOmM NH 4 CO 3 H (aq): (CH3CN:MeOH(l : l))) to afford compound 2 as a yellow solid. LC/MS (ESI): m/z 1026,4 [M+Na] + .
  • Compound 3 (FIGURE 3) is prepared using Method 1 described in Example 1 using (3-aminobicyclo[l . l. l ]pentan-l-yl)methanol in place of ethylamine.
  • Compound 4 (FIGURE 4) is prepared using Method 1 described in Example 1 using bicyclo[l . l. l ]pentane-l,3-diamine in place of ethylamine.
  • Compound 5 (FIGURE 5) was prepared using Method 2 described in Example 1 as follows: Step 1 : A suspension of Amphotericin B (15.0g, 16.23 mmol)) in 2: 1 DMF:MeOH(707 nil) was treated with pyridine (8.0 inL, 93.33 mmol.) and Fmoc-Succ (8.2 g, 24.35 mmol) at room temperature. After 3 h the reaction mixture was poured into Et?Q at 0 °C and stirred for 30 min to precipitate out the product. The crude product was collected and washed with additional and dried in vacuo. The crude product was dissolved in THF:MeOH (1 : 1, 360 mL) at O °C.
  • Step 2 A solution of compound 5-1 (2.0 g, 1.72 mmol) in THF (80 mL) was treated with triethylamine (0.24 mL, 1.72 mmol) followed by diphenyl phosphoryl azide (1.2 mL, 5.17 mmol) and heated to 50 °C. After 16 h the reaction was treated ethanoianime (0.83 mL, 13.79 mmol). After an additional 8 h at 50 °C, the reaction was poured into Et 2 0 (2.0 L) and the resulting yellow solid was isolated through filtration. The crude product was purified by HPLC to afford compound 5 (200 mg, 12%) as a light yellow colored solid. LC/MS (ESI) m/z 982.5 ! M - H )
  • Compound 6 (FIGURE 6) is prepared using Method 1 described in Example 1 using tert-butyl ((3-aminobicyclo[l . l. l]pentan-l-yl)methyl)carbamate in place of ethylamine.
  • Compound 7 (FIGURE, 7) is prepared using Method 1 described in Example 1 using cis-l ,3-diaminocyclopentane in place of ethylamine.
  • Compound 8 (FIGURE 8) is prepared using Method 1 described in Example 1 using trans- 1 ,3-diaminocyclopentane in place of ethylamine.
  • Compound 10 (FIGURE 10) is prepared using Method 1 described in Example 1 using 4-(aminomethyl)-lH-imidazol-2-amine in place of ethylamine.
  • Compound 12 (FIGURE 12) is prepared using Method 1 described in Example 1 using 3-aminotetrahydrofuran in place of ethylamine.
  • Compound 13 (FIGURE 13) was prepared in a manner similar to Compound 5 (Example 5) using 4-aminotetrahydropyran in place of ethanolamine. Compound 13 analysis; LC/MS m/z 1022.7 [M+H] +
  • Compound 14 (FIGURE 14) is prepared using Method 1 described in Example 1 using 1 -Boc-4-aminopipef dine in place of ethylamine.
  • Compound 15 (FIGURE 15) is prepared using Method 1 described in Example 1 using l-BOC-3-aminopyrrolidine in place of ethylamine.
  • Compound 17 (FIGURE 17) was prepared in a manner similar to Compound 5 (Example 5) using morpholine in place of ethanolamine.
  • Compound IS (FIGURE 18A) is prepared as follows (see FIGURE 18B):
  • Step 1 A solution of Amphotericin B in DMF and N-(9- fluorenylmethoxycarbonyl)-3-aminopropanal (3 eq.) is treated with NaBEUCN (3 eq.) followed by a drop of concentrated HC1 and stirred until completion at which point amberlite IRA-743 resin is added and stirred for 1 hour. The resin is filtered, and the reaction mixture is concentrated under vacuum and then diluted with Et 2 0. The resulting crude product is filtered off and purified by column chromatography to provide Int-7.
  • Step 2 A solution of Int-7 and imidazole (25 eq.) in DCM at 0 °C is treated with a solution of chlorotriethylsilane in THF (1 M, 20 eq.) After 1 .5 h the reaction is quenched with saturated aqueous sodium bicarbonate solution, and diluted with Et 2 0. The organic layer is washed with saturated aqueous sodium bicarbonate solution and brine. The organic layer is then dried over sodium sulfate, filtered and concentrated under vacuum to provide the crude product. Purification by column chromatography provides Int-8.
  • Step 3 A solution of Int-8 in THF is treated with triethylamine (1.1 eq.) followed by diphenyl phosphoryl azide (3 eq.). The reaction is heated to 50 °C overnight and then treated with ethylamine. After the reaction is complete, the mixture is cooled to room temperature, concentrated under vacuum and purified by column chromatography to provide Int-9.
  • Step 4 A solution of Iot-9 in THF:H 2 0 (9: 1 ) is treated with CSA (5 eq.) and stirred until completion, at which point the reaction is quenched with Et-jN, and concentrated under vacuum to provide the crude product. The crude product is purified by HPLC to provide Compound 18.
  • Compound 19 (FIGURE 19) is prepared using the procedure described in Example 18 using bicyclo[l. l. l]pentan-l-amine hydrochloride in place of ethylamine.
  • Compound 20 (FIGURE 20 A) is prepared as follows (see FIGURE 20B): A solution of Compound 1 in DMSO is treated with solid NaHCO ? followed by Mel The reaction is heated to 40 °C until complete and purified by RP-HPLC to provide Compound
  • Compound 21 (FIGURE 21) is prepared using the procedure described in Example 20 using Compound 2 in place of Compound 1.
  • Compound 22 (FIGURE 22A) is prepared as follows (see FIGURE 22B); A solution of Compound 1 in DMSO is treated with solid NaHC0 3 followed by Mel (1 eq.). The reaction is stirred at room temperature until complete and purified by RP-HPLC to provide Compound 22.
  • Compound 23 (FIGURE 23) is prepared using the procedure described in Example 22 using Compound 2 in place of Compound 1.
  • Compound 24 (FIGURE 24A) can be prepared using Method 1, Method 2 and/or Method 3 : [0263] Method 1 (FIGURE 24B): Step 1 : A solution of Int-2 in THE is treated with triethylamine (1.1 eq.) followed by diphenyl phosphoryl azide (3 eq.). The reaction is heated to 50 °C overnight and then treated with H 2 0 (3 eq.) and heated to 70 °C. After the reaction is complete, the reaction mixture is cooled to room temperature, concentrated under vacuum and purified by column chromatography to provide let- 10.
  • Step 2 A solution of Lit- 10 in CH 2 C1 2 is treated with triethylamine followed by ethyl iodide (1 eq.). After the reaction is complete, the reaction mixture is concentrated under vacuum and purified by column chromatography to provide Lit- 11.
  • Step 3 A solution of Int-8 in THF:H 2 0 (9: 1) is treated with CSA (5 eq.) and stirred until completion, at which point the reaction is quenched with EtiN, and concentrated under vacuum to provide the crude product. The crude product is purified by RP-HPLC to provide Int-12.
  • Step 4 A solution of Int-12 in DMSO is treated with piperidine (2 eq.) Upon completion, the reaction is purified by HPLC to provide Compound 24.
  • Step 1 To a solution of compound 2-3 (5.0 g, 0.90 mmol) in DMA (92 ml), was added 3A molecular sieves (500 mg), DIPEA (1.20 ml, 6.89 mmol) followed by DPPA (1.28 ml, 5.97 mmol) at room temperature. The reaction mixture for 2 h and then heated to 50 °C. After 2 h the reaction mixture was cooled to room temperature poured into a solution of Et 2 0:hexanes (7: 1, 1 .60 L). The reaction mixture was filtered over Celite® 545 and the collected solid was washed with Et 2 0:hexanes (7: 1 , 200 mL).
  • the crude isocyanate was then dissolved in THF (200 ml.) and then concentrated to approximately 60 mL.
  • the crude isocyanate solution was then added dropwise to a rapidly stirring solution of triethylamine (32.0 mL, 230.0 mmol) in THF:H 2 0 (1 : 1, 120mL) over 20 min.
  • the reaction was stirred for an additional 30 minutes at rt at which point the reaction was concentrated in vacuo using C3 ⁇ 4CN to aid in the removal of water from the reaction mixture.
  • the crude product was purified by HPLC to afford compound 24-1 as a yellow solid.
  • LC/MS (ESI) m/z 1099.3 [M+Na] + .
  • Step 2 A solution of acetaldehyde (1.2 eq) and 24-1 in DMF:MeOH (1 : 1) is stirred at room temperature for 3 hours and then treated with NaB3 ⁇ 4CN (3 eq.). The reaction mixture is stirred overnight and then poured into Et 2 0 and filtered over Celite® 545. The collected solid is then dissolved in THF MeOH and concentrated in vacuo to provide crude compound 24-2.
  • Step 3 A solution of compound 24-2 in 2:2: 1 CH 3 CN:THF:H 2 0 is cooled to 0 °C and treated with CSA (1 eq.). The reaction is warmed to 35 °C and stirred for 50 min at which time triethylamme (2.1 eq.) is added. The reaction is concentrated in vacuo and the crude product is purified by HPLC to provide Compound 24-3.
  • Step 4 To a solution of compound 24-3 in DMF is treated with Pd(PPh 3 ) 4 (0.1 eq.) followed by morpholine (25 eq.). The reaction is stirred for 16 h and then poured into Et 2 0 and filtered over Ceiite® 545. The collected solid is washed with Et 2 0, dissolved in THF/MeOH, and concentrated in vacuo to provide crude compound 24. The crude product is purified by HPLC to afford Compound 24.
  • Step 1 A solution of compound 24-1 in DMF is treated with triethylamme followed by ethyl iodide (1 eq.). After the reaction is complete, the reaction mixture is concentrated under vacuum and purified by column chromatography to provide Compound 24-2.
  • Step 2 A solution of compound 24-2 in 2:2: 1 O i -.C V ⁇ IF: ! ! O is cooled to 0 °C and treated with CSA (1 eq.). The reaction is warmed to 35 °C and stirred for 50 min at which time triethylamine (2.1 eq.) is added. The reaction is concentrated in vacuo and the crude product is purified by HPLC to provide Compound 24-3.
  • Step 3 To a solution of compound 24-3 in DMF is treated with ⁇ ( ⁇ 3 ) 4 (0.1 eq.) followed by morpholine (25 eq.). The reaction is stirred for 16 h and then poured into Et 2 0 and filtered over Ceiite® 545. The collected solid is washed with Et 2 0, dissolved in THF/MeOH, and concentrated in vacuo to provide crude compound 24. The crude product is purified by HPLC to afford Compound 24.
  • Compound 25 (FIGURE 25) is prepared using the procedures described in Example 24 using bromoethanol in place of ethyl iodide.
  • Step 1 A solution of Iiit-10 and dihydrofuran-3(2H)-one in CH 2 C1 2 is treated with sodium acetate followed by a NaBH(OAc) 3 and stirred until completion and the reaction is quenched with sat. aqueous NaHC0 3 . The aqueous phase is extracted with CH 2 C1 2 and the combined organic phases are dried over Na 2 S0 4 , filtered and concentrated under vacuum to provide crude product. The crude product is subjected to column chromatography to provide Int-13.
  • Step 2 A solution of Int-13 in THF:H 2 0 (9: 1) is treated with CSA (5 eq.) and stirred until completion, at which point the reaction is quenched with Et 3 N, and concentrated under vacuum to provide the crude product. The crude product is purified by RP-HPLC to provide Int-14.
  • Step 3 A solution of Int-14 in DMSO is treated with pipendine (2 eq.) Upon completion, the reaction is purified by RP-HPLC to provide Compound 26.
  • Compound 27 (FIGURE 27 A) can be prepared using Method 1 and/or Method 2:
  • Step 2 A solution of Int-15 in THF:H 2 0 (9: 1) is treated with CSA (5 eq.) and stirred until completion, at which point the reaction is quenched with Et 3 N, and concentrated under vacuum to provide the crude product.
  • the crude product is purified by RP-HPLC to provide Int-16.
  • Step 3 A solution of Int-16 in DMSO is treated with pipendine (2 eq.) Upon completion, the reaction is purified by HPLC to provide Compound 27.
  • Step 2 To a solution of compound 27-1 (35 mg, 31 ⁇ ) in 2:2: 1 CH 3 CN:THF:H 2 0 (1.56 mL) at 0 °C was added CSA (7.7 mg, 31 ⁇ ). The reaction was warmed to 35 °C and stirred for 50 min at which time triethylamine (8.8 LIL, 63 ⁇ ) was added. The reaction was concentrated in vacuo and the crude product was purified by RP- HPLC to provide Compound 27-2 as a yellow solid. LC MS (ESI) m/z 1127.5 i .M ⁇ Na
  • Step 3 To a solution of compound 27-2 (7.0 mg, 6.6 ⁇ ) in DMF (2 mL) was added Pd(PPh 3 ) 4 (2.7 mg, 2.3 ⁇ ) followed by morpholine (17.3 ⁇ , 0.19 mmol). The reaction was stirred for 16 h and then poured into Et 2 0 (10 mL) and filtered over Celite® 545. The collected solid was washed with hbO. dissolved in THF/MeOH, and concentrated in vacuo to provide crude Compound 27. The crude product was purified by HPLC to afford Compound 27 as a yellow solid. LC/MS (ESI) m/z 959.5 [M+Naf.
  • Compound 28 (FIGURE 28) is prepared using the procedure described in Example 27 using 2-Oxetanone in place of acetyl chloride.
  • Compound 29 (FIGURE 29) is prepared using the procedure described in Example 27 using 9H-Fluoren-9-ylmethyl (3-chloro-3-oxopropyl)carbamate in place of acetyl chloride.
  • Compound 30 (FIGURE 30) was prepared using Method 2 described in Example 27 using bicyclo[ 1.1.1 jpentane- 1 -carboxyiic acid in place of acetic acid.
  • Step 1 A solution of Int-10 in CH 2 C1 2 is treated with triethylamine followed by ethyl isothiocyanate (1.2 eq.). After the reaction is complete, the reaction mixture is concentrated under vacuum and purified by column chromatography to provide Int-17.
  • Step 2 A solution of Int-17 in THF:H 2 0 (9: 1) is treated with CSA (5 eq.) and stirred until completion, at which point the reaction is quenched with Et-jN, and concentrated under vacuum to provide the crude product. The crude product is purified by RP-HPLC to provide Int-18.
  • Step 3 A solution of Int-18 in DMSO is treated with piperidine (2 eq.) Upon completion, the reaction is purified by HPLC to provide Compound 31.
  • Compound 32 (FIGURE 32) is prepared using the procedure described in Example 31 using 2-isothiocyanatoethan-l-ol in place of ethyl isothiocyanate.
  • Compound 33 (FIGURE 33) is prepared using the procedure described in Example 31 using Fmoc-NH(CH 2 ) 2 -NCS in place of ethyl isothiocyanate.
  • Compound 34 (FIGURE 34) is prepared using the procedure described in Example 31 using isothiocyanatocyciobutane in place of ethyl isothiocyanate.
  • Compound 35 (FIGURE. 35A) is prepared as follows (see FIGURE 35B):
  • Step 1 A solution of Int-10 in CH 2 C1 2 is treated with triethylamine followed by methane sulfonyl chloride (1.2 eq. ). After the reaction is complete, the reaction mixture is concentrated under vacuum and purified by column chromatography to provide int-19.
  • Step 2 A solution of Int-19 in THF:H 2 0 (9: 1) is treated with CSA (5 eq.) and stirred until completion, at which point the reaction is quenched with Et-jN, and concentrated under vacuum to provide the crude product.
  • the crude product is purified by RP-HPLC to provide lnt-20.
  • Step 3 A solution of Isit ⁇ 20 in DMSO is treated with piperidine (2 eq.) Upon completion, the reaction is purified by HPLC to provide Compound 35.
  • Compound 36 (FIGURE 36) is prepared using the procedure described in Example 35 using benzenesulfonyl chloride in place of methanesulfonyl chloride.
  • Compound 37 (FIGURE 37) was prepared in a method similar to Compound 2 (Example 2) using bicycio[ 1. 1.1 ]pentan- 1 -ylmethanamine in place of ethylamme.
  • LC/MS (ESI) m/z 0 8.59 [M+Hf.
  • the broth microdilution assay method essentially followed the procedure described by CLSI (1 -3) and employed automated liquid handlers to conduct serial dilutions and liquid transfers.
  • Automated liquid handlers included the Multidrop 384 (Labsystems, Helsinki, Finland) and Biomek 2000 (Beekman Coulter, Fullerton CA).
  • the wells in columns 2-12 in standard 96-well microdilution plates (Costar 3795) were filled with 150 ⁇ of the correct diluent. These would become the 'mother plates' from which 'daughter' or test plates would be prepared.
  • the drugs 300 ⁇ , ⁇ at 4Qx the desired top concentration in the test plates
  • the Biomek 2000 was used to make serial two-fold dilutions through Column 11 in the "mother plate”.
  • the wells of Column 12 contained no drug and were the organism growth control wells.
  • the daughter plates were loaded with 185 i per well of the appropriate test media using the Multidrop 384.
  • the daughter plates were prepared using the Biomek FX which transferred 5 ⁇ iL of drug solution from each well of a mother plate to the corresponding well of the correct daughter plate in a single step.
  • a standardized inoculum of each organism was prepared per CLSI methods (1-3). For yeast isolates, colonies were picked from the primaiy plate and a suspension was prepared to equal a 0.5 McFarland turbidity standard. Suspensions were then diluted 1 : 100 in RPML 1640 medium, resulting in a final inoculum concentration of 0.5-2.5 x 103 CFU/mL per test well. For the fungal isolates, spore suspensions previously prepared in 0.85% saline and enumerated were diluted to achieve a final inoculum concentration of 0.2 - 2.5 x 104 CFU/mL per test well.
  • Standardized inoculum suspensions were transferred to compartments of sterile reservoirs divided by length (Beckman Coulter), and the Biomek 2000 was used to inoculate all plates.
  • Daughter plates were placed on the Biomek 2000 in reverse orientation so that plates were inoculated from low to high drug concentration.
  • the Biomek 2000 delivered 10 uL of standardized inoculum into each well of the appropriate daughter plate for an additional 1 :20 dilution.
  • the wells of the daughter plates ultimately contained 185 ⁇ , of the appropriate media, 5 ⁇ of drug solution, and 10 of inoculum.
  • the final concentration of DMSO (if used as a solvent) in the test well was 2.5%.
  • Plates were stacked 3 high, covered with a lid on the top plate, placed into plastic bags, and incubated at 35°C for approximately 24-48 hr for all yeast isolates excluding C. neofor ans (72 hr), and 48 hr for all fungal isolates excluding R. oryzae (24 hr) and T. rubrum (120 hr). Plates were viewed from the bottom using a plate viewer. An un-inoculated solubilit' control plate was observed for evidence of drug precipitation. MICs were read where visible growth of the organism was inhibited. MECs were read where evident for Aspergillus spp. where the growth shifted to a small, rounded, compact hyphal form as compared to the hyphal growth seen in the growth control well.
  • Red blood cell (RBC) preparation Packed defibrinated human red blood cells (Lampire Biological Laboratories, Pipersville, PA; Cat. No. 7243710; Unit No. LS 23- 80223D) were washed three times with buffer (10 mM Tris-HCl [pH 7.4], 0.9% NaCi) and resuspended to a final concentration of 3% RBCs prior to conducting the assays.
  • DMSO Pilot assay Testing the compounds at high concentrations (up to 100 ⁇ ) required a final DMSO concentration of 4% in the RBC lysis assay. A pilot study was conducted to measure hemolysis in the presence of different DMSO concentrations as follows:
  • Amphotericin B produced 83% hemolysis at 15 ⁇ and a maximum of 94% hemolysis at the highest concentration of 100 ⁇ .
  • Compound 5 produced a maximum of 84% hemolysis at 100 ⁇
  • Compound 11 produced a maximum of 4% hemolysis at 100 ⁇
  • Compound 17 produced a maximum of 34% hemolysis at 100 ⁇ .

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Abstract

L'invention concerne des composés représentés par les formules (I) et (II) telles que décrites dans la description, ou des sels pharmaceutiquement acceptables de ceux-ci, ainsi que des compositions pharmaceutiques comprenant de tels composés ou sels ou des associations de ceux-ci et des procédés pour la fabrication de ceux-ci. De tels composés, sels et compositions sont utiles pour l'inhibition de la croissance fongique. Par exemple, dans un mode de réalisation, des infections fongiques peuvent être traitées par l'administration de quantités efficaces de tels composés, sels et/ou compositions à un sujet qui en a besoin.
PCT/US2016/065097 2015-12-08 2016-12-06 Composés antifongiques et procédés s'y rapportant WO2017100171A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018106571A1 (fr) * 2016-12-06 2018-06-14 Kalyra Pharmaceuticals, Inc. Composés antifongiques et procédés
WO2019008506A1 (fr) * 2017-07-03 2019-01-10 Glaxosmithkline Intellectual Property Development Limited Dérivés de n-(3-(2-(4-chlorophénoxy)acétamido)bicyclo[1.1.1]pentan-1-yl)-2-cyclobutane-1-carboxamide et composés apparentés en tant qu'inhibiteurs atf4 pour le traitement du cancer et d'autres maladies
CN113056274A (zh) * 2018-09-07 2021-06-29 伊利诺伊大学评议会 具有降低的毒性的杂化两性霉素b衍生物
CN114315932A (zh) * 2021-12-29 2022-04-12 浙江天台药业股份有限公司 一种两性霉素b的杂质a或杂质b的分离纯化方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015054148A1 (fr) * 2013-10-07 2015-04-16 The Board Of Trustees Of The University Of Illinois Dérivés d'amphotéricine b ayant un indice thérapeutique amélioré
CA2951516A1 (fr) * 2014-06-12 2015-12-17 Shionogi & Co., Ltd. Derive de macrolide de polyene
WO2016112243A1 (fr) * 2015-01-08 2016-07-14 The Board Of Trustees Of The University Of Illinois Dérivés d'urée de l'amphotéricine b dérivée d'amines secondaires
WO2016168568A1 (fr) * 2015-04-15 2016-10-20 Revolution Medicines, Inc. Dérivés d'amphotéricine b

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015054148A1 (fr) * 2013-10-07 2015-04-16 The Board Of Trustees Of The University Of Illinois Dérivés d'amphotéricine b ayant un indice thérapeutique amélioré
CA2951516A1 (fr) * 2014-06-12 2015-12-17 Shionogi & Co., Ltd. Derive de macrolide de polyene
WO2016112243A1 (fr) * 2015-01-08 2016-07-14 The Board Of Trustees Of The University Of Illinois Dérivés d'urée de l'amphotéricine b dérivée d'amines secondaires
WO2016168568A1 (fr) * 2015-04-15 2016-10-20 Revolution Medicines, Inc. Dérivés d'amphotéricine b

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CARMODY, M. ET AL.: "Biosynthesis of Amphotericin Derivatives Lacking Exocyclic Carboxyl Groups", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 280, no. 41, 2005, pages 34420 - 34426, XP055390733 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018106571A1 (fr) * 2016-12-06 2018-06-14 Kalyra Pharmaceuticals, Inc. Composés antifongiques et procédés
WO2019008506A1 (fr) * 2017-07-03 2019-01-10 Glaxosmithkline Intellectual Property Development Limited Dérivés de n-(3-(2-(4-chlorophénoxy)acétamido)bicyclo[1.1.1]pentan-1-yl)-2-cyclobutane-1-carboxamide et composés apparentés en tant qu'inhibiteurs atf4 pour le traitement du cancer et d'autres maladies
CN111164069A (zh) * 2017-07-03 2020-05-15 葛兰素史密斯克莱知识产权发展有限公司 作为atf4抑制剂用于治疗癌症和其它疾病的n-(3-(2-(4-氯苯氧基)乙酰胺基)双环[1.1.1]戊-1-基)-2-环丁烷-1-甲酰胺衍生物以及相关化合物
CN113056274A (zh) * 2018-09-07 2021-06-29 伊利诺伊大学评议会 具有降低的毒性的杂化两性霉素b衍生物
EP3846823A4 (fr) * 2018-09-07 2022-04-20 The Board of Trustees of the University of Illinois Dérivés de l'amphotéricine b hybrides à toxicité réduite
JP7477177B2 (ja) 2018-09-07 2024-05-01 ザ ボード オブ トラスティーズ オブ ザ ユニヴァーシティ オブ イリノイ 毒性が低減されたハイブリッドアムホテリシンｂ誘導体
CN114315932A (zh) * 2021-12-29 2022-04-12 浙江天台药业股份有限公司 一种两性霉素b的杂质a或杂质b的分离纯化方法

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